Pharmacology Flashcards

Question

For what target site are the terms 'agonist' and 'antagonist' used

Answer 1

Acetylcholine - non-selective agonist of ACh receptors Atrophine - muscarinic cholinoceptor antagonist used as anaesthetic premediacation to dry up secretions

Answer 2

Local Anaesthetic - work by blocking voltage-gated NA+ channels in sensory axons so less action potential are propagated along the axons so perception of pain is reduced - usually ends in -caine (lidocaine) Calcium Channel Blockers - block voltage-sensitive Ca2+ channels - commonly used in cardiology for treatment of arrhythmias - usually end in -dipine (amlodipine)

Answer 3

Tricyclic antidepressants (TCAs) - prolongs the effect or noradrenaline which is below normal levels during clinical depression Cardiac Glycosides - these are cardiac stimulant drugs (e.g. digoxin) that interact with the Na+/K+ pump - if you give digoxin to a patient with heart failure, it will slow down their Na+/K+ pump and that has a knock on effect that increases the intracellular calcium concentration, therefore increasing the force of contraction

Answer 4

Enzymes Inhibitors - e.g. anticholinesterases - neostigmine - increases the concentration of acetylcholine in the synapse by decreasing the rate of breakdown of acetylcholine - used to treat Myasthenia Gravis False Substrates - e.g. methyldopa (antihypertensive) - works by subverting the normal pathway that produces NA by taking the place of DOPA leading to the production of methyl noradrenaline is worse at causing vasoconstriction than NA so you get reduced TPR and hence reduced blood pressure this is a FALSE TRANSMITTER Prodrugs - e.g. chloral hydrate - must go to the liver to be metabolised into trichloroethanol before it is effective - used to treat insomnia

Answer 5

Paracetamol - if someone overdoses they saturate the liver's microsomal enzymes so another set of enzymes (P450) starts breaking down the paracetamol and produces metabolites that cause damage to the liver and kidneys. Symptoms may not appear until 24-48 hours after the overdose, however at this point damage is irreversible

Answer 6

Non-specific drugs produce responses due to their physicochemical properties - General Anaesthetics - dampen synaptic transmission - Antacids - reduces the acidity of the stomach contents - Osmotic Purgatives - stimulate the voiding of gut contents

Answer 7

A molecule that binds to a receptor and stimulates it to generate a response (e.g. nicotine)

Answer 8

Substances that interact and bind to receptors but do not produce a response - they just get in the way of the agonist (e.g. atropine)

Answer 9

How powerful the drug is, is dependent of affinity and efficacy

Answer 10

How willingly a drug binds to its receptor

Answer 11

The ability of a drug to generate a response once it has bound to it receptor

Answer 12

An agonist that generates the maximal response

Answer 13

An agonist that generates a less than maximal response

Answer 14

To have a preference for interacting with a particular receptor type (receptors are rarely specific - normally interact with a few other receptors)

Answer 15

c. full agonists that are selective for a given receptor will have the same efficacy

Answer 16

d. transport protein

Answer 17

1. Receptor Blockade 2. Physiological Antagonism 3. Chemical Antagonism 4. Pharmacokinetic Antagonism

Answer 18

By simply binding to the receptor and therefore blocking the agonist from binding

Answer 19

Ion channel blockers - it means the more the tissue on which the drug is acting is being used (the more active they are) the more effective this type of blocker will be

Answer 20

- normal neurones fire at a relatively low rate so if you put local anaesthetic on them, there'll be relatively low blockage. - nociceptor neurones fire rapidly and because the action potentials are being generated rapidly so the ion channels are open more often - local anaesthetics work by binding to the inside of the ion channels after they open - if the channels are opening more often then there is more chance that they'll be blocked by LAs - this gives local anaesthetics a selective action on nociceptor neurones

Answer 21

Two drugs acting at different receptors causing opposite effects in the same tissue

Answer 22

- NA causes vasoconstriction of vasculature by binding to adrenoceptors - co-administering histamine acts on different receptor to cause vasodilation

Answer 23

Interactions between drugs in solution

Answer 24

- dimercaprol is a chelating agent which forms heavy metal complexes -\> more rapidly excreted by the kidneys so, is useful for things like lead poisoning. Is very uncommonly used in practice

Answer 25

- when one drug reduces the concentration of the other drug at the site of its action (absorption, excretion etc)

Answer 26

- repeatedly administer barbiturates increases the production of microsomal enzymes so, if we administer another drug (e.g. warfarin) that is metabolised by the enzymes then it is going to be metabolised quicker and its effect will be reduced

Answer 27

1. Pharmacokinetic Factors 2. Loss of Receptors 3. Change in Receptors 4. Exhaustion of Mediator Stores 5. Physiological Adaptation

Answer 28

Metabolism of the drug increases when repeatable given - barbiturates and alcohol

Answer 29

Cells repeatable stimulated by an agonist will endocytose some receptors leaving fewer on the cell surface - this is called down regulation - beta adrenoceptors

Answer 30

Denervation supersensitivity

Answer 31

A conformational change in the receptor occurs so that the drug can no longer bind

Answer 32

Amphetamines - amphetamine is a CNS stimulant that causes the blood-brain barrier from the blood and acts on noradrenergic neurones in the brain where it binds to uptake 1 protein and is taken into the central NA synthesis system causing a big increase in NA production - if you take a second dose the response is far less severe because NA stores have been exhausted

Answer 33

- sort of like a homeostatic response -\> the body is attempting the maintain a stable environment

Answer 34

- tiredness and nausea

Answer 35

- are ion channels so are VERY, VERY FAST - 4 or 5 subunits including a transmembrane alpha helices section e.g. nicotinic acetylcholine receptor and GABA

Answer 36

- must link to G protein so a MUCH SLOWER than Type 1 - 1 subunit and 7 transmembrane domains (alpha helices) e.g. beta-1 adrenoceptors in the heart

Answer 37

- results in the phosphorylation of intracellular proteins so SLOWER than both Type 1 and 2 (usually minutes) - single protein with 1 transmembrane domain and 1 intracellular domain e.g. insulin receptor and growth factor receptors

Answer 38

- activated by steroid and thyroid hormones so is the SLOWEST (can take hours) of all 4 receptors - drug must pass through the cell membrane (these receptors regulate DNA transcription via zinc fingers

Answer 39

c. chemical antagonism

Answer 40

e. increased metabolic degradation

Answer 41

1. administration 2. Absorption 3. Distribution 4. Metabolism 5. Excretion 6. voided REMEMBER: ADME

Answer 42

1. intravenous 2. intraperitoneal 3. intramuscular 4. dermal 5. subcutaneous 6. inhalation 7. ingestion

Answer 43

- systemic (entire organism exposed to the drug) - local (restricted to one area)

Answer 44

- enteral = via the GI tract (usually orally) - parenteral = avoids the GI tract (IV)

Answer 45

- bulk flow transfer -\> in the bloodstream in bulk to tissue - diffusion transfer -\> molecule by molecule over short distances

Answer 46

- IV = bulk flow - oral = diffusion

Answer 47

- lipid soluble (non-polar solvents) - diffusing through aqueous pores in the lipid (if they are polar) - carrier molecules - pinocytosis

Answer 48

5-9 (weak acids and bases)

Answer 49

- drugs exist in ionised and non-ionised form, forming a dynamic equilibrium of which the ratio depends on the pH of the environment and the pKa of the molecules - this alters the lipid solubility of the drug

Answer 50

- aspirin a weak acid with a pKa of around 3.4 - when aspirin enters the stomach, which has a pH of less than the pKa of aspirin, it is more readily non-ionised -\> aspirin exists mainly in the non-ionised form in the stomach meaning that it can readily diffuse across the lipid bilayer (as it is non-polar) - eventually the aspirin will make it into the small intestine, as the pH of the small intestine is greater than the pKa of aspirin, the aspirin becomes ionised -\> now its more difficult to get through the membrane

Answer 51

- for quick, short relief (e.g. headaches) give it as a soluble - for slow, long relief (e.g. arthritis) coat it in something that isn't digested in the stomach

Answer 52

- once a drug goes through the liver and into the systemic circulation, the aspirin is in an aqueous environment so you find a proportion of aspirin in an ionised form - it is effectively TRAPPED

Answer 53

- regional blood flow - extracellular binding (plasma protein binding) - capillary permeability - localisation in tissues

Answer 54

- tissues which are well perfused are likely exposed to a higher drug conc. - blood flow can change with activity such as skeletal muscle tissue

Answer 55

- continuous -\> normal vessels, not particularly permeable - fenestrated -\> more permeable - discontinuous

Answer 56

- fat isn't usually highly perfused - a very lipophilic environment -\> drugs which are lipophilic tend to localise in fatty tissue (brain, testes etc)

Answer 57

- liver - kidneys

Answer 58

- exhalation/lungs - sweating/skin - GI secretions - saliva - milk - genital secretions

Answer 59

- do most of xenobiotic excretion - the majority of the drug that is excreted will get into the urine via active secretion rather than ultrafiltration -\> you can't filter large, protein-bound drug complexes - glomerulus - drug-protein complexes are NOT filtered - proximal Tubule - active secretion of acids and bases - proximal and Distal Tubules - lipid soluble drugs are reabsorbed

Answer 60

- biliary excretion allows the concentration of large molecular weight molecules (most antibiotics) that are very lipophilic - active transport systems also secrete drugs into bile - active transport systems are geared for the transport of bile acids and glucuronides into the bile - drugs hitch a ride on this because they are non-polar and have a large molecular weight

Answer 61

- a drug or metabolite gets excreted into the gut but then it can get reabsorbed and returned to the liver via the enterohepatic circulation -\> leading to drug persistence

Answer 62

- IV sodium bicarbonate increases urine pH which ionises the aspirin making it less lipid soluble - less aspirin is reabsorbed in the proximal and distal tubules so there is an increase in the rate of excretion of aspirin

Answer 63

- the proportion of the administered drug that is available within the body to exert its pharmacological effect

Answer 64

- the volume in which a drug appears to be distributed - an indicator of the pattern of distribution

Answer 65

- the time taken for the concentration of the drug (in the blood/plasma) to fall to half its original value

Answer 66

- the volume of plasma cleared of a drug per unit time

Answer 67

a. ionised drug

Answer 68

- the rate of elimination of a drug where the amount of drug decreases at a rate that is proportional to the concentration of drug remaining in the body

Answer 69

- the rate of elimination of a drug where the amount is a constant per unit of time

Answer 70

- first-order - alcohol/ethanol is zero-order because alcohol dehydrogenase becomes saturated

Answer 71

- drugs tend to be lipophilic -\> must be metabolised to become more water soluble so hey can be excreted easily - metabolism tends to eliminate or reduce the pharmacological and toxicological activity -\> converts the drug into something more polar and, hence, soluble -\> more easily be excreted by the kidneys

Answer 72

- metabolic conversion of the drug into something that is different before the drug enters the general circulation (the effect that occurs the very first time the drug passes through the liver)

Answer 73

- LIVER = MAJOR - gut - kidneys - brain

Answer 74

- when you administer the drug and it is absorbed and taken to the liver, you want it to be released in to the systemic circulation in a pharmacologically active form - f the metabolism is extensive you may only release a small amount of the active drug into the systemic circulation, this is low bioavailability

Answer 75

- it releases only a small amount of the active form of the drug meaning that if the problem is in the systemic circulation the conc. may not be higher enough to have an effect - this can be overcome by giving it intravenously

Answer 76

- intestines - stomach - oesophagus and buccal cavity

Answer 77

- oxidation -\> create new functional groups - reduction -\> create new functional groups - hydrolysis -\> unmasks functional groups

Answer 78

- Phase I Reactions

Answer 79

- there is very little change in polarity, if it was lipophilic when it started it will still be pretty lipophilic etc

Answer 80

- primarily in the liver

Answer 81

- the cytochrome P450 system in the liver - in humans, the system is made up of 57 enzymes

Answer 82

- endoplamsic reticulum

Answer 83

- some drugs can inhibit or induce the CYP450 system -\> changing the ability of the system to handle certain drugs - the oral contraceptive pill is a common example -\> can loss contraceptive properties with certain other drug combinations

Answer 84

1. the drug binds to the iron in the catalytic site and an electron is donated by NADPH 2. this electron is picked up by the P450 complex and reductes Fe³⁺to Fe²⁺ 3. molecular oxygen binds to the catalytic site so P450 has Fe²⁺ and O₂ bound 4. Fe²⁺ loses an electron to become Fe³⁺ with oxygen picking up the extra electron and becoming unstable 5. a second electron is donated by NADPH reducing Fe³⁺ to become Fe²⁺ 6. Fe²⁺ donates an electron to oxygen (becoming Fe³⁺) and making the oxygen very unstable, however the drug still hasn't changed 7. the drug is converted into its hydroxylated derivative and loses the reactive oxygen as water by picking up two protons 8. drug is released and the P450 returns to the cycle with iron in its oxidised state (Fe³⁺) ready to undergo the next cycle

Answer 85

- at the centre of P450's catalytic site there is catalytic iron in its oxidised state (Fe³⁺) - all P450 enzymes have a porphyrin ring and iron (Fe³⁺) at its active site

Answer 86

- hydroxylation catalysed by CYP450 - 9f ever unsure on an enzyme starting an oxidation guess CYP450

Answer 87

- a narcotic, will put you to sleep

Answer 88

- depends on the drug, can be hundreds

Answer 89

- acetanlide becomes paracetamol by oxidation of C4 in the benzene ring

Answer 90

- anlide is toxic to blood cells

Answer 91

- forms an alcohol group

Answer 92

- you form an alcohol group

Answer 93

- N-demethylation -\> the carbon group that was attached to the nitrogen disassociates leaving a signle hydrogen behind if it was a tertiary amine, the remnants of the carbon group bind with an oxygen to forming a aldehyde, commonly formaldehyde (HCHO)

Answer 94

- O-demethylation -\> an alcohol group forms in place of the carbon group when its a teritary structure and the remnants of the carbon group form an aldehyde or a ketone, formaldehyde (HCHO)

Answer 95

- it is metabolised into morphine by the CYP450 complex causing all the relative effects, specifically as a painkiller - however, some people are a lot better at doing this metabolism compared to others hence to disparity

Answer 96

- N-oxidation -\> requires the formation of a dative bond, flavin containing monoxygenase - alcohol oxidation by alcohol dehydrogenase

Answer 97

- flavin containing monoxygenase defiiciency (aka fish odour syndrome) - humans generate trimethylamine in their GI tract (product of protein metabolsim -\> rimethylamine smells terrible - in the liver, flavin containing monooxygenase converts trimethylamine into trimethylamine N-oxide which is odourless and polar so it can be readily excreted in the urine - a small subset of the population has defective flavin containing monooxygenase so they can't metabolise trimethylamine and must sweat and breathe it out

Answer 98

- strange behavouirs - smoke or wear lots of perfume to mask the smell - despression -\> very high suicide rate

Answer 99

- in the gut as they are bacterial enzymes colonising the gut

Answer 100

- oxidations are far more common, hydrolysis is even less less common than reduction

Answer 101

- when there is an ester or an amide

Answer 102

- esterases = hydrolysis of an ester - amidase = hydrolysis of an amide

Answer 103

- can do but more readily uses NADPH

Answer 104

- glucuronidation (most common) - methylation - sulphation - acetylation - aminoacid conjugation - gluathione

Answer 105

- the name of the reaction and add transferase to the end of it to find the enzyme name

Answer 106

- the conjugate that is formed is almost always inactive (morphine is an exception) - less lipid soluble - more polar - easier to excrete

Answer 107

- xenobiotic is catalysed by glucuronyl transferase to form the glucuronide derivative of the xenobiotic - this derivate is polar so can be removed, usuallt though bile due to large molecular weight

Answer 108

- ibruprofen

Answer 109

- drugs with a amino group - acetylation occurs to an electron rich atom

Answer 110

- produce acetylated derivative of the drug and CoA which then goes into intermediary metabolism - use acetyl CoA as the high energy intermediate

Answer 111

- a methyl group is donated to an atom rich atom (N, S or O etc) via the high energy intermediate S-adenosyl methionine using the enzyme methyl transferase - methylation DECREASES polarity - in ZH, Z can be N, O or S

Answer 112

- for endogenous molecules such as noradrenaline -\> allows NA to convert into adrenaline - only occurs to drugs such as amphetamines which have a similar structure to NA

Answer 113

- sulphation

Answer 114

- xenobiotic is taken with PAPS which is the sulfate donor and gets sulfated to produce the sulfuric acid derivative of the molecule - the derivative is very polar and water soluble the reaction is catalysed by sulfotransferases

Answer 115

- a tripeptide molecule kept in large quantities in the liver and kidneys that protects the bodies from toxic metabolites such as electrophiles

Answer 116

- cysteine because it has the thiol part

Answer 117

- false, reduction is phase I

Answer 118

- true, to aid excretion

Answer 119

- false, glucuronidation is

Answer 120

- biological half-life of a drug is reduced - duration of exposure is reduced - accumulation of the drug in the body is avoided - potency/duration of the biological activity of the chemical can be altered - pharmacology/toxicology of the drug is governed by its metabolism

Answer 121

- drugs that mimic the action of acteylcholine in the body - therefore they are parasympathetic drugs

Answer 122

- eyes - salivary glands - sweat glands - lungs - heart - gut - bladder - vasculature

Answer 123

- contraction of the ciliary muscle - accommodates for near vision - contraction of sphincter pupillae (circular muscle of the iris) - this constricts the pupil (miosis) and increases drainage of intraocular fluid - lacrimation (tears)

Answer 124

- an increase in intraocular pressure -\> can cause damage to the optic nerves and retina and can ultimately lead to blindness

Answer 125

- aqueous humour is generated by the capillaries of the ciliary body, it flows into the anterior chamber of the eye - its role is to supply oxygen and nutrients to the lens and cornea because they don’t have a blood supply - the aqueous humour diffuses forwards across the lens, then across the cornea and it drains through the canals of Schlemm back into the venous system - in angle-closure glaucoma, the angle between the cornea and the iris becomes narrowed =\> reduces the drainage of intraocular fluid via the canals of Schlemm

Answer 126

- muscarinic agonist -\> causes contraction of the iris opening up the angle and increasing the drainage of intraocular fluid through the canals of Schlemm (has no effect on fluid production)

Answer 127

- most blood vessels do NOT have parasympathetic innervation - acetylcholine acts on vascular endothelial cells to stimulate NO release via M3 receptors -\> NO induces vascular smooth muscle relaxation -\> decrease in TPR

Answer 128

- decrease heart rate - decreased cardiac output (due to decreased atrial contraction) - vasodilation (via stimulation of NO release) - all of these can lead to a sharp DROP BLOOD PRESSURE

Answer 129

- non-vascular smooth muscle that has parasympathetic innervation responds in the opposite way to vascular smooth muscle - it contracts · Lungs - bronchoconstriction · Gut - increased peristalsis/motility · Bladder - increased bladder emptying

Answer 130

· Salivation · Increased bronchial secretions · Increased GI secretions (including gastric HCl production) · Increased sweating (SNS-mediated)

Answer 131

· Decreased heart rate · Decreased blood pressure · Increased sweating · Difficulty breathing · Bladder emptying · GI pain · Increased salivation and tears

Answer 132

1. Directly Acting 2. Indirectly Acting

Answer 133

- muscarinic receptor agonists

Answer 134

o Choline esters (bethanechol) o Alkaloids (pilocarpine)

Answer 135

- both very similar to acetylcholine

Answer 136

- non selective -\> stimulates all muscarinic receptors - good lipid solubility - half-life of 3-4 hours

Answer 137

- glaucomao -\> constricts sphincter pupillae and opens up the canals of Schlemm to increase the drainage of intraocular fluid

Answer 138

- general effects of parasympathetic discharge: o Blurred vision o Sweating o GI disturbance and pain o Nausea o Bradycardia o Hypotension o Respiratory distress

Answer 139

- can be given successfully as an eye drop -\> therefore a very low conc. reaches the systemic circulation

Answer 140

· M3 receptor selective agonist, still has an effect on all muscarinic receptors · It is resistant to degradation by acetylcholinesterase · It is orally active and has limited access to the brain · Half-life = 3-4 hours

Answer 141

- mainly used to assist bladder emptying and enhance gastric motility

Answer 142

o Sweating o GI disturbance and pain o Respiratory distress o Impaired vision o Nausea o Bradycardia o Hypotension

Answer 143

- inhibit acetylcholinesterase -\> decrease acetylcholine breakdown -\> increase the amount of acetylcholine in the synapse -\> increase the effect of normal parasympathetic nerve stimulation

Answer 144

- Reversible Anticholinesterases (PHYSOSTIGMINE, Neostigmine, Donepezil) - Irreversible Anticholinesterases (ECOTHIOPATE, Dyflos, Sarin)

Answer 145

o Acetylcholinesterase (true or specific cholinesterase) o Butyrylcholinesterase (pseudocholinesterase)

Answer 146

o Found in ALL cholinergic synapses (peripheral and central) o Very rapid action (\> 10 000 reactions per second) o It is highly selective for acetylcholine

Answer 147

o Found in plasma and in most tissues but NOT in cholinergic synapses o Broad substrate specificity - hydrolyses other esters e.g. suxamethonium o It is the principal reason for low plasma acetylcholine o Shows genetic variation so different people show different reactions to suxamethonium

Answer 148

o Enhanced muscarinic activity

Answer 149

o Further enhancement of muscarinic activity o Increased transmission at ALL autonomic ganglia (nAChRs) · This is because the anticholinesterase increases the acetylcholine concentration at ALL cholinergic synapses, muscarinic and nicotinic

Answer 150

o Becomes toxic o Depolarising block at autonomic ganglia and neuromuscular junction o The nicotinic receptors get overstimulated so they shut down

Answer 151

· They compete with acetylcholine for the active site on acetylcholinesterase · These drugs donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding · Carbamyl groups are removed by slow hydrolysis (this takes minutes rather than miliseconds) · This increases the duration of acetylcholine activity in the synapse

Answer 152

- postganglionic parasympathetic synapses

Answer 153

- 30 minutes

Answer 154

o Glaucoma - increases drainage of intraocular fluid o Atropine poisoning (common in children who eat atropa belladonna berries) · Atropine is a competitive muscarinic antagonist · Physostigmine increases the concentration of acetylcholine at the synapse so that the acetylcholine can outcompete the atropine until the atropine is cleared

Answer 155

· Irreversible anticholinesterase drugs are ORGANOPHOSPHATE compounds · Rapidly react with the enzyme active site, leaving a large blocking group · The blocking group is stable and resistant to hydrolysis so recovery requires the production of new enzymes (this takes days/weeks)

Answer 156

· Ecothiopate is the only one in clinical use but the others are used as insecticides and nerve gas

Answer 157

o Side-effects are that of parasympathetic discharge: · Sweating · Blurred vision · GI disturbance and pain · Bradycardia · Hypotension · Respiratory difficulty

