Pharmacology And Therapeutics Flashcards

Question

What neurotransmitter stimulates adrenoceptors?

Answer 1

Adrenaline or noradrenaline

Answer 2

Muscarinic receptors

Answer 3

Acetylcholinesterase

Answer 4

Acetyl CoA + Choline

Answer 5

Uptake 1 transport proteins

Answer 6

The effect of the body on the drug

Answer 7

The effect of the drug on the body

Answer 8

1) Receptors 2) Ion channels 3) Transport Systems 4) Enzymes

Answer 9

It is a muscarine antagonist

Answer 10

1) Voltage sensitive ion channels | 2) Receptor-linked ion channels

Answer 11

1) Local anaesthetics | 2) Calcium channel blockers

Answer 12

Tricyclic antidepressants (TCAs)

Answer 13

They slow down the transporter which elevates the amount of noradrenaline in the synapse

Answer 14

1) Enzyme inhibitors 2) False substrates 3) Prodrugs

Answer 15

Anticholinesterases (e.g. neostigmine)

Answer 16

Methyldopa- an antihypertensive drug | It takes the place of dopa and follows the same pathway producing false product

Answer 17

A drug which needs to be metabolised to produce it's active form, to allow it to work

Answer 18

Chloral hydrate which is converted into trichloroethanol

Answer 19

It is not a drug binding site but it allows a free reservoir of the drug in the blood

Answer 20

The affinity and the efficacy of the drug

Answer 21

Muscarinic- Atropine | Nicotinic- Hexamethonium

Answer 22

A drug which produces the maximal response from a cell

Answer 23

A drug which can be an agonist and an antagonist at some time

Answer 24

They have affinity but no efficacy

Answer 25

1) Competitive | 2) Irreversible

Answer 26

They bind to the same site as agonists. they shift the D-R curve to the right

Answer 27

They bind tightly or at different sites

Answer 28

Transport protein

Answer 29

1) Receptor blockade 2) Physiological antagonism 3) Chemical antagonism 4) Pharmacokinetic antagonsim

Answer 30

Different receptors produce opposite effects in the same tissue. e.g. Noradrenaline and histamine on blood pressure

Answer 31

The drug reduces the concentration of an agonist by forming chemical complexes e.g. Dimercaprol which forms heavy metal complexes (chelating agent)

Answer 32

An antagonist which decreases the concentration of active drug at the site of action. Can decrease absorption, increase metabolism, increase excretion e.g. barbiturates

Answer 33

The gradual decrease in responsiveness to a drug with repeated administration (days/weeks) e.g. diazepam (benzodiazepines) for epilepsy. Stops seizures at low doses

Answer 34

1) Pharmacokinetic factors 2) Loss of receptors 3) Change in receptors 4) Exhaustion of mediated stores 5) Physiological adaptation

Answer 35

Causes increased rate of metabolism of the drug | e.g. barbiturates: alcohol

Answer 36

Receptors are down-regulated by membrane endocytosis | e.g. β-adrenoceptors

Answer 37

Receptor desensitisation from a conformational change in the receptor e.g. nicotinic ACh receptor at the neuromuscular junction

Answer 38

Amphetamine | Enters the brain and is taken up into the presynaptic neurone and increases release of noradrenaline in the brain

Answer 39

It is homeostatic response where tolerance to the drug side effects occurs, e.g. you lose drowsiness or nausea

Answer 40

1) Ion-channel linked receptors 2) G-protein coupled receptors 3) Kinase-linked type 4) Intracellular steroid type receptors