Answer 158

o Side-effects are that of parasympathetic discharge: · Sweating · Blurred vision · GI disturbance and pain · Bradycardia · Hypotension · Respiratory difficulty

Answer 159

o Potent inhibitor of acetylcholinesterase o Slow reactivation of the enzyme by hydrolysis takes several days

Answer 160

o eye drops to treatment glaucoma -\> increases the drainage of intraocular fluid and has a prolonged duration of action

Answer 161

· Non-polar anticholinesterases (physostigmine, nerve agents) can cross the BBB · LOW doses -\> CNS excitation with the possibility of convulsions · HIGH doses -\> Unconsciousness, respiratory depression and death

Answer 162

- severely toxic - increase in muscarinic activity --\> CNS excitation --\> depolarising NM block

Answer 163

o INTRAVENOUS ATROPINE o Patient is put on a respirator because of the respiratory depression o If found in the first few hours the patient can be given Pralidoxime (IV) - this unblocks the enzymes

Answer 164

a. Acetylcholine

Answer 165

- ganglion blocking drugs

Answer 166

- blocking the receptor - blocking the ion channel itself

Answer 167

- effect the systme which is more dominant within the tissue at that time due to use dependency

Answer 168

a and b, both sympathetic effects as the parasymapthetic is blocked

Answer 169

- both vasocnstriction and renin production are inhibited leading to less TPR and water reabsorption

Answer 170

- smooth muscle: pupil dilation, decreased GI tone, bladder dysfunction and bronchodilation - exocrine secretions: decreased secretions

Answer 171

- 1^stanti-hypertensive - was to general so had horrible side effects so has be superseded by more selective agents

Answer 172

- only in surgery when controlled hypotension is required -\> because it is very potent but the effcts are very short lived so patient will find after the effects of the aneasthetic have worn off

Answer 173

- toxins and venoms -\> often bind irreversible unlike the drugs and prevent channel opening which causes total loss of autonomic function

Answer 174

Normal dose - little effect Toxic dose - mild restlessness through to severe agitation

Answer 175

Normal dose - sedation, amnesia Toxic dose - CNS depression or paradoxical CNS excitation (associated with pain)

Answer 176

- is a muscarinic receptor antagonist which acts on receptors within the iris of the eye to cause pupil dilation

Answer 177

- used in eye exams in order to examine the retina

Answer 178

- causes airways dilation - dry the throat by decreasing saliva produciton (reduces the risk of aspiration) - slightly increases the heart rate - if correctly chosen (hyoscine) has a sedative effect

Answer 179

- sensory information from the ear (labyrinth) and the eye are both coming in and meeting at the memory centre, the hippocampus - if there is a mismatch in the two bit of information the hippocampus triggers the vomitting centre (Area postrema - CVO) and nausea begins

Answer 180

- reduce the flow of information from the labyrinth to the brain -\> although there is still mismatch the response doesn't occur so neither does nausea

Answer 181

- dopaminergic neurones from the substantia nigra releases dopamine into the striatum which binds to D1 receptors, activating these allows the fine control of movement - M4 receptor has an inhibitory effect on this process - in Parkinson's you lose dopaminergic neurones so there is less stimualtion and therefore a loss of fine control

Answer 182

- as 60-70% of dopaminergic neurones have been lost the inhibitory effect of M4 receptors are no longer wanted so the antagonists can be used to take out the M4 receptors and the inhibitory effect - by no means a first line treatment

Answer 183

- is a muscarinic recepotr which means it blocks the parasympathetic induced bronchoconstriction

Answer 184

- ipratropim bromide has a large quaternary amine structure which means when given as an aerosol it doesnt cross the lipid membrane of the lungs to exit because of its positive charge -\> remains localised

Answer 185

- knocking out parasympathetic effects within the gut reduces smooth muscle contraction, gut motility and secretions to relieve some of the symptoms

Answer 186

- hot as hell -\> decreased sweating interferes with thermoregulation - dry as a bone -\> reduced secretions - blind as a bat -\> cyclopegia - mad as a hatter -\> CNS disturbance

Answer 187

d- physostigmine - reversibly blocks anti-cholinesterase so acetyl choline can outcompete the atropine until it is metabolised out of the system

Answer 188

- alpha 1 - vasoconstriction, relaxation of GIT - alpha 2 - inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions - beta 1 - increased cardiac rate and force, relaxation of GIT, renin release from kidney - beta 2 - bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis - beta 3 - lipolysis

Answer 189

PLC ---\> IP3 and DAG

Answer 190

decreased cAMP

Answer 191

increased cAMP

Answer 192

- cause the loss of sympathetic functions -\> enhance parasymathetic function

Answer 193

- cause the loss of parasympathetic functions -\> enhance symathetic function

Answer 194

- ALL adrenoceptors can be activated by NA and A - NORADRENALINE is more selective for ALPHA receptors - ADRENALINE is more selective for BETA receptors

Answer 195

- adrenaline - phenylephrine - clonidine - dobutamine - salbutamol

Answer 196

- non-selective

Answer 197

o CONCENTRATION - at low concentrations these drugs will be relatively selective but if you increase its concentration, the chance of binding to other receptors increases

Answer 198

o the key thing to consider here is BREATHING -\> the patient breathing must be breathing, even if you have a functioning cardiovascular system, you will have nothing to pump around o adrenaline acts MORE ON BETA RECEPTORS than noradrenaline and this stimulates bronchodilation and relaxation of the throat muscles o will also stimulate the heart so you get tachycardia, this will support the blood pressure o acts on alpha receptors and causes vasoconstriction o via the beta 2 receptors, slows down the release of histamine from the mast cells

Answer 199

o endothelial cells within the membranes of the blood vessels move apart so you get a lot of fluid moving into the tissues -\> leads to a fall in circulating fluid volume -\> fall in bp -\> ANAPHYLACTIC SHOCK and collapse of the circulatory system that leads to unconsciousness o contraction of bronchial smooth muscle and constriction of the muscles around the throat -\> causing respiratory distress o constriction of smooth muscle in the GI tract causing vomiting and diarrhoea

Answer 200

- obstructive conditions -\> asthma emergency or acute bronchospasm - selective beta-2 agonists are preferable

Answer 201

- allergic reactions and anaphylactic shock - pulmonary obstructive conditions -\> astham and acute bronchospasm - glaucoma cardiogenic shock - spinal anaesthesia - local anaesthesia

Answer 202

- cardiogenic shock - the sudden inability of the heart to pump sufficient oxygen-rich blood (occurs in MI or cardiac arrest) o beta 1 receptor is the main target -\> positive inotropic action

Answer 203

- spinal and local anaestheisa

Answer 204

o anaesthetising through the spine takes away the sympathetic output to the peripheral resistance vessels o meaning you get relaxation of peripheral resistance vessels so the patient won't be able to maintain their blood pressure - giving a little bit of adrenaline at the same time you can constrict the blood vessels so you can maintain the blood pressure

Answer 205

o adrenaline causes constriction of the blood vessels in the local area thus preventing the clearance of the anaesthetic from the area o if the anaesthetic was given without adrenaline then it will wear off faster

Answer 206

- Secretions - reduced and thick - CNS - minimal - CVS Effects: o Tachycardia, palpitations, arrhythmias o Cold extremities, hypertension o OVERDOSE - cerebral haemorrhage, pulmonary embolism - GIT - minimal - Skeletal muscle - tremor

Answer 207

- very selective to alpha 1 - minorly selective to alpha 2 - no really selectivity to beta 1 or 2

Answer 208

- more resistant to COMT degradation so stays in the system for a bit longer

Answer 209

o Vasoconstriction o Mydriatic (dilates pupil) o Nasal Decongestant -\> vasoconstriction in nasal sinus -\> less fluid leakage -\> less blockage

Answer 210

- hypertension due to vasoconstriction of vessels

Answer 211

- very selective to alpha 2 - moderately selective to alpha 1 - no really selectivity to beta 1 or 2

Answer 212

- clonidine will stimulate the pre-synaptic alpha 2 receptors -\> has a negative effect on the synthesis and release of noradrenaline - less noradrenaline -\> less stimulation at the effector organ -\> less vasoconstriction -\> fall in TPR and bp

Answer 213

- hypertension - migraines - glaucoma

Answer 214

- the brain - clonidine has a central action on the brainstem o within the brainstem it works on the baroreceptors in this pathway and reduces the sympathetic drive coming out of the brain o the reduction in sympathetic activity -\> reduced TPR and noradrenaline release at the nerve terminal thus reducing TPR further

Answer 215

- selective for beta 1 and beta 2 - no selectivity for alpha 1 or alpha 2

Answer 216

- less susceptible to uptake 1 and MAO breakdown -\> much longer plasma half-life (2 hours)

Answer 217

- Cardiogenic Shock - Acute Heart Failure - Myocardial Infarction

Answer 218

- you are trying to restore cardiac output - beta-2 receptors in vascular smooth muscle which causes dilation of the blood vessels in the muscles -\> pooling of blood within the muscles -\> decreased venous return -\> via baroreceptors, you get REFLEX TACHYCARDIA - the caused effect is opposite to what you are trying to achieve

Answer 219

- selective to beta 1 - some selectivity to beta 2 - very light selectvitiy to alpha 1 or alpha 2

Answer 220

o Cardiogenic Shock o Acute Heart Failure o Myocardial Infarction

Answer 221

- lacks reflex tachycardia because it is selective for beta 1 - short plasma half-life (2 minutes) so gives a lot of control

Answer 222

- IV infusion

Answer 223

- beta 2 selectivity - some selectivity to beta 1 - not selective for alpha 1 or alpha 2

Answer 224

- asthma - threatened premature labour

Answer 225

· Beta-2 mediated relaxation of bronchial smooth muscle · Inhibition of release of bronchoconstrictor substances from mast cells · The inhaler gives relatively localised effects on the lungs · You can also give salbutamol as tablets to control asthma - for chronic asthma conditions in hospital

Answer 226

- beta-2 mediated relaxation of uterine smooth muscle -\> prevents abortion of a foetus

Answer 227

o Reflex tachycardia o Tremor o Blood sugar dysregulation

Answer 228

- cocaine - tyramine -\> the cheese reaction

Answer 229

- Uptake 1 blocker for dopamine and noradrenaline - gives a high by causing an increase of dopamine in the synapse

Answer 230

- low doses: euphoria, excitement, increased motor activity - high doses: activation of chemotactic trigger zones -\> vomiting, CNS depression, respiratory failure, convulsions and death

Answer 231

- low doses: tachycardia, vasoconstriction and raised blood pressure - high doses: ventricular fibrillation and cardiac arrest

Answer 232

- a dietary amino acid - commonly found in cheese (hence being dubbed the cheese reaction) , red wine and soy sauce - it acts as a false neurotransmitter -\> isn't a problem in normal people (except from stimulating dreams) - tyramine acts as a weak agonist at the effector organ at which the noradrenaline will be stimulating the receptors while aslo piggy backing on the uptake systems and competing with NA for the uptake 1 site - this means that you get more NA hanging around in the synapse before displacing NA from the vesicles - normally, this displaced NA will be broken down by MAO but the tyramine competes with the NA for the binding site on the MAO - this means that there is less break down of the NA that has been displaced from the vesicles -\> builds up and leaks out into the synaptic cleft

Answer 233

- people on MAO inhibitors (e.g. to control depression)

Answer 234

- patients on MAO inhibitors have their MAO capabilities completely blocked - this inhibits the breakdown of NA -\> accumulation of NA in the synapse that leads to a hypertensive crisis - patients on MAO inhibitors are told to avoid cheese, red wine and soy sauce and anything else that has high concentrations of tyramine

Answer 235

- vasoconstriction, relaxation of the GIT

Answer 236

- inhibit transmitter release - contraction of vascular smooth muscle - CNS actions

Answer 237

- increase cardiac force and rate - relaxation of GIT - renin release from the kidneys

Answer 238

- bronchodilation - vasodilation - relaxation of visceral smooth muscle - hepatic glycogenolysis

Answer 239

- lipolysis

Answer 240

- appear on neurones and pre-synapses - act as a negative feedback regulator to prevent prolonged action

Answer 241

- alpha 1 and beta 1

Answer 242

- alpha 1 and beta 1

Answer 243

- beta 1 and 2

Answer 244

· Hypertension · Cardiac Arrhythmias · Angina · Glaucoma

Answer 245

- renin release -\> angiotensin II and aldosterone

Answer 246

· Sympathetic nerves that release the vasoconstrictor noradrenaline · Kidneys - regulates blood volume and vasoconstriction · Heart · Arterioles determine peripheral resistance (alpha 1 mediated vasoconstriction) · CNS - determines blood pressure set point and regulates some systems involved in blood pressure control and the autonomic nervous system

Answer 247

- most of the POSITIVE effects are from Beta 1 blockade and most of the NEGATIVE effects are from Beta 2 blockade

Answer 248

o act as anti-hypertensives mainly because of their antagonism of beta 1 adrenoceptors - in the heart to reduce heart rate and cardiac output but this effect disappears with chronic treatment - the heart resets itself - KIDNEYS to REDUCE RENIN PRODUCTION - PRIMARY EFFECT o beta 2 antagonism may be important, but it is not clear to what extent due to decreased noradrenaline o act in the CNS, if lipid soluble enough, to reduce sympathetic tone (beta 1 and 2) Back

Answer 249

- bronchoconstriction - cardiac failure -\> caused by slowing the heart too much - hypoglycemia - fatigue -\> due to reduced cardiac output and reduced muscle perfusion - cold extremities -\> loss of beta receptor mediated vasodilation of cutaneous vessels - bad dreams

Answer 250

o ASTHMA o COPD o CARDIAC FAILURE o DIABETES -\> masks symptoms of hypoglycemia - don't even know they are haing an attack - all due to beta 2 blockade

Answer 251

- binds to beta 1 receptors - causes NO release

Answer 252

- binds to beta 1 and 2 - inhibits K⁺ channels

Answer 253

- non-selective beta antagonist

Answer 254

- at rest, propranolol causes very little change in heart rate, cardiac output or arterial pressure - in exercise that you see the effects of propranolol on these variables

Answer 255

- all the typical adverse effects, caused by beta 2 antagonism

Answer 256

- historically called cardioselective beta blockers -\> are selective for beta-1

Answer 257

- mainly antagonises the effects of noradrenaline in the heart - also affect any tissue with beta 1 receptor e.g. kidneys

Answer 258

- its concentration -\> therefore it isnt safe to give to asthmatic patients despite having less of an effect on the airways

Answer 259

- when the hypertension is associated with an arrhythmia

Answer 260

- Atanolol is beta 1 specific so doesn't cause the side effects

Answer 261

- mixed beta and alpha -\> beta 1, beta 2 and alpha 1

Answer 262

- alpha 1 blockade -\> additional vasoconstrictor properties

Answer 263

- reduces the vasoconstriction due to targeting of alpha 1

Answer 264

- a1-receptors -\> postsynaptic on vascular smooth muscle -\> vasoconstriction - a2-receptors -\> presynaptic autoreceptors inhibiting NE release

Answer 265

- non-selective alpha antagonist

Answer 266

- causes vasodilation due to alpha 1 blockade

Answer 267

- blockade of presynaptic alpha-2 receptors removes the inhibitory effect of the alpha-2 receptors on noradrenaline release -\> increase in noradrenaline release -\> enhances the reflex tachycardia that appears with any blood pressure lowering agent - increased GIT motility - diarrhoea o NO LONGER IN CLINICAL USE

Answer 268

- highly alpha 1 selective antagonists

Answer 269

- vasodilation - less tachycardia than non-selective antagonists since they do NOT increase noradrenaline release from nerve terminals - cardiac output decreases, due to a fall in venous pressure due to dilation of capacitance vessels - hypotensive effect is dramatic -\> the postural hypotension is troublesome - unlike other anti-hypertensives, alpha-1 antagonists cause a decrease in LDL and an increase in HDL cholesterol -\> becoming popular again as an anti-hypertensive agent

Answer 270

- Propanolol - Pindolol - Atenolol - Carvedilol - Nebivolol - Sotalol

Answer 271

- Phentolamine - Prazosin

Answer 272

- not front-line treatment - are add ons if 2 or 3 methods don't work

Answer 273

- removes inhibitory effect of alpha 2 receptors on noradrenaline release -\> increase NA release -\> enhanced reflex tachycardia to low bp

Answer 274

- Methyldopa

Answer 275

- Methyldopa is taken up by the noradrenergic neurons and is decarboxylate and hydroxylated to form the false transmitter - alpha-methyl noradrenaline - it is NOT deaminated within the neuron by MAO and tends to accumulate in larger quantities than noradrenaline therefore it displaces noradrenaline from the synaptic vesicles - is less active than noradrenaline on alpha-1 receptors so is LESS EFFECTIVE AT CAUSING VASOCONSTRICTION - more active on presynaptic alpha-2 receptors, this means that the auto-inhibitory feedback mechanism operates more strongly and reduces noradrenaline release below normal levels - has some CNS effects, it stimulates the vasopressor centre in the brainstem to inhibit sympathetic outflow

Answer 276

o Renal and CNS blood flow is well maintained so it is widely used in patients renal insufficiency or cerebrovascular disease

Answer 277

o pregnant women because it has no adverse effects on the foetus despite crossing the blood-placenta barrier

Answer 278

- dry mouth - sedation - orthostatic hypotension - male sexual dysfunction o It is RARELY USED -\> causes postural hypotension

Answer 279

- arrhythmias

Answer 280

- Propanolol

Answer 281

o beta antagonists (beta blockers) - an increase in sympathetic drive to the heart via beta-1 can precipitate or aggravate arrhythmias due to its control on the pacemaker current and AV conductance - refractory period of the AV node is increased by beta antagonists -\> interferes with AV conduction in atrial tachycardias and slows down ventricular rate -\> even if with strange re-entry type electrical activity in the damaged tissue, it wont stimulate another heart beat because it's still in the refractory period

Answer 282

- pain that occurs when the oxygen supply to the myocardium is insufficient for its needs

Answer 283

- chest - arms - neck

Answer 284

- exertion - excitement

Answer 285

o due to a fixed narrowing of the coronary vessels e.g. atheroma o pain on exertion, but is enough flow for normal activity

Answer 286

o pain with less and less exertion, culminating with pain at rest due to atheromatous plaque beginning to rupture o you get a platelet-fibrin thrombus associated with the ruptured atheromatous plaque but without complete occlusion of the vessel o high risk of infarction

Answer 287

o coronary artery spasm -\> associated with atheromatous disease

Answer 288

o decrease heart rate and cardiac contractility -\> decreased CO -\> decreased systolic blood pressure o at low doses, beta-1 selective antagonists, METOPROLOL, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle -\> reduce the oxygen demand whilst maintaining the same degree of effort

Answer 289

o an increase in intraocular pressure due to aqueous humour produced by the blood vessels in the ciliary body via the actions of carbonic anhydrase

Answer 290

o blood flow in the ciliary body o blood pressure

Answer 291

o posterior chamber -\> through the pupil -\> anterior chamber -\> trabecular network in the canal of Schlemm

Answer 292

o beta-blockers

Answer 293

- maintains good blood supply to the CNS so reduces the risks of a migraine

Answer 294

o motor nerves are Cholinergic - action potential --\> depolarisation of the membrane --\> opening of voltage sensitive calcium channels --\> calcium influx --\> vesicles exocytosis - acetylcholine is synthesised from Acetyl CoA and Choline by choline acetyltransferase (CAT) (only found in cholinergic nerve terminals) - the targets for the acetylcholine at neuromuscular junctions are the nicotinic acetylcholine receptors on the END PLATE - nicotinic receptors are ion channel linked, when you stimulate the receptor you get a change in conformation and an influx of sodium ions - this results in a depolarisation of the membrane called the end plate potential - this is a GRADED potential - depends on how much acetylcholine is released and how many receptors are stimulated - once the end plate potential reaches a threshold then it generates an action potential that propagates in both directions from the end plate - the acetylcholinesterase, which breaks down the acetylcholine once it's had its effect, is bound to the basement membrane in the synaptic cleft - acetylcholinesterase breaks down acetylcholine to acetate and choline

Answer 295

o ganglionic (aka neuronal) o muscle

Answer 296

o span the membrane and have both intra- and extra-cellular components

Answer 297

o both must bind to acetylcholine before it becomes activated

Answer 298

- baclofen/diazepam -\> GABA receptor agonist

Answer 299

o is a benzodeizepam -\> used to treat spasticity following strokes or due to cerebral palsy

Answer 300

- prevent conduction of action potentials down motor neurones

Answer 301

- if it injected too close/directly into a motor neurone

Answer 302

- therapeutic = hemicholinium and calcium entry blockers - toxin = botulinium toxin

Answer 303

- depolarising - non-depolarising

Answer 304

- depolarising - suxamethonium - non-depolarising - tubocurarine

Answer 305

- inhibits calcium release within the muscle fibres themselves -\> prevents propagation – acts as a spasmolytic

Answer 306

- post-synaptic -\> act on nicotinic receptors on the motor end plate

Answer 307

- competitive nicotinic receptor antagonists

Answer 308

- nicotinic receptor agonists

Answer 309

- assisted respiration

Answer 310

- big molecules with relatively restricted movement around the bonds

Answer 311

- small molecules with rotationally movement around the bonds

Answer 312

- two bonded acetylcholine molecules - due to the flexibility one molecule can bind to two alpha subunits -\> therefore stimulating the receptor

Answer 313

- causes an extended end plate depolarisation -\> isn’t metabolised as quickly as acetylcholine so remains bound for longer - this leads to a depolarisation block of the NMJ (aka phase 1 block) due to overstimulation

Answer 314

- IV shot – slowly seeps into muscle fibres

Answer 315

- fasciculations (individual fibre twitches) -\> leads to flaccid paralysis (up to 5 minutes)

Answer 316

- pseudocholinesterase in the liver and plasma

Answer 317

- endotracheal intubation -\> relaxes skeletal muscle of the airways - muscle relaxant for electroconvulsive therapy -\> treatment for severe clinical depression if talking therapy and anti-depressants haven’t worked

Answer 318

- post-operative muscle pain - bradycardia - hyperkalaemia - raised intraocular pressure

Answer 319

- initial fasciculation ripping the muscle slightly

Answer 320

- direct muscarinic action in the heart - generally avoid as suxamethonium is given after general anaesthetic which has atropine (competitive muscarinic antagonist) with it

Answer 321

- burn patients - soft tissue injury - eye injuries or glaucoma

Answer 322

- competitive acetylcholine receptor antagonist - 70-80% is required to achieve full relaxation of muscles as it prevents the potential from reaching the threshold

Answer 323

- fasciculations (individual fibre twitches) -\> leads to flaccid paralysis (40-100 minutes)

Answer 324

o extrinsic eye muscles (relaxes first, gets back to normal last) o small muscles of the face, limbs, pharynx o respiratory muscles (relaxes last, gets back to normal first) - return in the opposite order

Answer 325

- relaxation of skeletal muscle during surgery -\> means less anaesthetic is needed - permit artificial ventilation

Answer 326

- anti-cholinesterases (neostigmine) -\> increase acetylcholine conc.

Answer 327

- does NOT cross the BBB or placenta - NOT metabolised at all -\> excreted in the urine (70%) and the bile (30%) - if there is any impairment in hepatic or renal function then it increases the duration of action of tubocurarine

Answer 328

- a non-depolarising NM blocker used instead of tubocurarine (same mechanism) in patients with hepatic or renal impairment - a chemically unstable molecule - due to the pH of the plasma it gets hydrolysed into two inactive fragments -\> duration of action isn’t affected by functionality

Answer 329

o ganglion block - it could block some of the nicotinic receptors in the ganglia o histamine release from mast cells - hypotension -\> due to ganglion blockade and histamines acting on the H1 receptors on the vasculature and cause vasodilation - tachycardia -\> may lead to arrhythmias -\> is a reflex in response to the hypotension or blockade of vagal ganglia - bronchospasm -\> caused by the histamine release - excessive secretions (bronchial and salivary) -\> caused by the histamine release - apnoea -\> why you always assist respiration in someone who's taking tubocurarine

Answer 330

- several channels are important in regulating the sinoatrial action potential - If Channel is responsible for allowing the action potentia to propagate -\> is a sodium channel that opens at the most negative potential -\> initially sodium influx occurs until a certain amount of depolarisation and then the calcium channels open - calcium channels come in TWO forms: -\> T type = transient and L type = long lasting - opening of the calcium channels increases the depolarisation - potassium channels opening is responsible for repolarisation

Answer 331

- beta adrenoceptors are coupled with adenylate cyclase and cause an increase in cAMP -\> is important in opening the If channel - sympathetic nervous system is responsible for causing this increase in cAMP and it also has a positive effect on calcium entry

Answer 332

- parasympathetic nervous system is negatively coupled with adenylate cyclase via muscarinic receptors -\> promotes the opening of potassium channels and prolongs repolarisation

Answer 333

- heart rate - afterload - contractility - preload

Answer 334

- beta blockers - calcium channel antagonists - ivabradine

Answer 335

- block beta receptors -\> less cAMP is made so less downstream signalling -\> longer initial depolarisation phase before calcium channels open

Answer 336

- block calcium channels (L-type) in the plasma membrane -\> reduced calcium influx of external calcium -\> reduced influx of calcium from the sacroplamic reticulum

Answer 337

- sarcoplasmic reticulum

Answer 338

- blocks sodium channels (If) -\> delays depolarisation to threshold levels

Answer 339

- beta blockers - calcium channel blockers

Answer 340

- rate slowing -\> act on the CARDIAC and smooth muscle - non-rate slowing -\> act on the smooth muscle

Answer 341

- reflex tachycardia -\> profound vasodilation triggers baroreceptors which signal to the heart

Answer 342

- organic nitrates are substrates for nitric oxide production - enters endothelial cells and promote NO production -\> NO then diffuses into the vascular smooth muscle and causes smooth muscle relaxation by activating guanylate cyclase

Answer 343

- angina when there is profound atherosclerosis reducing the blood flow to the heart

Answer 344

- promote potassium efflux so smooth muscle becomes hyperpolarised -\> has a reduced ability to contract -\> overall it promotes smooth muscle contraction/vasodilation

Answer 345

- increase coronary blood flow - vasodilation reduces TPR hence reduces afterload -\> heart has less work to do against the resistance - venodilation, which reduces venous return to the heart and hence reduces preload and contractility - reduction in afterload and preload causes a decrease in myocardial oxygen demand

Answer 346

- decreased heart rate and contractility

Answer 347

- decreased heart rate and contractility

Answer 348

- increased coronary blood flow, decreased preload and afterload

Answer 349

- increased coronary blood flow, decreased preload and afterload

Answer 350

- decreased heart rate

Answer 351

- beta blocker or calcium antagonist as background anti-angina treatment - ivabradine is a newer treatment - nitrate as symptomatic treatment (short acting)

Answer 352

- worsening of cardiac failure (CO reduction) -\> in angina with HF beta-blockers will reduce the work the heart has to do but, because of the HF it is dangerous -\> CO goes down -\> HF is worsened - bradycardia (heart block) -\> due to less conduction through AV node - bronchoconstriction (blockade of β2 in airways) - hypoglycaemia (in diabetics on insulin) due to decreased glycogenolysis/gluconeogenesis - cold extremities and worsening of peripheral arterial disease (β2 blockade in skeletal muscle vessels) -\> beta-2 receptors cause vasodilation, especially in peripheral tissue -\> e.g. blood flow to the hands is dependent on beta-2 mediated vasodilation - fatigue - impotence (sexual dysfunction) - depression - CNS effects (lipophilic agents) e.g. nightmares

Answer 353

- use a beta blocker whihc has vasodilator properties -\> should have equal affinity for beta 1 and 2 receptors or also antagonise a 1 receptors -\> e.g. pindolol or carvedilol

Answer 354

- asthmatics -\> due to bronchoconstriction - diabetics -\> due to hypoglycaemic properties

Answer 355

- bradycardia and AV block (Ca²⁺ channel block) - constipation -\> less gut contractions

Answer 356

- verapamil

Answer 357

- ankle oedema -\> vasodilation means more pressure on capillary vessels - headache/flushing - palpitations -\> baroreceptor reflex response - vasodilation/reflex adrenergic activation

Answer 358

- dihyrdopyridines

Answer 359

- supraventricular arrhythmias (e.g. amiodarone, verapamil) – can be atria/nodal tissue - ventricular arrhythmias (e.g. flecainide, lidocaine) - complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide)

Answer 360

- classification of anti-arrhythia drugs o CLASS I: Sodium channel blockade o CLASS II: Beta-adrenergic blockade o CLASS III: prolongation of repolarisation (membrane stabilisation, mainly due to potassium channel blockade) o CLASS IV: Calcium channel blockade

Answer 361

- despite still being used by most cardiologist lots of of modern dugs don't fit it -\> many drugs cross classes, particularly Na and K channel blockers -\> couldn’t be classified -\> e.g. amiodarone

Answer 362

- nodal tissue via the A1 receptor -\> negative effects on cAMP -\> decreased Ca channel opening and prolonged K channel opening -\> prolonged depolarisation and slower repolarization -\> helps to normalise tachyarrhythmia to normal sinus rhythm - vascular effects -\> stimulation of adenylate cyclase à increased cAMP -\> associated with relaxatiob of smooth muscle

Answer 363

- supraventricular tachyarrhythmias

Answer 364

- depresses SAN automatically and subsequently AV node conduction

Answer 365

- reduction of ventricular responsiveness to atrial arrhythmias

Answer 366

- complex action involving beta-blocking, calcium and potssium channel effects - major effects are attributable to potassium channel blockade

Answer 367

- supraventricular and ventricular tachyarrhythmias -\> often due to re-entry problems

Answer 368

- accumulates in the body -\> t½ 10 - 100 days causing: - photosensitive skin rashes - hypo- or hyper-thyroidism - pulmonary fibrosis

Answer 369

- when APs meet they tend to cancel each other out - in healthy tissue APs would pass down on either side, and if they crossed paths, they would MEET and CANCEL EACH OTHER OUT. This ensures that the AP proceeds in one direction. - tissue blocks leads to re-entry rhythm -\> if the tissue with a block has undergone its repolarisation phase, APs can reactivate the tissue -\> tachyarrhythmia

Answer 370

- work against it to prolong repolarisation -\> the re-entry AP comes into the tissue and reaches the AP point, the tissue hasn’t repolarised yet -\> the AP just dies and can't be propagated -\> reduce some of these arrhythmias - done with a potassium channel blocker like AMIODARONE

Answer 371

- inhibition of Na-K-ATPase -\> increased intracellular Ca²⁺ via effects on Na⁺/Ca²⁺ exchange -\> positive inotropic effect - central vagal stimulation by digoxin causes increased refractory period and reduced rate of conduction through the AV node (parasympathetic NS slows the heart) o overall they slow the heart rate and improve ventricular contraction -\> improves CO and restores normal rhythm

Answer 372

- AF and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce CO - digoxin reduces the conduction of electrical impulses within the AV node via the vagal stimulation -\> fewer impulses reach the ventricles and ventricular rate falls

Answer 373

- digoxin competes with potassium -\> if you have little potassium in your blood, then digoxin over-inhibits

Answer 374

- decreased renal Na absorption - decreased renal perfusion pressure - increased sympathetic activity

Answer 375

o very powerful vasoconstrictor à increased TPR o direct and indirect effects on the kidney - directly affects kidney to promote salt and water retention à increased blood volume - indirectly affects kidney by stimulating aldosterone production -\> aldosterone acts on the kidney o sympathetic activation o thirst activation

Answer 376

- enalapril -\> any drug ending with pril

Answer 377

- hypertension - heart failure - post-myocardial infarction - diabetic nephropathy - progressive renal insufficiency - procaution for patients at high risk of cardiovascular disease

Answer 378

- an effect on TPR -\> angiotensin II is a vasoconstrictor -\> blocking it will reduce TPR -\> decrease BP

Answer 379

- angiotensin II increases salt and water retention -\> drives up blood volume -\> increase in venous return - ACE inhibitors decrease venous return in HF patients -\> reduce work of the heart and decreased congestion in the system -\> stress on heart alleviated

Answer 380

- hypertension - heart failure - very similar to ACE inhibitors -\> have the same effects -\> decreased TPr and decreased venous return

Answer 381

- GENERALLY WELL TOLERATED. SIDE EFFECTS: - cough -\> ACEi only -\> prevents the breakdown of bradykinin -\> builds up and stimulates coughing - hypotension - urticaria/angioedema (rare) - hyperkalaemia - foetal injury - renal failure in patients with renal artery stenosis -\> angiotension can't bind to efferent arteriole so glomerulus pressure isn't maintained

Answer 382

1. membrane depolarisation opens voltage-gated Ca²⁺ channels (VGCCs) 2. Ca²⁺ enters & binds to calmodulin (CaM) 3. Ca²⁺-CaM complex binds to & activates myosin light chain kinase (MLCK) 4. MLCK mediated phosphorylation -\> smooth muscle contraction

Answer 383

elderly = uncoupling of BP from the RAS system as you get older -\> more due atherosclerosis etc - afro-Caribbean = to low plasma renin activity

Answer 384

- alpha 1 adrenoreceptor antagonists are used as a last resort as antihypertensive treatment - alpha 1 receptor is the predominant vasoconstricting receptor in the vasculature -\> blocking alpha 1 receptors reduces vasoconstriction -\> reduce TPR -\> decrease BP

Answer 385

primarily centred on the reward pathway (mesolimbic dopamine system) in the brain - reward pathway is a collection of dopaminergic neurones that originate in the ventral tegmental area and project down to the ventral striatum -\> in particular the nucleus accumbens

Answer 386

- excessive dopamine release within the nucleus accumbens

Answer 387

- snorting - drug enters nasal sinus -\> venous drainage -\> lung -\> heart -\> brain o mucous membranes of the nasal sinuses slow absorption

Answer 388

- eat or drink - stomach -\> small intestine -\> portal system -\> liver -\> heart -\> brain o very slow absorption due to the GI tract

Answer 389

- smoke - \> lungs -\> heart -\> brain - rapid absorption (seconds) -\> because the lungs are next to the heart -\> is the fastest administration route (slightly faster than IV)

Answer 390

- injecting - vein -\> heart -\> brain o rapid absorption (seconds)

Answer 391

- marcotics/painkillers - depressants - stimulants - miscellaneous

Answer 392

- opiate like drugs -\> heroin, morphine

Answer 393

- alcohol - benzodiaepines (valium) - barbiturates

Answer 394

- cocaine - amphetamine (speed) - caffeine - metamphetamine (crystal meth)

Answer 395

- cannabis - ecstasy

Answer 396

- the compounds that prodcue the high effect when taking cannabis - 60 out of the 400 compounds in cannabis sativa are cannabinoids

Answer 397

- tetrahyrdocannabinoid (THC)

Answer 398

- a compound believed to have a protective effect from the negative effects of THC

Answer 399

- oral = 5-15% of dose enters bloodstream - inhalation = 25-35% of dose enters bloodstream -\> anything inhaled suffers from about 50% loss automatically as only 50% gets far enough down into the lungs to diffuse into the bloodstream

Answer 400

- cannabis is very lipid soluble -\> accumulates in poorly perfused fatty tissues - in chronic cannabis users it will leak back out and can even be stored to a 4 times high concentration than in the bloodstream

Answer 401

- the major metabolite of THC - is even more potent that THC

Answer 402

- a large amount of cannabis is secreted by the bile (enterohepatic recycling) -\> therefore it goes down the bile duct -\> small intestine -\> potential reabsorption - 65% of 11-hydroxy-THC is secreted into the gut, which is then heavily reabsorbed back into the system - eventually the cannabis will be cleared -\> urine loss accounts for 25%

Answer 403

- the correlation is very poor due to the storage/accumulation in fatty tisses (the brain is key in this due to its high fat content) -\> significantly worse in chronic user

Answer 404

d. 30 days -\> due to accumulation and then seaping out of adipose tissue

Answer 405

- an endogenous substance produced by the endogenous cannabinoid system -\> behaves similarly to cannabis

Answer 406

- CB1 RECEPTORS -\>predominantly brain (hippocampus, cerebellum, cerebral cortex, basal ganglia) - CB2 RECEPTORS -\> predominantly on immune cells in the periphery

Answer 407

Anandamide binds to receptors -\> G-protein is negatively coupled to adenylate cyclase -\> depress the inhibition to the dopaminergic neurones by GABA - CB1 receptor is the most prevalent G-protein coupled receptor in the brain

Answer 408

- a depressant

Answer 409

- activation of CB1 and CB2 receptors induce euphoria -\> stimulation of the CB1 receptor will switch off and blocks GABA transmission -\> GABA suppresses the reward pathway -\> when the reward pathway needs to be activated, GABA is inhibited - cannabis hijacks this system -\> cannabis binds to CB1 receptors on GABA neurones -\> reduces firing rate of GABAergic neurones (depressant) -\> dopaminergic neurone firing increases -\> euphoria

Answer 410

- the part of the brain important in error detection and monitoring of behaviour - is heavily involved with performance monitoring and behavioural adjustments to avoid losses (ensure good things occur)

Answer 411

- hypoactivity in the ACC -\> cannabis users have problems adjusting their behaviour appropriately -\> an element of psychosis and schizophrenia - isn't clear whether cannabis causes psychosis and schizophrenia or whether suffers use cannabis to help symptoms

Answer 412

o cannabis has a positive effect on orexigenic neurones in lateral hypothalamus - cannabis switches off GABA -\> increases MCH neuronal activity - increased orexin production o also directly effects the AgRP neurones of the arcuate nucleus -\> stimulates appetite

Answer 413

- CB2 receptors are found in the periphery on immune cells -\> down regulation of immune response - affects the activity of NK cells, macrophages, mast cells, T lymphocytes and B lymphocytes - chronic cannabis users have an impaired immune system

Answer 414

- psychosis and possible schizophrenia - increased appetite via the hypothalamus - memory loss -\> Limbic regions (amnestic effects/↓BDNF) -\> similar to alcohol - psychomotor performance -\> cerebral cortex -\> similar to alcohol - immunosuppressant - tachycardia and vasodilation -\> conjunctivae (blood shot eyes)

Answer 415

- there is very low CB1 receptor expression in the medulla -\> important because the medulla contains the cardio-respiratory centre - substances such as alcohol and heroin have profound effects in the medulla, so can cause death cannabis doesn’t

Answer 416

- MS, chronic pain, stroke -\> CB receptor are trying to compensate for the disease process - infertility, obesity -\> CB receptor are part of the pathology of the disease

Answer 417

- diseases with chronic pain or upregualtion of CB receptors as a consequence of the disease -\> stroke or MS - examples of agonists are dronabinol, nabilone (both used in chemo patients to prevent nausea or to stimulate appetite in AIDS) and sativex (analgesic)

Answer 418

- obesity -\> rimonabant was one of the first anti-obesity agents to target the cannabinoid receptor -\> it was affective, but the problem was its propensity to cause depression, and suicide

Answer 419

- fatty acid amide hydrolase

Answer 420

- stimulant

Answer 421

- stimulant

Answer 422

- it is a powerful vasoconstrictor -\> constantly snorting cocaine leads to vasoconstriction of the blood vessels in the nose -\> necrosis then kicks in

Answer 423

- crushing up the leaves with an organic solvent to form a paste -\> extract is around 80% cocaine

Answer 424

- cocaine (erythroxylum) leaves are dissolved in acidic solution

Answer 425

- cocaine HCl -\> however it was also abused

Answer 426

- IV - oral - intranasal

Answer 427

- precipitate cocaine HCl mixed with an alkaline solution (e.g. baking soda) -\> once this solution dries and hardens, you end up with little cocaine rocks - crack can be purified by dissolving it in a non-polar solvent (e.g. ammonia or ether) -\> this is called freebase

Answer 428

- IV, orally and intranasal like other forms but also inhalation -\> faster onset - crack cocaine is probably the most prelevant drug on the planet

Answer 429

- intranasal and oral -\> slower onset but also a slower clearance/metabolsim

Answer 430

- 20-90 minutes

Answer 431

- metabolsied rapidly by liver AND plasma cholinesterases -\> is metabolised in th bloodstream - 75-90% of cocaine is broken down into inactive inert metabolites

Answer 432

- speed of onset -\> addiction is very closely correlated with how fast the effect comes on - speed of breakdown -\> is a powerful euphoric high very quickly, and it is then lost very quickly too -\> is a reason for continuously taking cocaine -\> reinforce the effect

Answer 433

- a local anaesthetic -\> blocks sodium channelo within nerves -\> reduced propagation of APs -\> suppression of pain sensation

Answer 434

- dopamine transporter takes molecules of dopamine from the synapse, and flips it back into the pre-synaptic cell -\> cocaine blocks these dopamine transporters -\> increase dopamine synaptic concentraion and therefore NA and serotonin are also affected

Answer 435

- no -\> cocaine blocks the reuptake protein and affinity and efficacy are related to interactions at the receptor

Answer 436

- must diffue across the plasma membrane -\> can only access sodium channels from the membrane/cytoplasmic side

Answer 437

- cocaine goes straight to the nucleus accumbens and blocks the dopamine transporter -\> results in many more dopamine molecules in the synapse, binding to dopamine receptors and stimulating euphoria

Answer 438

o mild-moderate -\> euphoria and dysphora, heightened energy, motor excitement, restlessness, insomnia, increased libido, mild to moderate anorexia, anger and inflated self-esteem

Answer 439

- irritability, hostility, anxiety, fear, withdrawl - extreme energy or exhaustion - total insomnia - compulsive motor sterotypies - incoherent speech - decreased libido - possible extreme violence - total anorexia - delusion of grandiosity

Answer 440

- reuptake is being blocked -\> dopamine is not being reabsorbed back into the presynaptic neurone/is not being recycled back into the neurone frequently enough - binging on cocaine leads to reuptake being prevented -\> dopamine will eventually be metabolised to a degree -\> will not get any dopamine back into the neurone -\> dopamine vesicles become fewer in number -\> loss in the positive/reinforcing euphoria, and more negative/stereotypic effects

Answer 441

o effects on the sympathetic nervous system - due to increased catecholamines (predominantly NA) - increased NA -\> increased work of the heart -\> increased BP -\> increased oxygen demand - increased NA (also inhibits NO) -\> vasoconstriction -\> decreased blood flow to the heart - sympathetic nervous system activates platelets -\> platelet adherence - overall it leads to decreased oxygen supply despite increased demand -\> ISCHAEMIA AND INFARCTION o decreased sodium transport creating a local anaesthetic effect -\> interferes with rhythm and left ventricular function

Answer 442

- causes increased agitation, locomotor activity and involuntary muscle contraction -\> all lead to an increase in body temperature -\> if in a hot environment htis can lead to hyperthermia - cocaine also increases the threshold of sweating and cutaneous vasoldilation three fold (must rise be 3 times as much) -\> effects the bodies mechanisms of cooling down

Answer 443

- cigarettes -\> tar droplets are the transporter for the nicotine - nicotine spray - nicotine gum - nicotine patch o last three are replacement therapies to wean off smoking

Answer 444

- nicotine spray 1mg (20-50%) - nicotine gum 2-4mg (50-70%) - cigarettes 9-17mg (20%) - nicotine patch 15-22mg/day (70%)

Answer 445

- cigarette smoke is quite acidic and nicotine has a high pKA of 7.9 - means that nicotine is very poorly absorbed in the buccal cavity as within the smoke it is ionised and in the alveoli it depends on pH

Answer 446

- the problem with cigarettes is that you get a spike of nicotine -\> this is the feeling that people want to replace, hence why they binge cigarettes - replacement methods don’t produce this high spike in nicotine because it is dangerous -\> idea of replacement methods is to maintain a low level of nicotine in the blood to interfere with the craving to smoke

Answer 447

- 1-4 hours -\> therefore is a powerful reinforcing agent (like cocaine) as effects are lost quickly -\> why people msoke lots of cigarettes a day

Answer 448

- vast majority (70-80%) of nicotine is broken down in the liver VERY QUICKLY by hepatic CYP2A6 - major metabolite is cotinine -\> it is an inactive and inert metabolism

Answer 449

- nicotine binds to the nicotinic acetylcholine receptor - NICOTINIC RECEPTORS ARE FOUND ALL THROUGHOUT THE AUTONOMIC NS -\>, nicotine can interfere with most autonomic functions

Answer 450

- is a stimulant -\> acts directly on the neurone itself to stimulate it -\> are lots of nACh receptors on the cell body of reward dopaminergic neurones - when the neurone is heavily stimulated, you get dopamine release in the nucleus accumbens -\> feeling of reward

Answer 451

- predominantly the volatile matter

Answer 452

- nicotine leads to consistent autonomic stimulation (in the CNS and adrenal glands) -\> increased HR and SV (sympathetic) - reduced blood flow/vasoconstriction of coronary and skin arterioles - vasodilation in the skeletal muscle arterioles - nicotine is pro-atherogenic -\> has a negative effect on the lipid profile -\> increases thromboxane (promotes platelet aggregation) and decreases NO o can all build up to major CVS events such as MI (unlike cocaine its a build up and unlikely to get acute events) o effects MAY be mitigated by exercise and diet

Answer 453

- is a stimulant -\> associated with weight loss - when people undergo smoking cessation they put on weight

Answer 454

o Parkinson's disease -\> long-term nicotine use increases the number of brain cytochromes (CYPs) -\> these cytochromes metabolise toxins (neurotoxins) -\> suggests that chronic nicotine has a positive impact on Parkinson’s disease because it decreases neurotoxins that are present and contribute to disease development o Alzheimer's disease -\> chronic nicotine use is associated with decreased beta-amyloid toxicity, and decreased amyloid precursor protein (APP) -\> nicotine has a positive effect on the progression of Alzheimer’s