Answer 41

Type 1 ion-channel linked receptors

Answer 42

Type 2 G-protein coupled receptors

Answer 43

Chemical antagonism

Answer 44

Increased metabolic degradation

Answer 45

``` Administration Absorption Distribution Metabolism Excretion ```

Answer 46

Local Systemic Enteral Parenteral

Answer 47

Intravenously

Answer 48

1) Bulk flow transfer (i.e. in the bloodstream) | 2) Diffusional transfer (i.e. molecule by molecule over short distances)

Answer 49

1) Diffusing through lipid 2) Diffusing through aqueous pores in the lipid 3) Carrier molecules 4) Pinocytosis

Answer 50

Where ions become trapped in the blood due to pH. Ionised and unionised form of the drug is in a dynamic equilibrium which causes slow release of the drug.

Answer 51

1) Regional blood flow 2) Extracellular binding 3) Capillary permeability 4) Localisation in tissues

Answer 52

Amount of blood flowing to different tissues varies when at rest compared to during strenuous exercise e.g. when exercising more blood (and drug) will be delivered to the muscles

Answer 53

If a drug is heavily bound to plasma proteins you would have to administer higher doses of the drug to have an effect. Ionised drugs can move through the H₂O filled gap junctions

Answer 54

Capillary permeability is dependent upon the organ in question

Answer 55

Kidneys and Liver

Answer 56

In the proximal tubule acids and bases are actively secreted | In the proximal and distal tubules lipid soluble drugs are reabsorbed

Answer 57

Biliary excretion- large molecular weight molecules can concentrate Active transport systems- into bile (bile acids and glucuronides) Drugs become trapped in bile and are deposited in the intestines to be excreted in the faeces, or they are reabsorbed into the blood and excreted in the urine

Answer 58

Drugs (or metabolites) are excreted into the gut (via bile) then reabsorbed and taken to the liver and excreted again (via bile). This leads to drug persistence

Answer 59

The proportion of the administered drug that is available within the body to exert it's pharmacological effect The amount of drug that appears in the circulation after it has left the liver

Answer 60

The time taken for the concentration of drug in the blood/plasma to fall to half of it's original value

Answer 61

The blood clearance is the volume of blood (plasma) cleared of a drug in a unit of time

Answer 62

a) Ionised drug

Answer 63

The rate of elimination of a drug where the amount of drug decreases at a rate that is proportional to the concentration of the drug remaining in the body. It applies to most drugs in clinical use

Answer 64

The rate of elimination of a drug where you get rid of the same amount of drug per unit time. Implies a saturable (usually enzymic) metabolic process which applies to very few drugs. Half life does not apply

Answer 65

The degradation and alteration of a drug by the liver, before it enters the systemic circulation

Answer 66

Oxidation Reduction Hydrolysis

Answer 67

``` Glucuronidation Acetylation Amino acid conjugation Sulphation Methylation Glutathione conjugation ```

Answer 68

Embedded on the smooth endoplasmic reticulum in the liver. It is an important enzyme in phase I oxidising reactions and it is involved in the metabolism of the majority of drugs

Answer 69

Hydroxylation

Answer 70

Pentobarbitone makes you sleep but the metabolised form is inactive

Answer 71

Acetanilide is a prodrug. It is toxic, but it is metabolised to form paracetamol.

Answer 72

Alcohol dehydrogenase

Answer 73

Zero order kinetics- it is saturable

Answer 74

NADH⁺ and NADPH⁺

Answer 75

Prepares a drug for phase II metabolism by introducing a functional group such as -OH, -NH₂, -SH or -COOH

Answer 76

Glucuronidation reactions

Answer 77

A sugar is added to the drug to produce a soluble molecule which can be excreted (often in bile)

Answer 78

Acetylation reactions

Answer 79

Acetyl CoA acts as a donor compound; an acetyl group is transferred to an electron-rich atom (N, O or S)

Answer 80

Methyl group is transferred to an electron-rich atom (N, O or S)

Answer 81

Conjugation reactions. They utilise -OH, -NH₂, -SH and -COOH

Answer 82

Drugs which mimic the action of acetylcholine, mainly in the peripheral nervous system

Answer 83

Choline acetyltransferase

Answer 84

Muscarinic receptors; will also generate a response in nicotinic responses but requires higher doses of acetylcholine

Answer 85

Vagus nerve

Answer 86

α, β, γ, δ and ε | Subunit combination determines the ligand binding properties of the receptor

Answer 87

Contraction of the ciliary muscle: accomodation for near vision Contraction of the sphincter pupillae: Constricts pupil (miosis) and improves drainage of intraocular fluid via the canals of Schlemm Lacrimation (tears)

Answer 88

Binds to M2 acetylcholine receptors in atria and nodes of the heart. decreases cAMP: 1) Decreased Ca²⁺ entry = decreased cardiac output 2) Increased K⁺ effect = decreased heart rate

Answer 89

Most blood vessels do not have parasympathetic innervation ACh acts on vascular endothelial cells to stimulate NO release via M3 acetylcholine receptors NO induces vascular smooth muscle relaxation Results in a decrease in TPR

Answer 90

Decreased heart rate Decreased cardiac output (due to decreased atrial contraction) Vasodilation (stimulation of NO production) All of these combine to produce a sharp drop in blood pressure

Answer 91

Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle- it has an excitatory effect Lung: bronchoconstriction Gut: Increased peristalsis Bladder: Increased bladder emptying

Answer 92

Salivation Increased bronchial secretions Increased gastrointestinal secretions (including gastric HCl production) Increased sweating (SNS mediated)

Answer 93

1) Choline esters (bethanechol) 2) Alkaloids (pilocarpine) Both drugs have very similar structures to acetylcholine

Answer 94

A non-selective muscarinic agonist with good lipid solubility. Particularly useful in ophthalmology as a local treatment for glaucoma Side effects: blurred vision, sweating, gastrointestinal disturbance and pain, hypotension, respiratory distress

Answer 95

A selective M3 acetylcholine receptor agonist. Mainly used to assist bladder emptying and to enhance gastric motility. Side effects: sweating, impaired vision, nausea, bradycardia, hypotension, respiratory difficulty

Answer 96

Increase the effect of normal parasympathetic nerve stimulation by slowing down the action of acetyl cholinesterase 1) Reversible anticholinesterases (e.g. physostigmine, neostigmine, donepezil) 2) Irreversible anticholinesterases (e.g. ecothiopate, dyflos, sarin)

Answer 97

Metabolise acetylcholine to choline and acetate 1) Acetylcholinesterase 2) Butyrylcholinesterase

Answer 98

Found in all cholinergic synapses (peripheral and central) | Very rapid action and highly selective for acetylcholine

Answer 99

Found in plasma and most tissues but not in cholinergic synapses with broad substrate specificity. It is the principal reason for low plasma acetylcholine. Shows genetic variation

Answer 100

Enhanced muscarinic activity

Answer 101

Further enhancement of muscarinic activity. Increased transmission at all autonomic ganglia

Answer 102

Depolarising block at autonomic ganglia and neuromuscular junction

Answer 103

Competes with acetylcholine for active site on the cholinesterase enzyme. Donates a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding. Carbamyl is removed by slow hydrolysis. Increases the duration of acetylcholine activity in the synapse e.g. physostigmine, neostigmine

Answer 104

Primarily acts at the postganglionic parasympathetic synapse. It is a reversible anticholinesterase drug. Used to treat glaucoma, aiding intraocular fluid drainage. Also used to treat atropine poisoning, particularly in children

Answer 105

Rapidly react with the enzyme active site, leaving a large blocking group. This is stable and resistant to hydrolysis, so recovery may require production of new enzymes e.g. ecothiopate

Answer 106

A potent inhibitor of acetylcholinesterase. Slow reactivation of the enzyme by hydrolysis takes several days. Used as eye drops to treat glaucoma. Side effects: sweating, blurred vision, GI pain, bradycardia, hypotension and respiratory difficulty

Answer 107

Non-polar anticholinesterase drugs can cross the blood-brain barrier Low doses: Excitation with possible convulsions High doses: Unconsciousness, respiratory depression, death