Answer 455

- is a stimulant and should cause euphoric effects - adenosine activates adenosine receptors, which tend to decrease the euphoric effect -\> adenosine therefore downregulates D1 function and decreases dopamine secretion - caffeine is an adenosine receptor antagonist -\> increases dopamine release and enhances tissue response to dopamine

Answer 456

- is orally administarted so there is a time delay, has a lower bioavailability and is released in small doses over a loner period of time

Answer 457

% ABV (alcohol by volume) x 0.78 = grams of alchol/100ml

Answer 458

% ABV x actual volume (ml) / 1000 - 1 unit = 10ml or 8g of absolute alcohol

Answer 459

- 14 units or less per week

Answer 460

- 8 or more units in one sitting - 18% of 16-24 do this on a weekly basis -\> this number is falling

Answer 461

- 20% in the stomach - 80% in the intestines

Answer 462

- alcohol is far more effectively absorbed from the small intestine -\> therefore in order to absorb alcohol quickly, it needs to get into the intestine as quickly as possible - a method to speed up alcohol getting to the intestines is to drink on an empty stomach - fluid stimulates gastric emptying - drinking on a full stomach delays gastric emptying - houses the alcohol in the stomach, where it is far less effectively absorbed

Answer 463

o 90% of alcohol dose is metabolised (85% of this is done in the first place it goes - the liver) the remaining 10% isn’t metabolised -\> excreted as pure alcohol o some excretion occurs through the lungs unchanged (e.g. breath test assesses amount of alcohol) o 2 major groups of enzymes that predominate alcohol metabolism - alcohol dehydrogenase (75%) - mixed function oxidases (25%) – includes CYP450 -\> its upregulation leads to alcohol tolerance

Answer 464

- predominatly in the stomach -\> does contain some alcohol dehydrogenase - females tend to have around 50% less alcohol dehydrogenase than males so this arm of metabolism is less effective

Answer 465

o blood alcohol levels in the woman are higher - females metabolise it less effectively due to having less alcohol dehydrogenase in the stomach -\> more alcohol gets across into the bloodstream - once in the blood, alcohol is less well diluted and distributed in females because men have more body water (59%) compared to females (50%)

Answer 466

o STEP 1: alcohol dehydrogenase and mixed fucntion oxidases convert alcohol into acetaldehyde -\> acetaldehyde is a very toxic, so we don’t want it building up in the blood o STEP 2: aldehyde dehydrogenase converts acetaldehyde to acetic acid which is inert and inactive -\> this reaction occurs in the liver and the stomach

Answer 467

- there is a very common genetic polymorphism in the aldehyde dehydrogenase enzyme -\> very common in Asian populations (Asian flush) - results in ineffective metabolism of acetaldehyde -\> builds up in the blood -\> toxicity (nausea)

Answer 468

- a drug that inhibits aldehyde dehydrogenase -\> is used in alcohol aversion therapy - if given to alcoholics, whenever they drink alcohol, acetaldehyde builds up -\> toxicity/nausea -\> puts them off alcohol

Answer 469

- not really -\> it has many targets

Answer 470

- weak for both -\> is not a very potent drug - large amount smust be consumed for it to have an effect

Answer 471

- is primarily a depressant - CNS agitation/excitement may occur at a very low level -\> self-confidence - CNS excitement is very dependent on your personality and environment (social/non-social)

Answer 472

- alcohol may directly affect the GABA receptor itself -\> increase function - DIRECT EFFECT - is evidence for alcohol acting pre-synaptically, to increase allopregnenolone - INDIRECT EFFECT - alcohol may decrease NMDA receptor activation by binding to the receptor via allosteric modulation - alcohol may interfere with calcium channel opening -\> impacts general neurotransmitter release

Answer 473

- behaves a bit like heroin when it comes to euphoria - alcohol binds to the opioid receptors in the CNS -\> switches off the GABA receptor via the opioid receptor (as opposed to cannabinoid receptors in cannabis) -\> GABA is switched off -\> increased firing rate of dopaminergic neurones -\> euphoria

Answer 474

- corpus collosum -\> passes info from left brain (rules, logic) to right brain (impulse, feelings) and vice versa -\> loss ofconnection occurs - hypothalamus -\> loss of control of appetite, emotions, temperature, and pain sensation - reticular activating system -\> loss of consciousness - hippocampus -\> loss of memory - cerebellum -\> lack of movement and coordination - basal ganglia -\> lack of perception of time

Answer 475

- vasodilation = acetaldehyde interferes with smooth muscle function in the arterioles -\> calcium entry is impaired and prostaglandins are promoted -\> cutaneous vasodilation -\> redness -\> is the principle behind Asian flush - tachycardia = depresses baroreceptor activity -\> no stimulation of the PNS and a loss of inhibition on the SNS -\> increased heart rate

Answer 476

- increased diuresis (polyuria) is related to increased acetaldehyde -\> acetaldehyde inhibits vasopressin production -\> less AQPs in the collecting ducts -\> LOSS OF FLUID - alcohol increases cortisol production (can produce ‘Cushing’s like’ syndrome) -\> alcohol increases ACTH - has a negative effect on testosterone secretion (can have feminisation symptoms)

Answer 477

- alcoholics recieve less carbohydrates becuase large amount of calories comes from alcohol -\> do not obtain enough thiamine -\> neurones required thiamine to function -\> brain regions with high metabolic demand become impaired - impaired metabolism -\> reactive oxygen species are formed -\> these can form mitochondrial damage -\> apoptosis

Answer 478

o Wernicke-Korsakoff syndrome caused by thiamine deficiency - Wernicke’s encephalopathy (reversible part) -\> 3rd ventricle & aqueduct -\> cortical atrophy occurs/loss of cerebral white matter -\> cauyses confusion, oculmotor symptoms and gait issues -\> can progress to dementia (no longer reversible) - Korsakoff’s psychosis (irreversible) -\> dorsomedial thalamus -\> loss of memory due affects on areas of the deep brain - hippocampus

Answer 479

o a consequence of alcohol dehydrogenase is the depletion of NAD⁺-\> drinking too much alcohol leads to lots of NAD⁺ being used up -\> NAD⁺ is needed for many stages in aerobic metabolism: - \> pyruvate starts getting converted to lactate - \> acetyl CoA starts getting converted to ketones - the liver is now exposed to lactic acid (acidosis) and ketones (ketosis) -\> the ability of the liver to metabolise fats and lipids is impaired -\> build up of fat in the liver and if the mixed function oxidase system is used a lot, free oxygen radicals are released into the blood

Answer 480

- acutely, after going on an alcohol binge, fatty liver is seen - is related to the inability to sufficiently metabolise (beta-oxidation) fats and lipids -\> are stored in the liver as triacylglycerols in the liver - iis reversible, and not particularly dangerous in isolation

Answer 481

- the Krebs cycle is being permanently disrupted -\> is a permanent generation of acidosis, ketosis and oxygen free radicals in the liver -\> creates a very pro-inflammatory environment

Answer 482

- the changes associated with chronic alcohol use - increased ketones, lactic acid, free radicals -\> these all promote WBC influx - in hepatitis, we see both blood and hepatic cytokine changes -\> increase in IL-6 and TNF alpha - hepatitis is still reversible if drinking is stopped

Answer 483

- long term, if the inflammatory profile remains fibroblasts may begin to infiltrate the liver -\> increase the amount of connective tissue being laid down, in place of active liver tissue -\> decreased hepatocyte regeneration, increased fibroblasts and decreased active liver tissue - at some point, there is so little left of active liver tissue, that a liver transport is required -\> liver failure

Answer 484

- is evidence that low levels of alcohol semi-regularly protects against CVS -\> e.g. a glass or red wine may have a protective effect against coronary artery disease -\> though to be the polyphenols that are beneficial - the amounts that have to be drunk are likely to have negative affects to other systems, mainly the liver and brain

Answer 485

- ulceration is common in chronic alcoholics -\> strongly associated with acetaldehyde - stomach cancer risk increases in alcoholics -\> alcohol migh have carcinogenic effects

Answer 486

- nausea = alcohol is an irritant -\> vagus -\> vomiting centre - headache = vasodilation and acetaldehyde build up - fatigue = 1. sleep deprivation and 2. ‘Rebound’ - poor quality - restlessness and muscle tremors =‘Rebound’ - polyuria and polydipsia = ↓ ADH secretion

Answer 487

- immobile for 3 weeks after major surgery or long flight - calf of right leg is swollen and collateral superficial veins are present - palpation reveals localised tenderness and pitting oedema - normal BP, HR, RR and SpO₂

Answer 488

- a score/test which predicts the likelihood of a DVT

Answer 489

- positive D-dimer test -\> suggests more than confirms - ultrasound -\> confirms

Answer 490

- positive D-dimer test suggests diagnosis of deep-vein thrombosis (DVT) -\> given interim treatment with parenteral anticoagulant -\> prevents anything worse from happening while further tests are ran to confirm the diagnosis - ultrasound scan confirms DVT -\> given maintenance treatment with oral anticoagulant -\> can be continued after discharged

Answer 491

- rivaroxaban -\> MOST COMMON - apixaban - warfarin -\> MOST COMMON - dabigatran o work as maintanence because they all have oral administration

Answer 492

- inhibits factor IIa

Answer 493

- can cause severe GI bleeding whihc can often lead to death

Answer 494

- inhibit factor Xa

Answer 495

- vitamin K antagonist -\> required for generation of factors II, VII, IX and X

Answer 496

- heparin (IV or SC) - low-molecular weight heparins (SC) -\> dalteparin -\> MOST COMMON o both have parenternal administrations

Answer 497

- both activate anti-thrombin (AT-III) - it is thought that low-molecular weight heparins may also affect Xa directly

Answer 498

- warfarin is cheaper but has lots of drug interactions so need monitoring - rivaroxaban is better but effects cannot be reversed

Answer 499

- trying to prevent pulmonary embolisms

Answer 500

- chest pain - dyspnoea - tachypnoea - low BP and SpO₂ with a high HR

Answer 501

- patient history - any known DVT etc - multiple-detector computed tomographic pulmonary angiography (CTPA)

Answer 502

- is mostly the same - interim will be given dalteparin or heparin -\> heparin is given for PE and not for DVT because they are more severe -\> heparin works faster but has a few more side effects - followed up with maintanence which is rivaroxaban or warfarin

Answer 503

o factors/elements that increase risk of thrombosis - rate of blood flow -\> flow is slow/ stagnating -\> no replenishment of anticoagulant factors and balance adjusted in favour of coagulation - consistency of blood -\> natural imbalance between procoagulation and anticoagulation factors - blood vessel wall integrity -\> damaged endothelia -\> blood exposed to procoagulation factors

Answer 504

- Non-ST elevated myocardial infarction (MI) -\> white thrombus -\> partially occluded coronary artery -\> ischaemia - ST elevated myocardial infarction -\> white thrombus -\> fully occluded coronary artery -\> not just reduced oxygen to cardiac muscle -\> is now lack of oxygen -\> leads to cell death and necrosis

Answer 505

- history of hypertension and hyperlipidaemia - shortness of breath, sweating, dizziness & chest pain - normal BP and HR with high RR and low SpO₂

Answer 506

- no changes on the ECG - elevated troponin in the blood

Answer 507

- white = occur in arteries, particularly coronary arteries -\> are white due to foam cells caused by macrophages and are associated with atherosclerosis - red = form in deep veins (DVTs)

Answer 508

o anti-platelet therapy - aspirin - clopidogrel

Answer 509

- NSTEMI = antiplatelets - STEMI = antiplatelets + thrombolytics

Answer 510

- damage to endothelium - atheroma formation - platelet aggregation o mainly associated with diet -\> high fat/high LDL

Answer 511

- activates platelets -\> changes there shape so they become sticky and attach to other platelets -\> amplifies clot formation

Answer 512

1. thrombin binds to protease-activated receptor (PAR) on platelet surface -\> PAR activation causes a rise in intracellular Ca²⁺ -\> exocytosis of ADP from dense granules 2. ADP activates P2Y₁₂ receptors -\> platelet activation/aggregation via auto/paracrine action 3. PAR or P2Y₁₂ activation liberates arachidonic acid (AA) -\> Cyclo-oxygenase (COX) becomes activated and generates thromboxane A₂ (TXA₂) from AA 4. TXA₂ activation -\> expression of GPIIb/IIIa integrin receptor on platelet surface GPIIb/IIIa -\> involved in platelet aggregation

Answer 513

- an oral antiplatelet drug - is an ADP (P2Y₁₂) receptor antagonsit -\> prevents platelet activation

Answer 514

- an oral antiplatelet drug - an irreversible COX-1 inhibitor -\> prevents TXA₂ formation -\> lack of GPIIb expression -\> no aggregation

Answer 515

- inhibits factors IIa and Xa and to a lesser extent IXa and XIa

Answer 516

- fibrin degradation products

Answer 517

- a CT scan - very important to know -\> thrombolytic treatment for a ischamic stroke will kill someone with a haemorrhagic stroke

Answer 518

- thrombolytic therapy -\> alteplase (tPA) -\> given ASAP

Answer 519

- clot forms within one of the atria of heart -\> more common if someone has atrial fibrillation or flutter - clot embolises -\> blocks one of the cerebral arteries -\> necrosis - clot causing strokes occurs differently to DVT and atherosclerotic plaque

Answer 520

- factor IIa binds to fibrinogen and converts it to fibrin strands

Answer 521

- convert plasminogen -\> plasmin -\> protease degrades fibrin - once the fibrin has broken down the clot will dissolve -\> restores blood flow

Answer 522

- extremely dangerous drugs -\> causes excessive bleeding - only used in emergency setting for ischaemic stroke and possible STEMI -\> evidence suggests it is only really worth it in stroke patients over 80

Answer 523

- good = HDL - bad = LDL

Answer 524

1. lipids enter the blood in two ways, one of which is absorption of fats from the diet -\> amount of the cholesterol that enters the circulation from the diet is very small (other lipids (such as triglycerides) are certainly absorbed) 2. triglycerides are absorbed as chylomicrons into the blood -\> if you ingest a very fatty meal and then take a blood sample, chylomicrons are present in the plasma 3. chylomicrons are broken down by lipases, into remnants -\> some of this ends up as atheroma, in the vascular wall

Answer 525

- is a pathway in which the liver generates different lipoproteins, which are then broken down and converted -\> some of the lipoproteins end up with the LDL receptor -\> this endogenous pathway forms around 80% of the cholesterol in the body - most circulating lipids are endogenous

Answer 526

o is a process where cholesterol is taken OUT of blood vessels and foam cells - foam cells -\> smooth muscle macrophages that are full of lipid (including cholesterol) - is a transformation of HDL (beneficial) back to LDL -\> by cholesteryl ester transfer protein (CETP) - way to BLOCK THIS PROCESS exsists -\> can block CETP and thus increase HDL and reduce LDL

Answer 527

1. endothelial dysfunction 2. fatty streak formation 3. formation of the atherosclerotic plaque

Answer 528

- endothelium becomes dysfunctional -\> problem because the endothelium is responsible for producing a lot of mediators - characterised by a series of early changes that precede lesion formation -\> changes include greater permeability of the endothelium, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall

Answer 529

- fatty streak is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-rich foam cells -\> derived from macrophages and T lymphocytes within the tunica intima - later on the lesions will also include smooth muscle cells - are usually formed in the direction of blood flow - most fatty streaks don’t actually develop into serious atherosclerosis, but it is an early stage and begins very early in human life

Answer 530

- results from the death and rupture of the foam cells in the fatty streak - formation of necrotic core occurs - migration of smooth muscle cells into the intima and laying down collagen fibres results in the formation of a protective fibrous cap over the lipid core -\> fibrous cap is extremely important because it separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors - stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous plaque

Answer 531

- calcium - coronary artery disease can be detected by doing a CT scan of the heart -\> detects any calcium -\> believed that the more calcium you have in the plaque, the more likely you are to be symptomatic - higher calcium = greater risk of CVD

Answer 532

- remnant lipids come from the chylomicrons (part of the breakdown process of chylomicrons) - are important because they are quite atherogenic -\> lots of remnant lipoproteins in the blood = higher risk of CHD compared to blood with fewer remnants

Answer 533

- VLDL - chylomicron remnant - IDL

Answer 534

-vulnerable plaques are characterised by thin fibrous caps, a core rich in lipid and macrophages and less evidence of smooth muscle proliferation -\> stable plaque has a very thick fibrous cap

Answer 535

- greater influx and activation of macrophages, accompanied by the release of matrix metalloproteinases that are involved in the breakdown of collagen

Answer 536

- stable plaque = will probably have symptoms due to the thick cap obstructing blood flow to the heart -\> PAIN - vulnerable plaque = only a very thin wall separating the lumen and lipid core -\> no pain -\> a surge in BP could lead to the breaking down of the thin fibrous cap-\> THROMBOSIS

Answer 537

- strongly associated with atherosclerosis and CHD events -\> 10% increase results in a 20% increase in CHD risk - modified by other risk factors (all these things will aggregate the effects of LDL cholesterol) -\> low HDL cholesterol, smoking, hypertension, diabetes

Answer 538

- HDL cholesterol is protective for risk of atherosclerosis and CHD (promotes reverse cholesterol transport) -\> lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD - HDL cholesterol tends to be low when triglycerides are high

Answer 539

- HDL cholesterol is lowered by smoking, obesity and physical inactivity

Answer 540

o act on the mevalonate pathway to inhibit HMG-CoA reductase - mevalonate pathway produces cholesterol as well as geranyl pyrophosphate and faeresyl pyrophospahe -\> are extremely important in the cell function -\> involved in the modification and activation of proteins - cell can't function properly without these lipids but it can function properly without cholesterol -\> cell must make these small lipids itself - by blocking cholesterol synthesis in the liver then the liver cells respond by making more LDL receptors -\> bind to circulating LDL and lower it

Answer 541

regards statins -\> doubling the dose of any of the statins, only achieves a 6% reduction in LDL cholesterol - applies to all statins and all doses -\> effectiveness of statin treatment depends on the level of cholesterol that you achieve

Answer 542

- effects that are not directly related to the reduction in cholesterol

Answer 543

- less platelet activation - lower thrombotic effect - increase plaque stability - reduced vascular inflammation - less SMC hypertrophy - reduced endothelial dysfunction - less SMC proliferation - reduced vasoconstriction o some believe statins should be used when people have high CRP

Answer 544

- a lipid lower drug -\> reduce plasma fatty acids and triglycerides - also reduces inflammation

Answer 545

- activation of peroxisome proliferator activated receptors (PPAR) -\> th ealpha receptors in particular

Answer 546

- diabetes with high glycerides

Answer 547

- lowers LDL, it increases HDL, it lowers triglycerides and increases fibrinolytic activity (clot dissolution) -\> everything you could possibly want to lower CVD risk - isn't used very much in clinical practice -\> not well tolerated -\> causes flushing, so it isn’t taken by patients

Answer 548

- inhibits cholesterol absorption - reduce LDL cholesterol a reasonable amount (15-20%) - useful as an additional treatment to statins -\> because of the rule of 6, you want to find something else that can be added to increase the effectiveness of statins at lowering cholesterol without just increasing the dose of the statin -\> ezetimibe decreases LDL further when given with a statin

Answer 549

- had a positive effect in increasing HDL and decreasing LDL -\> however, when they expanded the clinical trial they found that it was ACTUALLY KILLING people - were 'off-target' (could'nt have predicted the effect) ADVERSE effects of torcetrapib (CETP inhibitor) -\> might be due to activation of aldosterone synthesis leading to increased blood pressure

Answer 550

- PCSK9 is an inhibitor of the LDL receptor (breaks down the receptor) so it stops the LDL from reaching the LDL receptor LDLR and PCSK9 gene expression are coinduced by statins As a result, PCSK9 inhibition enhances the lipid-lowering effect statins Monoclonal antibodies are the most advancedPCSK9 inhibitors currently in development

Answer 551

- familial hypercholestroleamia patients

Answer 552

o analgesic properties -\> relief of mild-to-moderate pain (toothache, headache, backache), post-operative pain (opiate sparing so people can take less opiates) and dysmenorrhea (menstrual pain) o anti-pyretic -\> reduction of fever -\> influenza o anti-inflammatory -\> reduction of inflammation -\> Rheumatoid arthritis, osteoarthritis (plus other musculoskeletal inflammation), soft tissue injuries (strains and sprains) and gout

Answer 553

o inhibit COX enzymes -\> inhibits prostanoid synthesis (e.g. prostaglandins, thromboxane, prostacyclin) -\> inhibits inflammatory mediators - none of the factors are stored so NSAID effects are fast

Answer 554

- are 10 known receptors and 5 prostanoids (agonists) - prostanoids have both G protein-dependent & independent effects (not all actions G-protein mediated) -\> effects are extremely complex - side effects are both physiological and pro-inflammatory

Answer 555

- a prostanoid - can activate EP1, EP2, EP3 and EP4 -\> causes G-protein (cAMP dependent and independent downstream actions)

Answer 556

- increased pain perception - increased body temperature - acute inflammatory response - immune responses – both positive and negative - tumorigenesis - inhibition of apoptosis

Answer 557

- greater activation of P2X3 receptors - EP1 receptors and EP4 receptors (EP4 in periphery and spine) - endocannabinoids (neuromodulators in thalamus, spine and periphery) - decreasing beta-endorphin in spine o not mutually exclusive

Answer 558

- stimulates hypothalamic neurones initiating a rise in body temperature

Answer 559

- VERY complex process involving PGE₂-EP3 signalling - EP3 works through multiple mechanism

Answer 560

- bronchodilation - renal salt and water homeostasis - gastro-protection - vaso-regulation (dilation and constriction depending on receptor activated)

Answer 561

- COX inhibition favours leukotrienes production -\> these cause bronchoconstriction -\> worsening of asthma symptoms

Answer 562

- PGE₂ = involved in increasing renal blood flow - COX 1 and 2 are involved in the production of products at multiple points in the nephron

Answer 563

- constriction of afferent renal arteriole - reduction in renal artery flow - reduced glomerular filtration rate

Answer 564

- down-regulates HCl secretion -\> reduces irritaion - stimulates mucus and bicarbonate secretion -\> increases production of protective layer

Answer 565

- increased gastric and duodenal ulceration -\> high load on the stomach when taken orally

Answer 566

o vasoconstriction o salt and water retention o reduce the effects of anti-hypertensive drugs - becoming acknowledged that use of NSAIDs poses a risk of hypertension, MI and stroke

Answer 567

- they do lower stomach and duodenal ulceration massively -\> however, pose a higher risk of CVD

Answer 568

- analgesic use -\> usually occasional and relatively low risk of side effects - anti-inflammatory use -\> often sustained, higher doses and relatively high risk of side effects

Answer 569

- topical application - minimise NSAID use in patients with history of GI ulceration and treat H pylori if present (trigger factor for ulcers) - if NSAIDs are essential administer with omeprazole or other proton pump inhibitor - minimise NSAID use in patients with other risk factors and reduce risk factors where possible -\> e.g. alcohol consumption or anticoagulant or glucocorticoid steroid use