Answer 108

Donepezil and tacrine. Acetylcholine is important in learning and memory. Potentiation of central cholinergic transmission relieves Alzheimer's symptoms but does not effect degeneration

Answer 109

Organophosphate is an insecticide or nerve agent which causes severe toxicity (increased muscarinic activity, CNS excitation and depolarising neuromuscular block) Treatment: IV atropine, artificial respiration, IV pralidoxime (must be given within a couple of hours)

Answer 110

Pre- and post-ganglionic parasympathetic synapses

Answer 111

μ opioid receptors

Answer 112

Injected into venous system → heart → pulmonary circulation → aorta → systemic circulation → brain → brain capillaries →diffuses across blood-brain barrier (lipophilic) → binds opioid receptors

Answer 113

Pharmacokinetic tolerance means you produce more alcohol dehydrogenase so you have to drink larger quantities of alcohol to achieve the same results

Answer 114

The effects of fentanyl occur at a lower dose than heroin

Answer 115

Where the drug binds the receptor more readily, meaning the drug-receptor complex is formed for longer periods

Answer 116

A drug's ability to activate the receptor to produce a response

Answer 117

It is a competitive opioid receptor antagonist

Answer 118

Where drugs have a very similar structure, but the very small changes between them change the activity of the drug e.g. codeine, morphine and heroin

Answer 119

A partial agonist would not have as much of a response on the curve (it would have ∼ half the height)

Answer 120

ED50 (effective dose where you see 50% response) Potency ≈ affinity + efficacy Clinically efficacy is not relevant than potency

Answer 121

``` Liquids Syrups Tinctures Powders Soluble (effervescent) tablets Capsules Tablets Enteric-coated tablets ```

Answer 122

To alter bioavailability of a drug To improve the flavour of the drug To reduce the rate at which the drug is released into the blood

Answer 123

Ionisation affects whether the drug can be absorbed through the membrane. pH affects whether the drug is ionised or non-ionised.

Answer 124

When it needs to be absorbed quickly, for example for a headache so it works more quickly

Answer 125

When slow release of the drug is required, for example for long lasting pain relief in arthritis

Answer 126

To ensure the effects of the drug are similar to the original form of the drug and to minimise side effects of the new drug

Answer 127

A narrow range between a harmful effect and the desired therapeutic effect

Answer 128

Intravenous administration Use prodrugs Drug could work at very low doses or administered in high doses

Answer 129

Liver disease | Gastrointestinal diseases which affect absorption

Answer 130

They have no efficacy as they do not cause a response

Answer 131

1) Acetylcholine 2) Atropine (antagonist) 3) Acetyl-cholinesterase (enzyme in the synapse) 4) Adrenaline (adrenergic receptor) 5) Acetate (breakdown product)

Answer 132

All of the autonomic nervous system

Answer 133

A nicotinic receptor antagonist

Answer 134

1) Bind to and block the nicotinic receptor 2) Enter the ion channel and block passage through the channel Use dependent block: the more ACh present (the more active the channel) the more effective the antagonist Partial blockade: slows the ion channel down e.g. Hexamethonium and Trimetaphan

Answer 135

The effect will depend upon which arm of the autonomic nervous system is active. If parasympathetic is active it will block parasympathetic actions (e.g. Decrease gut motility, increase heart rate etc)

Answer 136

1) Increased heart rate | 3) Bronchodilation

Answer 137

It would inhibit blood vessel constriction and reduce renin secretion which would decrease blood pressure

Answer 138

Hexamethonium | Trimetaphan

Answer 139

Hexamethonium is primarily an ion channel blocker Trimetaphan is primarily a receptor antagonist But both drugs can have both actions

Answer 140

Drugs predominantly only target the autonomic nervous system. Toxins bind irreversibly to receptors, and target both the autonomic nervous system and the skeletal muscle, causing paralysis

Answer 141

They are only found on the post-synaptic neurones in the parasympathetic nervous system, and sweat glands, so they produce a much more specific effect

Answer 142

Atropine Hyoscine Tropicamide

Answer 143

These drugs are very similar with the exception of the CNS: Normal dose- Atropine has little effect on the CNS, but Hyoscine induces sedation and amnesia Toxic dose- Atropine induces mild restlessness and agitation whilst Hyoscine induces CNS depression or paradoxical CNS excitation associated with pain

Answer 144

Hyoscine | Atropine is less M1 selective

Answer 145

They block: Trachea and bronchiole constriction Salivary gland watery secretions Decrease in heart rate and contractility Plus they induce sedation

Answer 146

The cholinergic system inhibits the dopaminergic system in Parkinson's disease (The loss of dopaminergic neurones = less dopamine = less D1 receptor activation) M4 receptors also inhibit D1, amplifying the response Muscarinic receptor antagonists dampen down these effects

Answer 147

Used for asthma. Inhaled to produce effects. It is a similar structure to atropine, but it is a larger molecule, so it cannot cross the membrane to produce side effects

Answer 148

Parasympathetic nervous system increases GI motility and tone and increases secretions Muscarinic receptor antagonists block these effects, reducing the symptoms of IBS

Answer 149

Inability to focus on near objects

Answer 150

Answer: 4 (and 1) 2 and 4 are anticholinesterases (increase amount of ACh in the synapse) 5 can reverse anticholinesterase poisoning 4 is reversible 1 is a muscarine agonist

Answer 151

Botox Prevents ACh vesicles from docking with the membrane and exocytosing. Injected directly into the skeletal muscle it causes paralysis of the muscle

Answer 152

α1 = α2 > β1 = β2

Answer 153

β1 = β2 > α1 = α2

Answer 154

α2 receptor provides negative feedback to the neurone, to inhibit more noradrenaline release

Answer 155