Answer 570

o irreversibly binds to COX-1 enzymes - works by acetylating active sites of both COX enzymes -\> mainly COX-1

Answer 571

- inhibits thromboxane (made by COX-1) more than PGI₂ (made by COX-1 and 2) - platelts can't make more thromboxane as they don't have a nucleus -\> required to make more enzymes as others are permenantly inhibited - reduced platelet aggregation

Answer 572

- low dose = platelets do not have a nucleus -\> NO RE-SYNTHESIS of COX-1 in platelets à OVERALL REDUCED AGGREGATION OF PLATELETS - high dose = BARELY ANY ACTION ON PLATELET AGGREGATION -\> endothelial cell COS enzymes will be in a permanent state of inhibition

Answer 573

- gastric irritation and ulceration - bronchospasm in sensitive asthmatics - prolonged bleeding times - nephrotoxicity - side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1

Answer 574

- probably central AND peripheral mechanism - could be COX-3, cannabinoid receptors, endogenous opioids interaction, 5HT and adenosine receptor interaction

Answer 575

o overdose can cause irreversible liver failure - paracetamol is normally metabolised by the cytochrome P450 complex - its metabolsim produces a toxic metabolite (NAPQI), which is highly reactive/electrophile -\>at a therapeutic doset the NAPQI is produced is very small amounts and will be mopped up by glutathione - if glutathione is depleted (saturated with NAPQI) the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death

Answer 576

- compounds with thiol groups -\> usually intravenous acetylcysteine, occasionally oral methionine - if done early it can prevent liver damage

Answer 577

- e -\> thromboxanes causes platelet aggregation, but not much else

Answer 578

- e -\> assertion false, reason false - synthesis of PGI2 (prostacyclin) is inhibited by low dose aspirin, but it is not this action which decreases the risk of stroke -\> PGI2 actually reduces platelet aggregation -\> stroke risk decrease is due to the inhibition of thromboxane synthesis

Answer 579

- opiate = an alkaloid derived from the opium poppy - opioid = anything that has opiate like function, commonly synthetic

Answer 580

- morphine - codeine - thebaine - papaverine

Answer 581

- tertiary nitrogen = analgesia by permits receptor anchoring -\> extending the side chain to 3+ carbons generates an antagonist - tertiary nitrogen allows the molecule to bind the receptor by giving it affinity and permits receptor anchoring -\> side chain attached to the nitrogen determines the efficacy - 2 alcohol groups have a role in binding -\> not as much as the tertiary nitrogen

Answer 582

- heroin = **diacetyl**morphine - codeine = **methyl**morphine

Answer 583

- they are both prodrugs of morphine which have increased lipid solubility - codeine -\> morphine occurs outside the brain - heroin -\> morphine occurs inside the brain

Answer 584

- orally - IV

Answer 585

- opioids are weak bases -\> pKa \> 8 -\> will be very ionised in the stomach -\> poor absorption - once they enter the small intestines, they are well absorbed - opioids are heavily metabolised in the liver (first pass) -\> this impacts their bioavailability -\> all of the above are missed by giving via IV - pH of the blood is around 7.4, opioids are largely ionised in the blood (80%) -\> only 20% of opioids remain unionised -\> unionised form accesses tissues readily because it is more lipophilic

Answer 586

o more lipid soluble = more potent - exception to this is codeine

Answer 587

- morphine produces active metabolites -\> morphine-6-glucoronide is the most potent active metabolite of morphine (10% of the blood levels of morphine at any one time) -\> active metabolites are less likely to cause the negative (e.g. repsiratory depression) than morphine -\> individuals who don’t metabolise morphine very well are more likely to have negative side effects

Answer 588

- cleared very slowly -\> is very lipid soluble so builds up in fatty tissue - effects therefore last long so it isnt as addictive

Answer 589

- codeine is metabolised by two cytochrome P450 enzymes o one enzyme activates codeine (CYP2D6) to morphine -\> 5-10% of the codeine is converted via this route o the other enzyme (CYP3A4) deactivates codeine o poor metabolism -\> codeien has little effect - is a very common polymorphisms in CYP2D6 enzyme -\> people may have good metabolism of codeine -\> more powerful effect (more morphine)

Answer 590

- opioid receptors

Answer 591

- endorphins - enkephalins - dynorphins/neoendorphins

Answer 592

- Mu - delta - kappa

Answer 593

- are acted on by endorphins, heroin and morphine - loacted in the in the cerebellum, caudate nucleus, nucleus accumbens and PAG - important in pain and sensation

Answer 594

- are acted on by enkephalins - located in the nucleus accumbens, cerebral cortex, hippocampus and putamen - important in motor and cognitive function

Answer 595

- acted on by dynorphins/neoendorphins - located in the hypothalamus, putamen and caudate - important neuroendocrine role (via the hypothalamus)

Answer 596

- depressants

Answer 597

- hyperpolarise cells -\> hyperpolarisation (increase K+ efflux) -\> nerves can’t fire - reduce the Ca²⁺ inward current -\>massively impacts exocytosis and NT release - decrease adenylate cyclase activity within the cell

Answer 598

- analgesia - euphoria - depression of cough centre (anti-tussive) * - depression of respiration (medulla)* * - stimulation of chemoreceptor trigger zone (nausea/vomiting)* * - pupillary constriction* * - GI effects* * (italics = side effects)*

Answer 599

- pain is sensed peripherally, and is recognised by sensory neurones -\> relay this information to the spinal cord -\> spinothalamic neurones relay this information to the thalamus -\> doesn’t process the information, but it directs it to the cortex - thalamus also directly activates the descending pain tolerance pathway -\> simultaneously, the cortex has an additional impact on the pain tolerance pathway - the PAG region is the integrating centre for the pain tolerance pathway -\> receives all information and determines output, it relays to the NRM (effector arm) * - thalamus switches the PAG on automatically -\> not long after, the cortex modulates this signal* - the NRM, descending neurones leave to suppress the feelings of pain that are reaching the brain - the NRPG is an auto-feedback element of the brain -\> is away of switching on pain tolerance without any higher centre functioning at all -\> isn't as powerful as PAG, but is still an important * - most of the information goes to the thalamus, but some filters through the NRPG and automatically switches on pain tolerance*

Answer 600

- activates the descending pain tolerance pathway -\> called PAG - directs information to the cortex

Answer 601

- effector arm of the PAG

Answer 602

- auto-feedback element of the brain -\> can switch on pain tolerance without higher centre involvement

Answer 603

- hypothalamus constantly gives information to the rest of the brain about current state of health - in a poorer state of health, you are likely to be more sensitive to pain -\> want sick people to be in pain so that they don’t expend their energy doing activities

Answer 604

- is the sympathetic nervous system effector -\> is largely independent of the analgesia system - if your stress pathway is activated, the LC is active -\> automatic signal to dampen down pain - when you injure yourself playing sport, it doesn’t hurt very much at the moment in time -\> makes sense in terms of flight or fight - if the SNS is active it **suppresses** pain information from the periphery to the brain

Answer 605

- certain amount of signal comes down and reaches the dorsal horn, to suppress information moving from periphery to brain - substantia gelatinosa is a mini brain in the spinal cord -\> processing and modification of the signal takes place

Answer 606

- act in the dorsal horn to prevent information relay from periphery to the spinothalamic tract (DEPRESSANT) - also act in the NRPG, PAg and NRM pathways -\> mechanism here is disinhibition (i.e. switching off GABA) -\> suppress the normal inhibitory signal in the pink regions -\> more pain tolerance

Answer 607

- opioids enter the brain and bind to their receptors -\> depress the firing rate of GABA interneurons (much like cannabis) - means less inhibition on dopaminergic neurone -\> increases its firing rate -\> increased dopamine secretion into the nucleus accumbens -\> feelings of reward - it is this mechanism that gives you a high after exercise

Answer 608

o ACh and neurokinin (NK) are the two NTs involved in coughing -\> C-fibres send information up to the cough centre, via the vagus nerve o 5-HT1A receptors are important -\> have negative feedback receptors for serotonin -\> serotonin is anti-cough o opioids decrease the firing rate of C-fibres -\> less information relay to the brain from irritation in the airways - also act in the cough centre, with a direct depressant effect on the cough centre, and inhibit 5-HT1A feedback receptors -\> opioids prevent the 5-HT1A receptors from activating -\> more serotonin available in the cough centre (anti-cough effect)

Answer 609

- 2 important aspects of respiratory rhythm generation: central chemoreceptors and the Pre-Botzinger complex - central chemoreceptors are sensing the blood for carbon dioxide -\> information is relayed to the medullary control centre -\> provides a tonic drive (what level of respiration needed) - Pre-Botzinger complex is required for breathing within the medulla -\> particularly inspiration - opioids inhibit both the chemoreceptors and the pre-Botzinger complex -\> seen in overdose -\> what kills people

Answer 610

- via a direct effect at the chemoreceptor trigger zone - GABA keeps the CTZ suppressed -\> opioids switch this inhibition off -\> CTZ signals to the medullary vomiting centre, and you feel nauseous

Answer 611

- excessive constriction of the pupil

Answer 612

- opioid receptors are expressed in the Edinger-Westphal nucleus and therefore influence miosis - optic nerve is the sensory nerve that relays information to the pretectal nucleus -\> signals are transmitted to parasympathetic nerves in the EWN -\> opioids can influence the parasympathetic nerves here -\> GABA suppress the parasympathetic nerves -\> opioids switch inhibition off -\> miosis

Answer 613

- an opioid -\> heroin - normally when passed out pupils dilate due to lower brain activity but not with opioids

Answer 614

- opioid receptors everywhere within the enteric nervous system - opioids activation leads to less motility and fewer secretions

Answer 615

- is NOT an allergic response - results from a direct interaction of opioids with mast cells -\> causes histamine release -\> seems to involve PKA, and doesn’t seem to involve opioid receptors - is caused by morphine and codeine mainly due to an OH in carbon position 6

Answer 616

- nothing to do with the liver and pharmacokinetics - comes about at the level of tissues -\> RECEPTOR INTERNALISATION - arrestin is a very important protein in terms of driving receptor internalisation -\> constant recycling - if opioids are constantly available, cells are suppressed -\> opioid receptors are withdrawn from the cell -\> arrestin protein concentration increases -\> increased internalisation -\> TOLERANCE

Answer 617

- withdrawal is associated with psychological craving and also physical withdrawal (flu-like) - cells try to upregulate activity to compensate for the opioids (increase in adenylate cyclase) -\> once opioids are removed, adenylate cyclase is overactive

Answer 618

- coma - respiratory depression - pin-point pupils - hypotension

Answer 619

- naloxene -\> is an opioid antagonist - has 3 carbons chain on the tertiary nitrogen

Answer 620

o ulcerative colitis o Crohn's disease - 10% are indeterminate - features of both

Answer 621

o genetics - \> 201 loci identified - \> white, western europeans seem the most susceptible o environmental -\> most important are smoking, diet and microbiome

Answer 622

- Th1-mediated e.g. IFN-gamma, TNF-alpha, IL-17, IL-23 - florid T cell expansion - defective T cell apoptosis

Answer 623

- Th2- mediated .g. IL-5, IL-13 - limited clonal expansion - normal T cell apoptosis

Answer 624

- Crohn's = all layers - ulcerative colitis = mucosa and submucosa

Answer 625

- Crohn's = any part of the GI - ulcerative colitis = rectum, spreading proximally

Answer 626

- Crohn's = patchy - ulcerative colitis = continuous

Answer 627

- Crohn's = common - ulcerative colitis = not common

Answer 628

- Crohn's = not always - ulcerative colitis = curative

Answer 629

- ulcers - diarrhoea - abdominal pain - fevers - excessive sweating - anaemia - arthritis - weight loss - skin rashes o *doesn't just affect the gut*

Answer 630

- aminosalicylates -\> e.g. mesalazine, olsalazine - glucocorticoids -\> e.g. Prednisolone - immunosuppressive agents -\> e.g. Azathioprine

Answer 631

- olsalazine ( 2 linked 5-ASA) has to be activated/metabolised by the gut flora -\> so only works in the colon -\> if this is where the inflammation is most serious, it is better - mesalazine will be absorbed all the way through the gut

Answer 632

1. absorbed in the gut and is metabolised in to N-acetyl 5-ASA by NAT-1 2. N-acetyl 5-ASA binds to PPAR*y* -\> this triggers the formation of a transcription regulator (includes N-acetyl 5-ASA and PPAR*y*) 3. this downregulates inflammatory factors such as NF-KB/MAPK (less pro-inflammatory cytokines) and COX-2 (less prostaglandins)

Answer 633

- first line for both inducing and maintaining remission -\> probably better than glucocorticoids

Answer 634

- literature is unclear - is ineffective in inducing remission in Crohn’s - gGlucocorticoids are probably better in Crohn’s - may be effective in a subgroup of patients

Answer 635

- prednisolone - fluticasone - budesonide

Answer 636

- glucocorticoids act at multiple points in the inflammation seen in bowel disease - can inhibit the production of IL-1 and TNF-alpha by dendritic cells. Dendritic cells are thought to have an important role in IBD - are very potent anti-inflammatory and immunosuppressive actions of GCs -\> when given systemically, chronic glucocorticoid administration causes many unwanted effects

Answer 637

- hypertension - diabetes - osteoporosis - reactivation of infection (due to immunosuppression) - easy bruising - poor wound healing - thin skin o *similar to the symptoms of Cushing's*

Answer 638

- topically administer glucocorticoid: fluid, foam enemas, suppositories and oral preparations - use a lower dose in combination with another drug (e.g. 5-ASA and glucocorticoids) - use an oral or topically administered drug with high hepatic first pass metabolism -\> e.g. Budesonide -\> little escapes into the systemic circulation

Answer 639

- more side effects when we treat someone with prednisolone, compared to when we treat someone with budesonide -\> problem with this is that the standard glucocorticoid (prednisolone) is actually BETTER than budesonide at inducing remission in active Crohn’s

Answer 640

- use of glucocorticoids is in decline, due to evidence that aminosalicylates are superior - are best avoided due to their side effects

Answer 641

- remain the drugs of choice for inducing remission in Crohn’s -\> budesonide is preferred if the disease is mild - patients are likely to get side effects if GCs are used to maintain remission (long-term use)

Answer 642

- a pro-drug that has to be activated by the gut flora to 6-mercaptopurine -\> can give 6-mercaptopurine directly - is a purine antagonist, and is therefore immunosuppressive

Answer 643

- metabolised into 6-MeMPN -\> inhibits de novo purine synthesis - metabolised into TGN -\> acts as a flase purine molecule o INTEREFERES WITH DNA SYNTHESIS AND CELL PROLIFERATION

Answer 644

o impairs - \> cell-mediated and antibody-mediated immune responses - \> lymphocyte proliferation - \> mononuclear cell infiltration - \> synthesis of antibodies o enhances - T cell apoptosis due to increased damage to the cells

Answer 645

- used with some success in ulcerative colitis -\> but there is no real reason to use it if the response is good with 5-ASA

Answer 646

- has no benefit at all in active disease -\> mainly used to maintain remission - Cochrane review shows it be glucocorticoid-sparing (co-administered to reduce steroid dose) - has a slow onset -. 3 to 4 months treatment for clinical benefit to be observed

Answer 647

- pancreatitis - bone marrow suppression hepatotoxicity - increased risk (around 4-fold) of lymphoma and skin cancers o nearly 10% of patients have to stop it due to side effects

Answer 648

- nutrition-based therapies - faecal microbiota replacement therapies - antibiotic treatment with rifaximin

Answer 649

- no evidence for probiotics in food stuffs have any impact at all in Crohn’s disease - some evidence for probiotics for maintenance of remission in Ulcerative Colitis - probiotics are as effective as 5-ASA in inducing and sustaining remission in ulcerative colitis

Answer 650

- re-populating a patient’s bowel with healthy gut flora may solve the problem - insufficient evidence for FMT-\> but 2 out of 3 RCTs showed benefit in UC -\> more studies are needed

Answer 651

- interferes with bacterial transcription by binding to RNA polymerase - induces and sustains remission in moderate Crohn’s disease - may be beneficial in ulcerative colitis too

Answer 652

- are now a number of drugs that have been approved for use in IBD -\> include anti-TNF alpha antibodies e.g. infliximab (iv) - other antibodies are effective, but some have more side-effects - new humanised antibodies are coming -\> e.g. entanacept, which may have fewer side effects

Answer 653

- anti-TNF alpha reduces activation of TNF a receptors in the gut -\> reduces downstream inflammatory events - also binds to membrane associated TNF alpha -\> induces cytolysis of cells expressing TNF alpha - promotes apoptosis of activated T cells

Answer 654

- infliximab is given intravenously and has a very long half-life (9.5 days) - most patients relapse after 8–12 weeks, therefore the infusion needs to be repeated every 8 weeks

Answer 655

- has been used successfully in the treatment of Crohn’s disease - 60% of patients respond within 6 weeks -\> don't understand the underlying pathology - potentially curative -\> but many patients relapse with this treatment - successful in some patients with refractory disease and fistulae -\> great for maintaining fistula closure o no effect on ulcerative colitis -\> expected as it Th-2 driven

Answer 656

- emerging evidence that up to 50% lose response within 3 years time -\> this is after only 60% responding to it -\> due to production of anti-drug antibodies and increased drug clearance

Answer 657

- 4-5x increase in incidence of tuberculosis -\> also a risk of reactivating dormant TB - increased risk of septicaemia - worsening of heart failure - increased risk of demyelinating disease (e.g. multiple sclerosis) - increased risk of malignancy - can be immunogenic -\> azathioprine reduces risk, but raises the risk of tuberculosis and malignancy

Answer 658

- early use is better than using it as a last resort - combined infliximab and azathioprine therapy may be more effective than the antibody alone

Answer 659

o permeable to water -\> can move across the tubule cells quite easily - throughout the kidney is an osmotic force, which tends to draw water out of the lumen, across into the blood -\> glomerulus filters protein-free fluid but blood has LOTS of plasma proteins o quite permeable to sodium - Na-K-ATPase channels are on the basal side of the cell -\> works to retain the concentration gradient for sodium -\> if sodium diffuses into the cell on the apical side, it needs to be removed on the other side to maintain a concentration gradient o no HCO₃^- channels -\> H⁺ actively pumped out of cell by H+-ATPase -\> H⁺ + HCO₃^- = carbonic acid -\> carbonic acid -\> CO₂ + water -\> CO₂ diffuses in and reforms H₂CO₃^- befores it dissociates into HCO₃^- - don’t want H⁺ to accumulate -\> Na-H-exchanger antiporter on membrane -\> lots of Na reabsorbed in PCT so this is useful (Na also reabsorbed with glucose) - HCO₃^- exchanges out with Cl^- via the bicarbonate/Cl^- exchangers into blood o lots of movement of amino acids and glucose across the cell, into the blood -\> always coupled with sodium o glucoronidation in phase II metabolism -\> special transporters recognise the side chains and functional groups revealed in phase I metabolism -\> kidney then moves the drug molecule into the lumen of the kidney for excretion in the urine

Answer 660

o descending limb - highly permeable to water -\> cells have loose tight junctions - not many mitochondria -\> don’t pump ions o ascending limb - Na⁺ and Cl^- are pumped out - very tight junctions -\> impermeable to water - lots of mitochondria -\> very high metabolic activity o CREATES THE HEAVILY CONCENTREATED INTERSTITIAL SPACE FOR MATER REABSORPTION IN THE LoH, DCT and CD -\> **COUNTERCURRENT MECHANISM**

Answer 661

- Na-Cl transported on the tubular side (apical membrane) -\> on the basal membrane is the Na-K-ATPase (ensures that the concentration gradient is maintained and that Na is reabsorbed into the blood) - potassium and chloride transporters are also present on the basal side.

Answer 662

o major hormones influencing the collecting duct are aldosterone and vasopressin - aldosterone is a mineralocorticoid -\> binds to the MR receptor and influences nuclear transcription -\> increases transcription of Na channels and Na-K-ATPase - vasopressin interacts with the V2 receptor, and sticks aquaporin channels into the apical membrane -\> provides a mechanism for water to move across the cell

Answer 663

o steroid hormone -\> diffuses into cell and binds with steroid hormone intracellular receptors bound to chaperone proteins -\> chaperone protein released from receptor -\> dimerization of steroid hormone-receptor complexes -\> enters nucleus -\> transcription of gene for Na-K-ATPase -\> increased capacity to reabsorb sodium

Answer 664

- an autosomal dominant inherited disease of high bp - mutation in tha aldosterone activated sodium channel -\> always switched on -\> Na⁺ retention is increased -\> hypertension

Answer 665

- work by inhibiting the reabsorption of Na and Cl (i.e. increase excretion of Na and Cl) -\> losing more ions to the urine means that water will follow - increase the osmolarity of the tubular fluid -\> i.e. decrease the osmotic gradient across the epithelia

Answer 666

1. osmotic diuretics -\> e.g. mannitol 2. carbonic anhydrase inhibitors -\> e.g. acetazolamide 3. loop diuretics -\> e.g. frusemide (furosemide) 4. thiazides -\> e.g. bendrofluazide (bendroflumethiazide) 5. potassium sparing diuretics -\> e.g. amiloride, spironolactone

Answer 667

- acts throughout the kidney - filtered by the glomerulus but NOT reabsorbed -\> are pharmacologically inert -\> increases the osmolarity of the tubular fluid -\> less water leaves becuase of a lower osmotic drive so more is excreted - no action on Na reabsorption

Answer 668

- pulmonary oedema - cerebral oedema

Answer 669

- acetazolamide acts in the proximal tubule - inhibits both versions of the enzyme, apical membrane bound and cytoplasmic enzyme -\> bicarbonate and hydrogen aren’t converted to carbon dioxide and water effectively - little CO2 and water that gets in won’t be converted back to bicarbonate and hydrogen ions -\> less hydrogen ions means that there is less Na-H exchange at the apical membrane -\> less Na enters the cells and is reabsorbed, so less water follows via osmosis -\> more water excreted

Answer 670

- osmotic diuretics - carbonic anhydrase inhibitors

Answer 671

- loop diuretics -\> can increases water excretion by 30%

Answer 672

- ascending loop of Henle -\> targeting the triple transporter

Answer 673

- prevent Na from moving across the cell, and into the interstitium -\> impacts the counter-current effect -\> Na reabsorption is massively impaired - in the PCT and LoH, there is something called potassium recycling -\> potassium is constantly being reabsorbed and lost-\> constant movement of potassium replenishes a certain amount of positive charge to the lumen -\> there is repulsion within the tubule -\> if potassium recycling is interfered with potassium movement is reduced and the excess positive charge is diminished -\> less Ca, Mg and Na move through this paracellular route -\> lower interstitial concentration -\> less osmotic movement

Answer 674

- potassium is constantly being reabsorbed and lost-\> constant movement of potassium replenishes a certain amount of positive charge to the lumen -\> there is repulsion within the tubule -\> if potassium recycling is interfered with potassium movement is reduced and the excess positive charge is diminished -\> less Ca, Mg and Na move through this paracellular route

Answer 675

- increased water excretion - increased potassium loss - decrease reabsorption of calcium and magnesium

Answer 676

- hypokalaemia - hyponatraemia - hypovolaemia - metabolic alkalosis - hyperuricaemia - hypotension

Answer 677

- target the apical side -\> act on Na-Cl transport in the distal tubule -\> has its effect as it is being excreted - further along the kidney you get, the less powerful the diuretic effect becomes -\> because there is less fluid and less sodium to impact -\> maximum of 5-10% Na and water loss o action on Na⁺ reabsorption -\> inhibit Na⁺ and Cl^- reabsorption in early distil tubule o action on water reabsorption -\> increased tubular fluid osmolarity = decreased H₂O reabsorption in the collecting duct

Answer 678

- increased water excretion - increased sodium delivery to distal tubule -\> increased potassium loss (same as loop diuretics) - increased magnesium loss - increased calcium reabsorption

Answer 679

- effect the renin secretion - over time, patients suffer a degree of hyponatraemia (due to Na loss) -\> because low Na concentration in the kidney stimulates renin secretion - diuretics cause a lower sodium load to pass through the lumen, which stimulates renin secretion -\> over time diuretics tend to directly promote renin secretion -\> NOT HELPFUL because renin increases aldosterone, which promotes reabsorption - often, diuretics are given WITH ACE inhibitors, to reduce the effect - in the case of loop diuretics, they influence renin secretion indirectly (through hyponatraemia) and directly (blocking the triple transporter)

Answer 680

- aldosterone receptor antagonists -\> e.g. spironolactone - inhibitors of aldosterone-sensitive sodium channels -\> e.g. amiloride

Answer 681

- are MR inhibitors -\> decreases the ability of aldosterone to produce Na channels and Na-K-ATPase - increased tubular fluid osmolarity = less water reabsorption in the CD

Answer 682

- Na blocking drug -\> prevents Na from getting into the cell in the first place - increased tubular fluid osmolarity = less water reabsorption in the CD

Answer 683

- potassium sparing -\> only effect the CD and DCT where there isn't much sodium

Answer 684

o action on Na reabsorption: Inhibit Na reabsorption (and concomitant K⁺ secretion) in DCT -\> 5% o action on water reabsorption: tubular fluid osmolarity = decreased H₂O reabsorption in the collecting duct - other effects: decreased reabsorption Na⁺ to distal tubule and increased H⁺ retention (deacreased Na⁺/H⁺ exchange)

Answer 685

- hyperkalaemia

Answer 686

- hypokalaemia - hyponatraemia - hypovolaemia - metabolic alkalosis - hyperuricaemia - hypotension

Answer 687

- diuretics directly affect the transporter that moves uric acid into the lumen - there is a transporter on the basal side of kidney cells that exchanges organic ions with uric acid -\> diuretics compete for and interfere with this protein -\> less exchange occurs, leading to less uric acid moving into the cell and tubule from the blood -\> uric acid builds up in the blood -\> can be associated with gout

Answer 688

o oedema o heart failure o thiazides are first line treatments for hypertension in Afro-Caribbean people and anyone over 55 years -\> tend to have salt sensitive hypertension which is associated with low renin -\> no point giving them ACE inhibitors - thiazides promots fluid loss and reduce bp

Answer 689

o initial response is good (4-6 weeks) -\> due to decreased plasma volume -\> but, after 4-6 weeks, the plasma volume is restored = diuretic effect is lost o thiazides chronic use = VASODILATORY EFFECT - decreased T.P.R., activation of eNOS (endothelium) - Ca²⁺ channel antagonism - opening of K_Ca channel (smooth muscle)

Answer 690

- acute = within 1 hour - sub-actue = 1-24 hours - latent = more than 2 days

Answer 691

- mild = noticed but requires no change in therapy - moderate = requires a change in therapy, may require additional treatment, and possibly hospitalisation - severe = disabling, life-threatening, or ones that cause damage to the foetus

Answer 692

- Type A: Augmented pharmacological effect - Type B: Bizarre - Type C: Chronic - Type D: Delayed - Type E: End-of-treatment

Answer 693

- reaction is often an extension of the pharmacologic effect of the drug that we already know about -\> therefore usually predictable and often dose dependent - responsible for at least two-thirds of ADRs - can either have a linear increase in toxicity (digoxin) or can have a tipping point which once over can have detrimental effect (paracetamol)

Answer 694

- tend to be more dramatic and are less understood - are idiosyncratic (particular to given individuals) or immunologic reactions -\> include allergy and “pseudo-allergy” - are rare and unpredictable - exampels are chloramphenicol and aplastic anemia or ACEi and angioedema (pseudo-allergy)

Answer 695

- are associated with long-term use of drugs -\> involve dose accumulation (total dose someone’s exposed to over a period of time) - examples are methotrexate (used in chemotherapy and as an immunosuppressant) and liver fibrosis or anti-malarial drugs and ocular toxicity

Answer 696

- often have delayed effects and are not strongly linked to dose - may happen at low dose - include carcinogenicity due to immunosuppressants or teratogenicity because of thalidomide

Answer 697

- withdrawal reactions = opiates, benzodiazepines, corticosteroids - rebound reactions = clonidine, beta-blockers, corticosteroids - “adaptive” reactions = neuroleptics (major tranquillisers)

Answer 698

o clonidine used to be used as an anti-hypertensive o is an alpha 2 agonist, so it reduces the release of noradrenaline from sympathetic neurones -\> reduction in sympathetic outflow leads to a drop in bp - missing one or two doses of clonidine, can lead to a substantial RISE in blood pressure -\> long-term use of clonidine causes long-term suppression of peripheral noradrenaline production, which, in turn, leads to a compensatory upregulation in adrenergic receptors on the post-synaptic neurone -\> this upregulation in receptors means that when the inhibition of NA release by clonidine is removed, NA starts being produced again and has more receptors to act on and can cause a much great effect =HUGE RISE IN BLOOD PRESSURE o isn't used an more because there are plenty of other anti-hypertensives

Answer 699

- Type I -\> immediate, anaphylactic (IgE) -\> e.g. anaphylaxis with penicillin - Type II -\> cytotoxic antibody (IgG, IgM) -\> e.g. methyldopa and hemolytic anemia - Type III -\> serum sickness (IgG, IgM) antigen-antibody complex -\> e.g. procainamide-induced lupus - Type IV -\> delayed hypersensitivity (T cell) -\> e.g. contact dermatitis

Answer 700

- a condition which presents like an allergy but is pharmacologically mediated instead of immunologically

Answer 701

- 5% of people who take these drugs get bronchospasm - aspirin inhibits COX enzymes -\> a reduction in prostanoid/prostaglandin synthesis (bronchodilators) - instead, the body makes more leukotrienes which are pro-inflammatory and bronchoconstrictors

Answer 702

o 10-20% of people taking ACE inhibitors suffer from a chronic, dry cough - due to accumulation of inflammatory peptides (e.g. bradykinin) in the lung -\> bradykinin triggers cough through sensory receptors in the lung o in 1-5% of people taking the drug, people may suffer from angioedema - angioedema = has many of the same signs and symptoms of anaphylaxis, but much less severe

Answer 703

- antibiotics - anti-neoplastic drugs - anticoagulants - cardiovascular drugs - hypoglycemic drugs - anti-hypertensive drugs - NSAID/analgesics - CNS drugs

Answer 704

o subjective report -\> e.g. patient complaint o objective report -\> direct observation of events and abnormal findings - physical examination - laboratory test - diagnostic procedure

Answer 705

- a public way of detecting adverse reactions, which was introduced in 1964 after thalidomide -\> before which there was NO SYSTEM of checking whether drugs that were marketed were effective or safe o ADR suspected -\> ADR confirmed (high probability) -\> frequency estimated -\> prescribers informed

Answer 706

- pharmacodynamic interactions = related to the drug’s effects in the body -\> receptor site occupancy - pharmacokinetic interactions = related to the body’s effects on the drug -\> due to absorption, distribution, metabolism and elimination (ADME) - pharmaceutical interactions = drugs interacting outside the body -\> most commonly found with IV infusions

Answer 707

- additive -\> put two drugs together, they produce an effect that is the sum of the drugs -\> overlapping toxicities e.g. ethanol & benzodiazepines - synergistic actions of antibiotics -\> two drugs potentiate each others’ actions to get a greater effect than expected - antagonistic effects -\> drugs that antagonise each others’ actions e.g. anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)

Answer 708

o chelation -\> irreversible binding of drugs in the GI tract - tetracyclines and quinolone antibiotics can be involved in chelation with ferrous sulfate (Fe²⁺), antacids (Al³⁺, Ca²⁺, Mg²⁺) and dairy products (Ca²⁺) - form a stable chelate -\> don’t absorb the mineral ion or the antibiotic

Answer 709

- competition between drugs for protein or tissue binding sites increases free (unbound) concentration due to displacement -\> enhanced pharmacological effect - PB interactions are not usually clinically significant -\> warfarin is an exception -\> is very tightly bound to proteins, so even displacing a small amount can have drastic effects

Answer 710

- probenecid and penicillin = good -\> reduces elimination of penicillin -\> makes it last longer - lithium and thiazides = bad -\> thiazides reduce clearance of lithium -\> can lead to fatal toxicity

Answer 711

- pharmacogenetics = study of genetically determined inter-individual differences in therapeutic response to drugs and susceptibility to adverse effects - pharmacogenomics = use of genome-based techniques in drug development

Answer 712

- emotional -\> misery, apathy, pessimism, low self-esteem, loss of motivation, anhedonia (inability to enjoy pleasureable activities) - biological -\> slowing of thought and action, loss of libido, loss of appetite, sleep disturbance

Answer 713

- unipolar - bipolar

Answer 714

o mood swings are in same direction -\> feel down o relatively late onset (adulthood) o can be split into reactive depression (75%) and endogenous depression (25%) - reactive depression: depression in response to stressful life events, that is non-familial - endogenous depression: depression that is unrelated to external stresses, with a familial pattern o drug treatment -\> is the same treatment for reactive and endogenous

Answer 715

- depression in response to stressful life events - is non-familial/inherited - 75% of unipolar depression

Answer 716

- depression that is unrelated to external stresses - has a familial/inheritable pattern - 25% of unipolar depression

Answer 717

- oscillating depression and mania (hyper-excitability with symptoms opposite to depression) - less common than unipolar depression - tends to have an early adult onset - a strong hereditary tendency

Answer 718

- lithium -\> not a conventional anti-depressant -\> more of a mood stabilising drug

Answer 719

- depression = a functional deficit of central monoamine transmission - mania = a functional excess of central monoamine transmission - this hypothesis is based on pharmacological evidence, but the biochemical evidence inconsistent

Answer 720

- noradrenaline - serotonin/5-HT

Answer 721

- several weeks - with anti-depressants there is a down-regulation of a2, beta and 5-HT receptors (monoamine receptors)

Answer 722

- blocks NA and 5-HT re-uptake - positive effect on mood

Answer 723

- increases stores of NA and 5-HT - positive effect on mood

Answer 724

- inhibits NA and 5-HT storage - negative effect on mood

Answer 725

- inhibits NA synthesis - negative effect on mood

Answer 726

- inhibits NA synthesis - negative effect on mood

Answer 727

- increases CNS responses to NA and 5-HT - positive effect on mood

Answer 728

- have 2 main chemical groups -\> deibenzazepines and dibenzcycloheptenes - all have a 3 ring structure

Answer 729

o are neuronal monoamine re-uptake inhibitors o prevents NA and 5-HT uptake much more so than dopamine - other receptor actions on α2 receptors, muscarinic AchRs, histamine receptors and 5-HT receptors -\> some of these are important to the action of TCA other contribute to the side effects of TCAs - alpha 2 receptors -\> if TCAs bind to and antagonise these receptors, they enhance the release of NA, block the inhibitory control over NA, and allow a greater increase of NA into the synaptic cleft - is a delayed down-regulation of β-adrenoceptors & 5-HT2 receptors

Answer 730

- rapid oral absorption - highly plasma protein bound (90 – 95% of TCAs are PPB) -\> important in terms of interactions - have hepatic metabolism -\> TCAs are metabolised in the liver and generates active metabolites which are weaker but still functioning - undergo renal excretion (as glucuronide conjugates) - plasma t1/2 = 10-20 hours -\> relatively long half life, so can be given once a day due to the long duration of action

Answer 731

- atropine-like effects -\> dry mouth, blurred vision, constipation, urinary retention -\> amitriptyline seems to have more muscarinic antagonist activity than some of the other TCAs so it is worse with it - postural hypotension (mediated through the vasomotor centre) -\> is a CENTRAL EFFECT - sedation (TCAs cause H1 antagonism) -\> patients feel drowsy during the day -\> many depressed patients have trouble sleeping, so this can be taken advantage of -\> ask the patient to take the TCA just before bed

Answer 732

- CNS -\>: excitement, delirium, seizures -\> coma and respiratory depression - CVS -\> cardiac dysrhythmias -\> ventricular fibrillation and sudden death - TCAs that are muscarinic antagonists also affect vagal input to the heart o MUST BE HANDLED WITH CARE -\> commonly utilised in attempted suicide

Answer 733

o many exist - increased TCA effects when co-administration with aspirin and phenytoin (anti-convulsant) - warfarin can displace TCAs from their binding sites -\> moves plasma levels of TCA into a toxic range - hepatic microsomal enzymes metabolise TCAs, so TCA effects increase if co-administered with drugs that are metabolised by the same enzyme system -\> e.g. neuroleptics and oral contraceptives - potentiation of CNS depressants with TCAs (alcohol in particular) - an interaction with antihypertensive drugs (monitor BP closely) -\> difficult to predict

Answer 734

- amitriptyline

Answer 735

- phenelzine

Answer 736

- MAO-A -\> preference for NA and 5-HT - MAO-B -\> preference for dopamine

Answer 737

- in Parkinson's -\> MAO-B inhibitors are used to increase dopamine levels in the brain

Answer 738

- no -\> inhibit both MAO-A and MAO-B as well as other enzymes

Answer 739

- irreversibly bind to MAO enzymes and therefore blocks the breakdown of NA, 5-HT and dopamine - all of these chemicals therefore build up and have a larger effect on the brain -\> occurs very fast - causes a down-regulation of β-adrenoceptors and 5-HT2 receptors so the clinical effects aren't seen for a while

Answer 740

- all MAOi's have got a single ring structure - are many different classes -\> phenelzine is a hydrazine - phenelzine has a single ring with a carbon side chain -\> on the end is a hydrazine functional group which is VERY REACTIVE -\> forms the covalent bonds with the MAO enzyme -\> irreversible inhibition

Answer 741

- rapid oral absorption - short plasma t_1/2 (few hours) but longer duration of action due to irreversible inhibition -\> taken either once a day or every other day - metabolised in the liver and excreted in the urine

Answer 742

- atropine-like effects (much less than with TCAs) - postural hypotension (common) -\> probably a vasomotor mediated effect - sedation with long-term usage -\> becomes seizures in over dose - weight gain (possibly excessive) -\> associated with increase appetite with MAOIs - hepatotoxicity (due to hydrazines) -\> is rare (e.g. 1 in 10,000 patients)

Answer 743

- tyramine is metabolised by MAOs -\> if they are being inhibited, we may encounter problems -\> ‘Cheese reaction’ -\> tyramine-containing foods + MAOI leads to a hypertensive crisis (throbbing headache, increased blood pressure and intracranial haemorrhage -\> patient must avoid foods high in tyramine (mature cheese, red wine etc.) - react with TCAs to produce hypertensive episodes (avoid) - react with pethidine to cause hyperpyrexia, restlessness, coma & hypotension

Answer 744

- an indirectly acting sympathomimetic amine (has actions similar to activation of the SNS) - under normal circumstances, there are not sufficient levels of tyramine in the body to cause problems

Answer 745

- using reversible MAO-A inhibitors (RIMA) such as moclobemide -\> are slective for MAO-A - has fewer interactions but has a shorter duration of action -\> must be taken 2-3 times a day - aren't as effective anti-depresants as traditional MAOi

Answer 746

- fluoxetine

Answer 747

- selective 5-HT re-uptake inhibition (SSRIs selectively inhibit the reuptake of 5-HT) - less troublesome side effects than other anti-depressants, so they are safer in the case of overdose - BUT are less effective against severe depression

Answer 748

- oral administration of SSRIs - plasma t_1/2 (18-24 hours) -\> given once a day, orally - is a delayed onset of action (2-4 weeks before we see the optimal anti-depressant action of SSRIs) - fluoxetine competes with TCAs and for the hepatic enzymes -\> co-administration must be avoided (same with MAOi as they interact)

Answer 749

- a couple of ring structures with an aliphatic side chain

Answer 750

- fewer unwanted effects than TCAs/MAOIs -\> massive advantage -\> makes them the frontline treatment (providing its not severe depression) - 10% of patients complain of GI side effects (nausea, diarrhoea) - some people complain of insomnia - 30% of patients complain of loss of libido

Answer 751

o a SNRI -\> shows dose-dependent Reuptake inhibition of both 5-HT and NA - 5HT \> NA (SNRI) -\> increasing the dose increases NA re-uptake inhibition - a very high dose of venlafaxine inhibits the dopamine transporter too o is 2^nd line treatment for severe depression

Answer 752

- an α2 Receptor antagonist -\> increases NA and 5-HT release in the brain by blocking the inhibitory control over NA and 5-HT -\> increases NA & 5HT release in the brain - other receptor interactions may contribute to antidepressant activity (sedative - histamine antagonism) - useful in SSRI-intolerant patients

Answer 753

- D: Inhibition of central NA & 5HT reuptake

Answer 754

- C: Monoamine oxidase inhibitors (MAOIs)

Answer 755

o TOXIC to the lining of the stomach o cisplatin affects enterochromaffin cells (toxic to them) and causes destruction of these cells -\> causes the release of free radicals -\> EXCESSIVE 5-HT RELEASE from the stomach o 5-HT goes on to act on 5-HT_3A receptors, located on: - nerve fibres to the nucleus tractus solitarius (NTS) (cpnnected to the VC via nerves) - nerve fibres to the vomiting centre (VC) - nerve fibres to chemoreceptor trigger zone (CTZ) o as a result of increased serotonin, there is increased activity of the solitary tract -\> increased activity of the VC -\> NAUSEA AND VOMITING. o also a direct link between cell bodies in the stomach and the vomiting centre o nerve fibres stretching from the stomach to the chemoreceptor trigger zone (outside the BBB so detects things in blood an feeds this information back to the vomiting centre) -\> increases the chances of nausea and vomiting

Answer 756

o ONDANSTERON -\> a 5-HT_3A receptor antagonist -\> less 5-HT binding -\> less nausea and vomiting - given with two other things: - glucocorticoids -\> reduces free radical production -\> remove effects of free radicals - aprepitant -\> neurokinin-1 receptor antagonist -\> dampens down the trnsmission from the NST to the VC

Answer 757

- in the connection between solitary tract and the vomiting centre

Answer 758

- hyoscine -\> non-selective muscarinic receptor antagonist -\> most effective treatment for motion sickness - promethazine -\> H₁receptor antagonist

Answer 759

- blocks the histamine H₁ receptors -\> receptors may be pre-synaptic or post-synaptic receptors are somehow involved in the signalling process from the hypothalamus to the CTZ - blocking histamine receptors reduces the likeliness of vomiting being triggered

Answer 760

- a mismatch between the labyrinth and the vestibular system

Answer 761

- blocks all 5 of the muscarinic receptors - no one is entirely sure how the cholinergic system plays a role in vomiting -\> but because hyoscine is such an effective agent against motion sickness, we know ACh is involved - muscarinic receptors are most likely to be involved in signalling from labyrinth to vestibular system

Answer 762

- delayed emptying of the stomach due to it being unable to contract -\> triggers the vomiting reflex - symptoms are abdominal pain and bloating - often linked to T2DM

Answer 763

- delayed stomach emptying due to reduced stomach contraction - 5-HT release and direct stimulation of the VC by nerves -\> involves dopamine₂ receptors - activation of 5-HT receptors on the VC and the chemoreceptor trigger zone

Answer 764

- metoclopramide -\> dopamine D₂ receptor antagonist - 5-HT receptor antagonist

Answer 765

- prokinetic -\> stimulates gastric emptying by acting on the stomach itself (stimulates contractility) - inhibits D2 receptors in the vomiting centre -\> blocks likelihood of vomiting from D2 stimulation - is a 5-HT_3A receptor antagonist -\> inhibits activation of CTZ

Answer 766

o vomiting centre (area postrema) -\> innervated by the nucleus of the tractus solitarius - chemoreceptor trigger zone communicates with the vomiting centre

Answer 767

- cytotoxic drugs - motion sickness - gastrointestinal problems

Answer 768

- 5-HT_3A receptor antagonists - histamine H₁ receptor antagonists - muscarinic receptor antagonists - dopamine D2 receptor antagonists

Answer 769

- chemotherapy induced N&V

Answer 770

- motion sickness

Answer 771

- motion sickness

Answer 772

- gastroparesis induced N&V

Answer 773

- headaches - constipation

Answer 774

- drowsiness

Answer 775

- drowsiness, dry mouth and a bit of constipation

Answer 776

- extra-pyramidal side effects - galactorrhoea

Answer 777

o MAIN = AGE o are genetic components too -\> APP, PSEN, ApoE - APP = mutation in amyloid precursor protein and/or presenilin gene increased risk of early onset Alzheimer's disease - ApoE = Apo lipoprotein E miutation -\> increased risk of late onset Alzheimer's

Answer 778

**- memory loss -\>** especially recently acquired information = MOST PROMINENT SYMPTOMS - disorientation/confusion -\> forgetting where they are - language problems -\> stopping in the middle of a conversation - personality changes -\> becoming confused, fearful, anxious - poor judgement -\> such as when dealing with money

Answer 779

1. amyloid precursor protein (APP) is cleaved by **a****-secretase** 2. sAPPa released, but the C83 fragment remains 3. C83 is then digested by g-secretase, and the products removed

Answer 780

1. APP cleaved by **b****-secretase** 2. sAPPb released, but the C99 fragment remains 3. C99 is then digested by g-secretase, releasing **b****-amyloid (A****b****) protein** 4. Ab forms toxic aggregates à formation of beta-amyloid plaques which associate with neuronal cells and increase the likelihood of their death

Answer 781

- soluble protein present in neuronal axons that form the internal skeleton of neuronal cells - is important for assembly & stability of microtubules

Answer 782

- hyper-phosphorylated tau is **insoluble** -\> self-aggregates to form neurofibrillary tangles -\> are neurotoxic -\> results in microtubule instability -\> neuronal cell death - correlates with symptoms very well -\> more tau hyper-phosphorylation the worse the disease

Answer 783

o caused due to inappropriate activation of microglial cells - increased release of inflammatory mediators & cytotoxic proteins - increased phagocytosis - decreased levels of neuro-protective proteins

Answer 784

- donepezil - GOLD STANDARD -\> anticholinesterase - rivastigmine -\> anticholinesterase - galantamine -\> anticholinesterase - memantine -\> NMDA receptor blocker

Answer 785

- reversible acetylcholinesterase (found only in the NS) inhibitor - effective uin treating symptoms for around a year - long-plasma half-life so only 1 tablet a day is required

Answer 786

- pseudo-reversible AChE/BChE inhibitor -\> inhibits acetylcholinesterase and butyrylcholinesterase - 8 hour half-life (relatively short) -\> needs to be administered 2-3 times a day but it has be reformulated as transdermal patch formulation which require less applications - -nhibition of butyrylcholinesterase enzyme leads to more **side effects** (liver problems)

Answer 787

- reversible cholinesterase inhibitor with a 7-8 hour half-life - a7 nAChR agonist -\> agonist of specific isoforms (neuronal included in this) of the nicotinic ACh receptor (in the CNS)

Answer 788

* -* use-dependent non-competitive NMDA receptor blocker with low channel affinity -\> more the NMDAr is activated, the more likely memantine is to have an inhibitory effect -\> occurs with a lot of neuron degeneration such as in moderate and severe Alzheimers -\> only licensed for moderate to severe/late Alzheimers - long plasma half-life

Answer 789

**1. gamma****-secretase inhibitors** -\> tarenflurbil and semagacestat **2. beta-amyloid antibodies** -\> bapineuzumab and solanezumab -\> aducanumab is in clinical trials and is looking psitive at the moment **3. tau inhibitors** -\> methylene blue

Answer 790

- most important inhibitory NT in the brain

Answer 791

- glutamate - a bit strange seeing that glutamate is the most important excitatory NT in the brain

Answer 792

- GABA-A = sit on the post-synaptic membrane and are chloride ionphores -\> type I receptors - GABA-B = sit on pre-synaptic membrane and are G-protein coupled -\> type II -\> have a regulatory effect on GABA secretion and production

Answer 793

- GABA binds to GABA-A receptors which are ion channel linked - when stimulated by GABA, the ion channel changes conformation to transiently become a chloride ion -\> chloride is negative, so they **hyperpolarise** the post-synaptic cell -\> cell has a very negative potential -\> harder to excite/less likely for a action potential to occur

Answer 794

o GABA taken up by the surround glial cells OR back into the pre-synaptic terminal

Answer 795

**- GABA transaminase (GABA-T)** is the enzyme in the first step - GABA -\> succinic semialdehyde - second enzyme is **succinic semialdehyde dehydrogenase (SSDH)** to produce succinic acid - succinic acid goes back into the TCA cycle in the cells and as glutamate also arises from the TCA cycle -\> a GABA shunt is formed - around 10% of the activity of the TCA cycle is involved in generating GABA as a transmitter

Answer 796

- both are mitochondrial enzymes

Answer 797

- GABA-T and SSDH can be unhibited -\> increases GABA levels in the brain -\> enhances GABA in the CNS -\> anticonvulsant/anti-epileptic effects

Answer 798

**- sodium valproate** -\> GABA-T and SSDH inhibitor and Na blocker **- vigabatrin** -\> GABA-T inhibitor

Answer 799

- GABA receptor protein - benzodiazepine receptor protein - barbiturate receptor protein - chloride channel protein

Answer 800

- GABA binds to the GABA-A receptorat the GABA receptor protein - this causes the GABA receptor protein and benzodiazepine receptor protein link together -\> mediated by a peptide called GABA modulin - result is a momentary opening of the chloride channel protein -\> hyperpolarisation

Answer 801

- a competitive antagonist for the GABA-A receptor -\> binds to the GABA receptor protein

Answer 802

- benzodiazepine receptor protein

Answer 803

- facilitate GABA mediated opening of the Cl^- channel - facilitate GABA binding to its own receptor

Answer 804

- a competitive benzodiazepine antagonist -\> competes with benzodiazepine for its binding site

Answer 805

- barbiturate receptor protein

Answer 806

- facilitate GABA mediated opening of the Cl^- channel - facilitate GABA binding to its receptor but this is not reciprocated - at higher concentrations, barbiturates can have a direct action on the chloride channel

Answer 807

- benzodiazepines = increase the FREQUENCY of chloride channel opening - barbiturates = increase the DURATION of the chloride channel opening

Answer 808

o barbiturates are LESS selective than benzodiazepines - barbiturates also reduce excitatory transmission via some antagonist action at glutamate receptors -\> contributes to their anxiolytic and hypnotic effects - also have other membrane effects -\> e.g. direct action on Cl channel at higher concentrations - their reduced selectivity may explain: induction of surgical anaesthesia (we can't do that with benzodiazepines) and the fact that they are less safe than the benzodiazepines

Answer 809

- anti-spastics -\> diazepam -\> their action is at the spinal cord and reduces AP propagation in alpha motor neurones - antiolytics - sedatives/hyponotics

Answer 810

- anaesthetics -\> thiopentone -\> generally used to induce anaesthsia -\> maybe swapped to a different anaesthic for longer operations - anticonvulsants - anti-spastics - anxiolytics - sedatives/hypnotics

Answer 811

- a drug which removes anxiety without impairing mental or physical activity (“minor tranquillisers”)

Answer 812

- a drug which reduces mental and physical activity without producing loss of consciousness

Answer 813

- a drug which induces sleep

Answer 814

- barbiturates all have a six-membered ring (4 carbons and 2 nitrogens) in the middle -\> differ in their substituent groups

Answer 815

- a barbiturate useful in the severe intractable insomnia - has a half-life of 20-25 hours

Answer 816

o they have many side effects - possess low safety margins -\> depress respiration -\> overdosing is lethal - alter natural sleep by decreasing REM sleep -\> leads to hangovers and irritability - enzyme inducers -\> barbiturates induce microsomal enzymes -\> must avoid co-administration (e.g. warfarin) - potentiate effect of other CNS depressants (e.g. alcohol) - tolerance occurs in the tissue and pharmokinetically - dependence -\> withdrawal syndrome = insomnia, anxiety, tremor, convulsion and death

Answer 817

- tricyclic -\> classic three-ring structure (2 six-membered and 1 seven-membered) - are around 20 available – but they _all_ act at _GABA__Areceptors - all have similar potencies & profiles, and have the same mechanism

Answer 818

- well absorbed per orally -\> peak plasma concentration is reached after about 1 hour - sometimes given IV in the treatment of status epilepticus (continuous seizure activity) -\> is a medical emergency unlike other seizures

Answer 819

- the liver

Answer 820

- in the urine as glucuronide conjugates

Answer 821

- short-acting - long-acting -\> have a slower metabolism or generates active metabolites

Answer 822

- oxazepam -\> metabolised in the liver to its inactive glucuronide - temazepam -\> metabolised initially to oxazepam, which is then converted to the glucuronide conjugate -\> this occurs pretty fast though - both have a half-life of around 8 hours

Answer 823

- diazepam -\> metabolised via temazepam and oxazepam to the glucuronide - some diazepam is metabolised through nordiazepam then oxazepam - diazepam has slower metabolism than the other two and it also generated active metabolites - diazepam has a half-life of around 32 hours

Answer 824

o anxiolytics -\> generally the longer acting benzodiazepines **- diazepam** - chlordiazepoxide - nitrazepam o sedatives/hypnotics -\> generally the shorter acting benzodiazepines **- temazepam** **- oxazepam** - exception = nitrazepam (t1/2 = 28 hours) -\> can be used as a sedative/hypnotic (it also has a daytime anxiolytic effect

Answer 825

- wider margin of safety -\> overdose = prolonged sleep which is rousable -\> also have an intravenous shot of flumazenil (competitive antagonist) to overcome this - mild effect on REM sleep -\> do not induce the hangover effect - do NOT induce liver enzymes - have less tolerance and dependency than barbiturates

Answer 826

- sedation -\> when being used as anxiolytics patients will feel a little drowsy - confusion, ataxia -\> impaired manual skills - potentiate other CNS depressants (e.g. alcohol and barbiturates) - tolerance -\> less than barbiturates because of tissue tolerance only - no pharmacokinetic tolerance - dependence -\> associated with withdrawal syndrome but less than barbiturates - free plasma concentration of benzodiazepines can be increased by giving aspirin and heparin or other plasma protein binding drugs

Answer 827

- a short acting cyclopyrrolone -\> acts at benzodiazepine receptor but it is _NOT_ a benzodiazepine - enhances GABA-mediated neurotransmission by binding to the BZ binding site - similar efficacy to benzodiazepines - minimal hangover effects but dependency still a problem

Answer 828

- some antidepressant drugs -\> SSRIs -\> less sedation and dependence however they have delayed response/long-term treatment - some anti-epileptic drugs -\> e.g. Valproate, tiagabine - some antipsychotic drugs -\> e.g. Olanzapine, quetiapine - propranolol -\> non-selective beta-blocker -\> improves the physical symptoms of anxiety -\> e.g. Tachycardia (b₁) and Tremor (b₂) - buspirone -\> 5-HT_1A agonist -\> has fewer side-effects e.g. less sedation compared to benzodiazepines however has a slow onset of action (maximal anxiolytic effect may be seen in days/weeks)

Answer 829

- E -\> temazepam

Answer 830

- production of dopamine = L-tyrosine -\> L-DOPA -\> dopamine - dopamine is stored in vesicles at the synaptic terminal - process utilises the enzymes -\> tyrosine hydroxylase (rate limiting) and DOPA decarboxylase

Answer 831

- dopamine transporter - noradrenaline transporter

Answer 832

- MOA-A = metabolises DA, NE & 5-HT - MAO-B = metabolises DA **only** - catechol-O-methyl transferase (COMT) = metabolises all catecholamines -\> more widely distrubuted than the other pre-synaptic intracellular MAO enzymes

Answer 833

- nigrostriatal pathway -\> important in Parkinson's - mesolimbic pathway/reward pathway -\> important in schizophrenia - mesocortical pathway -\> important in schizophrenia - tuberoinfundibular pathway

Answer 834

- cell bodies of the nerve are present within the substantia nigra pars compacta (SNc), and the nerves project up to the striatum - inhibition of these neurones results in movement disorders - MPORTANT IN Parkinson's

Answer 835

- cell bodies are located in the ventral tegmental area (VTA), and the axons project up to the Nucleus Accumbens (NAcc) - BRAIN REWARD PATHWAY - IMPORTANT IN SCHIZOPHRENIA

Answer 836

- cell bodies start in the VTA, but this time they project to the cerebrum (various areas of the cortex) - is important in executive functions and complex behavioural patterns - activation associated with positive schizophrenia symptom while inhibition associated with negative schizophrenia symptoms -\> IMPORTANT IN SCHIZOPHRENIA

Answer 837

- cell bodies in the arcuate nucleus project to the median eminence - regulates prolactin secretion - inhibition results in hyperprolactinaemia

Answer 838

- age - genetics can increase the chance of early onset but not the normal form -\> SNCA and LRRK2

Answer 839

- severe loss of dopaminergic projection cells in SNc (nigrostriatal tract) -\> patients have lost 80% of their dopaminergic cells before symptoms - Lewy bodies & neurites are found within neuronal cell bodies & axons -\> consist of abnormally phosphorylated neurofilaments, ubiquitin & a-synuclein -\> no-one quite knows how they are involved in the pathology

Answer 840

- motor symptoms = CARDINAL SYMPTOMS = resting tremor, bradykinesia, rigidity, postural instability - autonomic nervous system effects = olfactory deficits, orthostatic hypotension, constipation - neuropsychiatric = sleep disorders, memory deficits, depression, irritability

Answer 841

o dopamine replacement therapy for Parkinson's - converted to DA by DOPA decarboxylase (DOPA-D) - can cross the blood-brain barrier (BBB)

Answer 842

- cannot simply give DA because it will enter the periphery -\> acts of CTZ and cause nausea and vomiting due to its breakdown by peripheral DOPA-D (not just found in the brain) - has long-term side effects -\> dyskinesias and ‘on-off’ effects - is not disease modifying, it just reduces the symptoms of PD

Answer 843

- by giving levodopa in adjunction with carbidopa and benserazide which are DOPA-D inhibitors - don't cross the BBB -\> prevent peripheral conversion but not in the CNS - reduces the required dose of levodopa and takes away some of the symptoms

Answer 844

- both are COMT inhibitors -\> reduces the breakdown of levodopa in the brain - can only be given with levodopa -\> doesn't work by itself

Answer 845

- dopamine replacement -\> levodopa = GOLD STANDARD - dopamine receptor agonists - monoamine oxidase B (MOA_B) inhibitors

Answer 846

o artificial stimulation of the dopamine receptors 1. ergot derivatives = bromocriptine and pergolide - act as potent agonists of dopamine D₂ receptors (are effectibe) however, these are associated with cardiac fibrosis and increase likelihood of valvular disease 2. Non-ergot derivatives = ropinirole and rotigotine - ropinirole is also available as extended-release formulation and rotigotine is also available as a patch

Answer 847

- reduce the amount of levodopa required as well as increasing the amount of time before levodopa is needed - the longer someone is on levodopa the higher the chance of the dyskinesias and 'on-off' effects are to occur -\> when they do the drug has stopped working - give longer controlled Parkinson's - is associated with the cheese reaction

Answer 848

- selegiline (deprenyl) - rasagiline

Answer 849

- mesolimbic and mesocortical

Answer 850

- ethnic minorities

Answer 851

- 20-30 years less than average -\> probably due to likelihood to abuse drugs to control symptoms - is a link between schizophrenia and cannabis use

Answer 852

o positive = increased mesolimbic dopaminergic activity -\> hallucinations, delusions/paranoia, thought disorder/denial about oneself o negative = decreased mesocortical dopaminergic activity -\> affective flattening/lack of emotion, alogia/lack of speech, avolition/apathyloss of motivation

Answer 853

- labotomy or electroconvulsive therapy

Answer 854

- chlorpromazine - haloperidol

Answer 855

- probaly a D2 receptor antagonist - not known exactly -\> was discovered as a treatment while looking a=for a new antihistamine -\> is also an effective antihistamine

Answer 856

- high incidence = anti-cholinergic effects, especially sedation - low incidence = extrapyramidal side-effects (EPS) - drug is also a muscarinic receptor antagonist -\> this causes the side effects

Answer 857

- a very potent D2 antagonist -\> 50 times more so than chlorpromazine - therapeutic effects develop over 6-8 weeks - little impact on negative symptoms -\> maybe even worsening - causes Parkinson’s like movement due to effects on the mesocortical pathways

Answer 858

- high incidence = EPS (extra-pyramidal side effects)

Answer 859

- second generation targets serotonin rather than dopamine

Answer 860

- clozapine - risperidone - quetiapine - aripiprazole

Answer 861

- very potent antagonist of 5-HT_2Areceptors -\> inhibits these receptors - also has actions on M1, H1 receptors and alpha-1 receptors and dopamine D2 receptor

Answer 862

- clozapine -\> only drug to show efficacy in treatment of resistant schizophrenia and negative symptoms -\> no-one knows how it does so but it does

Answer 863

o has a severe side effect profile - can cause potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain

Answer 864

- very potent antagonist of serotonin and D2 receptors

Answer 865

- more EPS & hyperprolactinaemia (medication is inhibiting dopamine receptors in the tuberoinfundibular pathway) than other atypical antipsychotics, weight gain

Answer 866

- very potent H1 receptor antagonist as well as affecting the dopamine receptors

Answer 867

o partial agonist of D₂ & 5-HT_1Areceptors - in theory = when there is too much activity, the partial agonist acts as an inhibitor and reduces positive symptoms and when there is little activity, the partial agonist increases activity and reduces negative symptoms - however in practice, it is no more efficacious than typical antipsychotics

Answer 868

- reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics

Answer 869

- loss of consciousness -\> **ALL the general anaesthetic agents** can do this at **low** concentration - suppression of reflex responses -\> **ALL the general anaesthetic agents** can do this at **high** concentration - relief of pain (analgesia) - muscle relaxation - amnesia

Answer 870

o anaesthetic potency increases in direct proportion with oil/water partition coefficient -\> in other words **anaesthetic potency is directly correlated with lipid solubility** o TWO main problems with that explanation: - at therapeutic doses, changes to the lipid bilayer were **_minute_** - how would the change in the membrane impact on _membrane proteins_ anyway? o rise in temperature seemed to have the same effect on the membrane as the general anaesthetic so this was a poor explanation

Answer 871

- redcued neuronal excitability or - altered synaptic function

Answer 872

- intravenous GA agents alter synaptic function, primarily through enhancement of GABA-A receptors -\> POTENTIATION - IV GAs are slightly _more selective_ -\> they target the **GABA-A receptor** - GABA-A receptor is made up of **5 subunits** -\> subunit composition is different in different brain regions

Answer 873

- euphoria due to GABA-A importance in bring about euphoria

Answer 874

o GABA-A is a type 1 ionotropic receptor so it is comprised of **5 subunits** -\> subunit combination is different in _different parts of the brain_ o IV agents seem to target _specific_ subunits in the GABA-A receptor: - beta-3 = suppression of reflex responses (important at the synaptic level) - alpha-5 = amnesia (extra-synaptic)

Answer 875

- inhalational GA agents alter synaptic function and have an affect on GABA -\> probably 50% less powerful (other targets are involved): **GABA-A Receptors** and **Glycine Receptors** (glycine is an inhibitory neurotransmitter) - are far _less selective_ for GABA-A than the IV agents - seem to be more selective for **alpha-1** containing GABA -\> important in **suppression of reflex responses**

Answer 876

- inhalational

Answer 877

- **blocks the NMDA-type glutamate receptors** to induce its anaesthetic effect -\> less GABA specific and _more glutamate specific_ - competes at the binding site for glycine on the glutamate receptor -\> glycine is an important **CO-AGONIST** of NMDA receptors which allows the full receptor response to be transduced -\> interfering with glycine will interfere with NMDA

Answer 878

o important for the **analgesic effects and amnesia** but don't influence the loss of consciousness or hypnotic effects of inhaled agents - increasing the concentration of the inhalational agent leads to a reduction in nerve conduction via an effect on **nicotinic acetylcholine receptors** -\> INHIBITION - agent enters the brain, binds to and blocks the ACh receptor -\> ANALGESIA

Answer 879

o enhancing the opening of TREK (background leak K+ channels) -\> hyperpolarisation -\> reduced neuronal excitability - important in terms of suppression of reflex responses

Answer 880

- IV agents mainly affect **GABA-A -\>** seem to be a lot more selective - inhalation agents are far less selective - therefore a GENERAL RULE is that a higher dose of inhalation agents is needed compared to IV

Answer 881

- unconscious = massive decrease in cortical activity o thalamus is a _relay station_ for information going between the cortex and the rest of the CNS -\> **depressing the excitability of thalamocortical neurones** -\> disconnection of the periphery from brain -\> mediated by background leak K⁺ channels leading to hyperpolarisation and enhanced GABA function -\> both occur due to GA o **reticular activating system** also affects consciousness -\> thalamocortical neurones respond to sensory information and also impacted by the RAS -\> ghe greater the firing of the RAS, the greater the level of arousal -\> anaesthetics interfere with this process by blocking the RAS neurones

Answer 882

o location = **depression of reflex pathways in the _DORSAL HORN OF THE SPINAL CORD_** - GABA and glycine receptors are important targets here - anaesthetic agents that _enhance GABA and glycine function_ in the dorsal horn will decrease the activity of the dorsal pathways -\> suppresses the reflex responses

Answer 883

- GAs tend to cause amnesia at a pretty _LOW DOSE_ -\> amnesia tends to be the first effect - are a lot of GABA receptors in the **hippocampus** that have the **alpha 5** subunit -\> GAs suprress these subunits -\> _decrease in synaptic transmission_ in the hippocampus (where most memory formation occurs) -\> loss of memory

Answer 884

- IV agents are injected into the blood, travel to the brain and have their anaesthetic effects -\> excretion rate is difficult to control if it has been injected straight into the blood - inhaled gaseous agent enters the blood but a large amount is excreted -\> gives good control over the agent -\> can **control inhalational agents** better

Answer 885

- if you fill the lungs with anaesthetic agent, this anaesthetic will diffuse across into the blood - if it dissolves POORLY in the blood (has a low blood:gas partition coefficient) a fairly large proportion remains in gaseous form within the blood -\> agent transfers into the brain very effectively - component that is dissolved in the blood (in a liquid form) will diffuse poorly into the brain o for control you want an anaesthetic agent that has a low blood:gas partition coefficient, because this makes it MORE available to the brain and because if it is POORLY DISSOLVED IN THE BLOOD (low blood:gas partition coefficient), it is EASIER to clear it from the brain - simply remove the source and it will quickly diffsue out

Answer 886

- induce with the intravenous -\> often propofol - maintain with the inhalational -\> allows us to have control -\> often enflurane

Answer 887

- inhaled = rapidly eliminated and rapid control of the depth of anaesthesia - IV = fast induction and less coughing and excitatory phenomena (seizures)

Answer 888

- obesity -\> GA are very lipid soluble -\> why 24 hrs after surgery you may feel drowsy again -\> leaking back into the blockstream - had to balance how much GA is needed to maintain anaethesia and not cause lots of longer-term effects

Answer 889

- induction = IV GA agents

Answer 890

- maintenance = inhalaed GA agents

Answer 891

- opiods -\> e.g. IV fentanyl

Answer 892

- neuromuscular blocking drugs -\> e.g. suxamethanium

Answer 893

- benzodiazepines -\> e.g. IV midazolam

Answer 894

- definition = drugs that reversibly block neuronal conduction when applied locally - all local anaesthetics are weak bases and sodium ion channel blockers

Answer 895

- Phase I = Depolarisation: when neurones are depolarised due to a stimulus VGSCs open -\> sodium rushes into the neurone -\> generates a rapid depolarisation phase - Phase II = Repolarisation: within a millisecond the sodium channels closeand VGKCs open -\> potassium leaves the neuronal cell -\> allows the neurone to enter a repolarisation phase - Pase III = Refractory Period: sodium channels have been restored to their resting state, however potassium channels remain open -\> it isharder for a cell to generate another AP but it can - Phase IV = RESTING STATE: both sodium and potassium channels have restored to their resting state -\> cell responds normally to depolarising stimuli o action potentials are all or nothing

Answer 896

- aromatic region - basic amine side chain - linked by an ester or amide bond

Answer 897

- ester LA = cocaine - amide LA = lidocaine

Answer 898

- benzocaine -\> doesn’t have the basic amine side chain -\> just has an alkyl group on the side - has weak LA properties, and is lipid soluble so is used as a surface anaesthetic -\> is useful in throat lozenges

Answer 899

o hydrophilic pathway - inject a local anaesthetic close to sensory, pain-conducting neurones -\> unionised form of the LA is lipid soluble and is able to pass through the connective tissue sheath, to gain access to the sensory axons inside the neurone - once the lipid-soluble form of the LA is inside the axon, an equilibrium is established (unionised and ionised versions of the LA) - the **ionised form** of the LA has the anaesthetic property -\> ionised form binds to the inside of the VGSCs and stereochemically hinders the influx of Na ions - in order for the ionised form of the LA to be able to bind to its target site, the VGSCs must be open

Answer 900

- the more the neurones are active, the more the VGSCs will be opening and closing -\> the more time they are spending in the open state - means that the LAs can bind to their target sites more effectively and gives LAs a degree of selectively -\> pain neurones are firing rapidly so these will be blocked more commonly/often than motor neurones

Answer 901

- close to the nociceptive neurones - if introduced close to motor neurones, we will see weakness and relaxation of skeletal muscles

Answer 902

o the hydrophobic pathway -\> is more important for the more lipid-soluble LAs - as the unionised form crosses the axonal membrane, some can drop into the ion channel and convert into the cation ionised form to block the ion channel -\> means that, by the hydrophobic route, the LAs can drop into a closed channel as well as the open channels in the hydrophilic pathway o may also influence channel gating -\> influences mechanism -\> some LAs prefer the inactive state of the sodium channels -\> by binding this holds them open for longer

Answer 903

- infected/damaged tissue tends to be more acidic -\> more LA is is in the unactive unionised form in the acidic conditions (LAs afre weak bases)

Answer 904

- prevent the generation and conduction of action potentials because they block the VGSCs

Answer 905

o selectively block small diameter fibres and non-myelinated fibres - pain impulses are conducted by narrow nonmyelinated fibres

Answer 906

- surface - infiltration - IV regional - nerve block - spinal - epidural

Answer 907

- applied to mucosal surface -\> mouth, bronchial tree, eyes, nose and throat - administrated in spray form or powder form - problems is that high concentrations of the LA are needed to gain an effective anaesthetic action -\> high concentrations can lead to **systemic toxicity**

Answer 908

- LA is injected subcutaneously into tissues -\> accesses the sensory nerve terminals directly - is the applications in minor surgery (suturing and stitching) - adrenaline co-injection often given too -\> because adrenaline causes vasoconstriction (not extremities) -\> increases the duration of action of the local anaesthetic, reduces the incidence of systemic side effects (thus limits toxicity) -\> adrenaline is not given in the extremities because it could lead to ischaemic damage

Answer 909

- given distal to a pressure cuff which acts to shut off the blood supply - has applications in limb surgery (more major surgery) - systemic toxicity may occur if there is premature cuff release -\> rushes straight to the heart and then possibly the CNS -\> should keep the cuff on for 20 minutes minimum

Answer 910

- local anaesthetic is injected close to the nerve trunks e.g. dental nerves - low doses can be used however there is a relatively slow onset (minutes) - vasoconstrictor co-injection with nerve block anaesthesia often occurs

Answer 911

- LA is injected into the sub-arachnoid space -\> has an action on the spinal roots - useful in abdominal, pelvic and lower limb surgery when GA is too dangerous -\> anaesthetic mixes with the CSF (injected at L3/L4) - decreases blood pressure, and may produce a prolonged headache (accesses brain) -\> decreased bp due to LA aacting on small-diameter pre-ganglionic sympathetic ANS neurones - glucose can be mixed with the LA -\> increase in specific gravity -\> allows level/area of control by adding glucos and tilting the table

Answer 912

- injected into fatty tissue of epidural space (not as deep as spinal anaesthesia) -\> action on the spinal roots - used for abdominal, pelvic and lower limb surgery (same as spinal) but also for painless childbirth - disadvantages compared to spinal are a slower onset, and higher doses required -\> higher doses = more likely to experience systemic side effects - advantage compared to spinal is are more restricted action and less effects on blood pressure

Answer 913

- absorption through muscous membranes = good - plasma protein binding = 70% - metabolism = hepatic N-dealkylation - plasma half-life = 2 hours

Answer 914

- absorption through muscous membranes = good - plasma protein binding = 90% - metabolism = hepatic and plasma non-specific esterases - plasma half-life = 1 hour

Answer 915

o CNS = stimulation, restlessness, confusion and tremor -\> PARADOXICAL EFFECTS -\> due to inhibitory GABAergic neurones in the CNS being more sensitive to local anaesthetics, than other receptors -\> removes the inhibitory effect o CVS = myocardial depression, vasodilatation, decreased BP -\> due to Na channel blockade

Answer 916

o CNS euphoria and excitation o CVS = increased cardiac output, vasoconstriction and increased BP -\> can cause cardiac arrythmias - both due to the sympathomimetic action of cocaine

Answer 917

- epigastric pain - burning sensation that occurs after meals

Answer 918

o **carbon-urea breath test** -\> give the patient a lot of urea and as H. pylori metabolises urea to nitrogen, if you get increased levels of nitrogen, this means the H. pylori infection is present o **stool antigen test** -\> involves testing for H. pylori antigens within the stool of the patient o **history of the presenting complaint** -\> pain and burning only comes after eating food

Answer 919

- amoxicillin and clarithromycin/metronidazole -\> antibiotics to treat H. pylori infection -\> once infection is gone the stomach heals itself - proton pump inhibitor for a week -\> reduces acid production to alleviate symptoms

Answer 920

- a gram negative, motile, microaerophilic bacterium - is a commensal bacteria in the vast majority of people

Answer 921

o ulcer formation - increased gastric acid formation due to increased gastrin and/or decreased somatostatin - gastric metaplasia -\> cell transformation due to excessive acid exposure - downregulation of defence factors -\> less epidermal growth factor and bicarbonate production o virulence - urease -\> catalyses urea into ammonium chloride and monochloramine which both damage epithelial cells and urease is also antigenic so evokes an immune response - certain virulent strains produce CagA (antigenic) or VacA (cytotoxic) -\> more intense tissue inflammation

Answer 922

- constant epigastric pain - constant burning sensation

Answer 923

o **carbon-urea breath test** -\> give the patient a lot of urea and as H. pylori metabolises urea to nitrogen, if you get increased levels of nitrogen, this means the H. pylori infection is present o **stool antigen test** -\> involves testing for H. pylori antigens within the stool of the patient o **history of the presenting complaint** -\> pain and burning which is more constant in nature o **endoscopy** -\> look at the ulcer in the stomach - GOLD STANDARD

Answer 924

- amoxicillin and clarithromycin/metronidazole -\> all 3 can be given in the case of an individual with recurrent peptic ulcers - next consider adding quinolone or tetracycline in addition - addition of BISMUTH -\> protects the mucus layer - always a proton pump inhibitor (omeprazole) for 4-12 weeks -\> reduces acid production to alleviate symptoms and also reduce further damage to the ulcerated/vunerable areas

Answer 925

- H pylori negative peptic ulcer caused by prolonged NSAID use -\> most likely to be aspirin

Answer 926

- NSAIDs can be directly cytotoxic and can also reduce mucus production -\> breakdown of barrier -\> epithelia exposure -\> ulceration - NSAIDs may increase the likelihood of bleeding by acting as an anti-platelet agent -\> H. pylori does NOT have this effect -\> symptoms of NSAID caused peptic ulcers can be worse - increased acidity -\> peptic ulcer

Answer 927

- removal of NSAID drugs -\> can’t always do this -\> e.g. in individuals with other co-morbidities - proton pump inhibitor or histamine H₂ receptor antagonist (Ranitidine) for 4-8 weeks

Answer 928

1. **Acetylcholine (ACh)** released from neurones (vagus or enteric) acts on muscarinic (M3) receptors -\> increased intracellular Ca²⁺ 2. **Prostaglandins (PGs)** released from local cells act on EP3 receptors -\> increased cAMP 3. **Histamine** released from enterochromaffin-like cells (ECL) act on H2 receptors -\> increased cAMP 4. **Gastrin** released from blood stream acts on cholecystokinin B receptors -\> increased intracellular Ca²⁺ o all cause extra secretion by either increasing intracellular calcium or cAMP which causes translocation of secretry vesicles to parietal cell apical surfaces -\> increased H⁺ secretion

Answer 929

o gram positive -\> prominent, thick _peptidoglycan cell wall_ - e.g. *Staphylococcus Aureus* o gram negative -\> outer membrane with _lipopolysaccharide_ - e.g. *Escherichia Coli* o mycolic bacteria -\> outer _mycolic acid layer_ - e.g. *Mycobacterium Tuberculosis*

Answer 930

**- dihydropteroate (DHOp)** is produced from paraaminobenzoate (PABA) by DHOp synthase, and converted into dihydrofolate (DHF) **- tetrahydrofolate (THF)** is produced from DHF by DHF reductase -\> THF IS IMPORTANT IN DNA SYNTHESIS

Answer 931

**- DNA gyrase** (aka topoisomerase) releases tension from the DNA molecules and therefore allows the process of DNA replication to take place

Answer 932

**- RNA polymerase** produces RNA from a DNA template -\> prokaryotic RNA polymerase differs from eukaryotic RNA polymerase

Answer 933

**- ribosomes -\>** RNA molecules go through the prokaryotic ribosomes, which produce protein from RNA templates - prokaryotic ribosomes = 70S -\> 30s and 50s - eukaryotic ribosomes = 80S -\> 40s and 60s

Answer 934

- antibiotics that inhibits DHOp synthase -\> prevents prokaryote nucleic acid synthesis - most bacteria are resistant to sulphonamides

Answer 935

- antibiotic which inhibits DHF reductase -\> prevents prokaryote nucleic acid synthesis

Answer 936

- antibiotics that inhibit DNA gyrase and topoisomerase IV -\> prevents prokaryote DNA replication

Answer 937

- a combination of trimethoprim and sulphonamide

Answer 938

- antibiotic that inhibits bacterial RNA polymerase -\> reduces subsequent protein production -\> bacteria cell death

Answer 939

- mycobacterium infection -\> TB

Answer 940

- aminoglycosides (e.g. Gentamicin) - chloramphenicol -\> not a class but a single drug **-** macrolides (e.g. Erythromycin) - tetracyclines

Answer 941

**1. Peptidoglycan synthesis** - a pentapeptide is created on N-acetyl muramic acid (**NAM**) -\> N-acetyl glucosamine (**NAG**) then associates with NAM forming peptidoglycan **2. Peptidoglycan transportation** - peptidoglycan is transported across the cell membrane by a bactoprenol molecule -\> once it is in the periplasm, it undergoes a few steps before being incorporated into the bacterial wall **3. Peptidoglycan incorporation** - is incorporated into the cell wall -\> transpeptidase enzyme cross-links peptidoglycan pentapeptides

Answer 942

- binds to pentapeptide -\> prevents peptidoglycin synthesis - class includes vancomycin

Answer 943

- inhibits bactoprenol regeneration -\> prevents transportation of peptidoglycan

Answer 944

- binds covalently to transpeptidase inhibiting peptidoglycan incorporation into the cell wall

Answer 945

- glycopeptide

Answer 946

- carbapenems - cephalosporins - penicillins

Answer 947

- lipopeptides -\> disrupt gram-positive cell membranes - polymyxins -\> binds to LPS & disrupts gram-negative cell membranes

Answer 948

- unnecessary and inappropriate prescription -\> 50% of antibiotic prescriptions not that bad in the UK - livestock farming -\> 30% of UK antibiotic use is in livestock farming - lack of regulation -\> over-the-counter availability in Russia, China, India - lack of development -\> very few new antibiotics have been developed in recent years

Answer 949

1. beta-lactamase 2. production of additional targets 3. alteration in the target enzymes 4. hyper-production 5. alteration in drug permeation

Answer 950

- hydrolyse the C-N bond of the beta-lactam ring of beta lactam antibiotics

Answer 951

- beta lactamases target the beta lactam ring -\> the resistant antibiotics tend to have molecules around the beta lactam ring (shields it – steric hindrance) - prevents the beta lactamase accessing the ring - examples include flucloxacillin and temocillin

Answer 952

- must be co-administrated with clavulanic acid -\> confers beta-lactamase resistance

Answer 953

- bacteria can introduce an additional target on top of the current target -\> this new target is unaffected by the drug - e.g. =*E Coli* -\> produces a different DHF reductase enzyme, making them resistant to trimethoprim

Answer 954

- alteration of the enzyme targeted by the drug -\> enzyme is still effective, but the drug is now ineffective - e.g. = S Aureus -\> mutations in the ParC region of topoisomerase IV confers resistance to quinolones

Answer 955

- bacteria significantly increase levels of DHF reductase -\> antibiotic is overwhelmed an cannot keep up with the additional production - e.g. = *E Coli* -\> produces additional DHF reductase enzymes making trimethoprim less effective - this resistance mechanism isn’t utilised by bacteria much as it puts a lot of strain on the bacteria itself

Answer 956

- is a very commonly utilised mechanism of resistance - alterations in drug permeation = reductions in aquaporins so a harder route for the antibiotic to enter the cell and/or increased efflux systems - the bacteria reduces methods of influx and increase efflux mechanisms to limit drug interaction - e.g. = primarily of importance in gram-negative bacteria

Answer 957

- superficial = outermost layers of skin - dermatophyte = skin, hair or nails - subcutaneous = innermost skin layers - systemic= primarily respiratory tract

Answer 958

- azoles - polyenes

Answer 959

- azole anti-fungal drugs inhibit cytochrome enzymes that are present in the fungal cells -\> inhibition of cytochrome P450-dependent enzymes involved in membrane sterol synthesis -\> is normally important in ergosterol production which is incorporated into the fungal cell wall

Answer 960

- punches holes into the cell membrane of the fungal cells - interacts with cell membrane sterols forming membrane channels -\> cells burst - can also punches holes in the cell membranes of all cells -\> BAD SIDE EFFECTS -\> is more selective for fungal cells

Answer 961

- viruses have nucleic acid (genetic material), which is either RNA or DNA -\> this is protected by a coat of proteins (capsid) - bigger viruses also have a lipid envelope and envelope proteins

Answer 962

- only *chronic infection* requires treatment - hepatitis A can only be an acute infection -\> patient is poorly for a month, but then gets better so there is no need for treatment - hepatitis B and C can become chronic infections -\> is associated with chronic inflammation at the liver -\> cirrhosis and hepatocarcinoma may result -\> vaccination is important for hepatitis B

Answer 963

- daily tenofovir for the rest of there life -\> a nucleotide analogue - is a reverse transcriptase inhibitor - sometimes given with Peginterferon alfa

Answer 964

- B = DNA - C = RNA

Answer 965

- the complete, infective form of a virus outside a host cell, with a core of RNA and a capsid

Answer 966

- ribavirin and peginterferon alfa -\> ribavirin is a nucleoside analogue -\> prevents viral RNA synthesis - boceprevir is a protease inhibitor -\> most effective against hepatitis C genotype 1 - usually cured with 3 months -\> can take longer with advanced disease with cirrhosis

Answer 967

o attachment of the virus to the host cell and entry into host cell - viral proteins must merge with host cell receptors on the cell surface and then interact with leukocyte membrane receptors à viral capsid endocytosis o replication and Integration - within the cytoplasm, the reverse transcriptase enzyme converts viral RNA into DNA -\> DNA is transported into the nucleus, and is integrated into the host DNA - takes place over a couple of days -\> once this happens, there is nothing we can do to cure it -\> all that can be done is try to inhibit viral replication o assembly and release - host cell’s ‘machinery’ is utilised to produce viral RNA and essential proteins - virus is assembled within cell -\> mature virion is released out of the cell

Answer 968

- is ALWAYS A COMBINATION THERAPY -\> usually 2 or 3 antiretroviral drugs

Answer 969

- cell wall - DNA synthesis - protein synthesis

Answer 970

- HIV entry inhibitors - HIV replication inhibitors - HIV integrase inhibitors - HIV protease inhibitors

Answer 971

- chemotherapy and bone marrow transplant due to leukaemia - the donated bone marrow had the CCR5-delta 32 mutation -\> provides immunity to HIV strains as the virus cannot enter the cell

Answer 972

- HIV glycoprotein GP120 attaches to the CD4 receptor which are found mainly on WBCs - GP120 also binds to either CCR5 or CXCR4 which act as co-receptors - GP41 penetrates host cell membrane - viral capsid enters the cytoplasm of the cell

Answer 973

- enfuvirtide binds to HIV GP41 transmembrane glycoprotein -\> prevents HIV fusion and entry - maraviroc blocks the CCR5 (the co-receptor) chemokine receptor -\> if GP120 doesn’t find CCR5, the HIV capsid cannot enter the cell -\> is very well tolerated

Answer 974

o nucleoside reverse transcriptase inhibitors -\> e.g. zidovudine (AZT) - activated by a 3-step phosphorylation process o nucleotide reverse transcriptase inhibitors -\> e.g. tenofovir - bind to the active site of the RT enzyme -\> therefore compete o non-nucleoside RT inhibitors -\> e.g. efavirenz = most used antiretroviral drug globally - no phosphorylation required - binds to allosteric sites on the RT enzyme

Answer 975

- insert viral DNA into host DNA

Answer 976

- raltegravir (anothe 2 are now available) - integrase inhibitors block the viral integrase enzyme, normally responsible for integration of HIV DNA into the genome

Answer 977

- saquinavir - usually also administrated with ritonavir which reduce the inhibitors first pass hepatic metabolism by CYP450

Answer 978

* - gag* precursor encodes all viral structural proteins - HIV protease cleaves *Gag* precursor protein -\> allows the proteins to become functional -\> without this step, the virus would be ineffective

Answer 979

- nucleoside analogues

Answer 980

- nucleoside analogues = **Acyclovir** - blocks the activity of enzymes that copy DNA into RNA

Answer 981

- double stranded DNA virus surrounded by tegument and enclosed in a lipid bilayer

Answer 982

- multipartite single stranded RNA virus containing envelope proteins called neuraminidase and hemagglutinin -\> neuraminidase cleaves the sialic acid on the host cell allowing release while hemagglutinin is important in cell entry

Answer 983

- neuraminidase inhibitor call **oseltamivir** - problem is that it must be inhaled as soon as you are infected with the influenza virus -\> owever, by the time symptoms become apparent, it is too late - BEST way to stop influenza is by yearly vaccination

Answer 984

- epilepsy is a neurological condition causing frequent seizures - seizures are “*sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex*” -\> over-excitation due to too much glutamatergic activity - glutamate is the main excitatory NT within the CNS -\> over-activity causes hyper-excitability

Answer 985

- electroencephalography (EEG) -\> more constant, less regular firing - magnetic resonance imaging (MRI)

Answer 986

o generalised - tonic-clonic seizures - absence seizures - tonic-atonic seizures - myoclonic seizures - status epilepticus o partial/focal seizures - simple - complex

Answer 987

- the increased synchronization begins simultaneously in both hemispheres of brain

Answer 988

- loss of consciousness -\> muscle stiffening -\> jerking/twitching -\> deep sleep -\> wakes up - MOST COMMON MANIFESTATION OF EPILEPSY

Answer 989

- breif staring episodes with behavioural arrest

Answer 990

- sudden muscle stiffening (tonic)/sudden loss of muscle control (atonic) - similar to tonic-clonic without the clear different phases

Answer 991

- sudden, brief muscle contractions -\> see lots of muscle movement

Answer 992

- over 5 minutes of continuous seizure activity - LEAST COMMON BUT, MOST DANGEROUS

Answer 993

- simple = retained awareness/consciousness - complex = impaired awareness/consciousness

Answer 994

- seizures which begins within a particular area of brain, and may spread out

Answer 995

- increase in excitatory neurotransmitter -\> most commonly glutamate - decrease of inhibition -\> most commonly GABA

Answer 996

1. action potential arrives at the pre-synaptic terminal 2. voltage-gated Na⁺ channel (VGSC) opens -\> membrane depolarisation 3. voltage-gated K⁺ channel (VGKC) opens à membrane repolarisation 4. Ca²⁺influx through VGCCs à vesicle exocytosis 5. synaptic vesicle associated (SV2A) protein (docking protein) allows vesicle (containing glutamate) attachment to the presynaptic membrane 6. glutamate is released into the synapse 7. glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors)

Answer 997

- voltage-gated sodium channel blockers - voltage-gated calcium ion blockers - glutamate exocutosis and receptors

Answer 998

- fast onset with a long half-life/time of action

Answer 999

- carbamazepine - lamotrigine

Answer 1000

- mechanism = stabilises the inactive state of the Na⁺ channel -\> more likely to remain in an inactive state -\> reduced neuronal activity - uses = tonic-clonic and partial seizures - issues = enzyme inducer of the cytochrome P450 pathways -\> reduces the activity of a number of other drugs and also can cause potentially lethal skin side effects (Steven Johnson Syndrome & toxic epidermal necrolysisEN) in individuals with HLA-B\*1502 allele -\> more common in Chinese people

Answer 1001

- mechanism = directly inactivates Na⁺ channels -\> reduces glutamate neuronal activity - uses = tonic-clonic and absence seizures - issues = no notable issues

Answer 1002

**- ethosuximide** is a T-type calcium channel (predominantly found in neurones) antagonist -\> T-type and not L-type as targetted by hypertensive treatments - mechanism = T-type Ca²⁺channel antagonist -\> reduces activity in relay thalamic neurones -\> prevents the propagation of the AP -\> decreased neurotransmission - uses = absence seizures

Answer 1003

- levetiracetan - topiramate

Answer 1004

- mechanism = binds to synaptic vesicle associated protein (SV2A) -\> prevents and reduces glutamate exocytosis - uses = myoclonic seizures

Answer 1005

- mechanism = inhibits NMDA and kainate receptors and also affects VGSCs & GABA receptors -\> affects a few receptors so a bit of a ‘dirty drug’ - uses = myoclonic seizures -\> MOST COMMON USES IS NEUROPATHIC PAIN AND NOT EPILEPSY

Answer 1006

1. GABA can be released tonically (released naturally without stimulation) or following neuronal stimulation 2. GABA activates inhibitory post-synaptic GABA_A receptors 3. GABA_A receptors are chloride (Cl^-) channels -\> leads to **membrane hyperpolarisation** 4. GABA is taken up by the GAT transporter 5. GABA is then metabolised by GABA transaminase (GABA-T) 6. GABA is broken down back into glutamate

Answer 1007

o mechanism = a positive allosteric modulator of GABA-A receptors -\> doesn’t activate the channel alone, but it increases the activity of the GABA that binds to the channel - increases GABA activity, but doesn’t increase the amount of GABA in the synapse - GABA receptor activated more -\> PAM -\> increases GABA-mediated inhibition o uses = status epilepticus -\> administrated as a rectal gel

Answer 1008

o mechanism = inhibits GABA transaminase enzyme -\> increases GABA-mediated inhibition - has dual mechanism of action: - \> inhibits GABA-T -\> increases the amount of GABA - \> reduces the amount of glutamate being formed o uses = all forms of epilepsy apart from status epilepticus due to diazepam being so more effective

Answer 1009

- carbamazepine - lamotrigine - valproate

Answer 1010

- ethosuximide - lamotrigine - valproate

Answer 1011

- valproate

Answer 1012

- levetiracetam - valproate - topiramate

Answer 1013

- diazepam

Answer 1014

- carbamazepine - lamotrigine - levetiracetam - valproate

Pharmacology Flashcards

(1089 cards)