``` Adrenaline (non-selective) Phenylephrine (α1) Clonidine (α2) Dobutamine (β1) Salbutamol (β2) Higher concentrations of drugs will start to lose selectivity and effect other receptors ```

Answer 156

Adrenaline works on β-receptors (preferably to α-receptors) causing: - bronchodilation (β2) - tachycardia (β1) - ↑ vasoconstriction (α1) It will have a small effect on breathing and heart rate

Answer 157

Asthma emergencies Acute bronchospasm associated with chronic bronchitis or emphysema β2 receptor causes bronchodilation Suppression of mediator release

Answer 158

Glaucoma = increased intraocular pressure due to poor drainage of the aqueous humour Adrenalin causes decreased production of aqueous humour due to vasoconstriction of the ciliary body blood vessels

Answer 159

Adrenaline causes vasoconstriction which reduces blood supply and prevents removal of the local anaesthetic. This prolongs the action of the drug Act on the α1 receptor

Answer 160

``` 1) Secretions Reduced and thickened mucous 2) CNS Minimal 3) CVS effects - tachycardia, palpitations, arrhythmias - cold extremities, hypertension - overdose - cerebral haemorrhage, pulmonary oedema 4) GIT Minimal 5) Skeletal muscle Tremor ```

Answer 161

``` It is chemically related to adrenaline but it id resistant to degradation by the COMT gene (but not MAO) - Vasoconstriction - Mydriatic - Nasal decongestant Most selective for α1 > α2 > β1/2 ```

Answer 162

Found on adrenergic presynaptic neurones Decreases release of NA and decrease synaptic drive Most selective for α2 > α1 > β1/2

Answer 163

Treatment of hypertension and migraine Reduces sympathetic tone- inhibition of NA release = decrease in Renin-Angiotensin-Aldosterone-System which causes ↓ heart rate and ↓ vasoconstriction

Answer 164

It is chemically similar to adrenaline but it is less susceptible to uptake 1 and MAO breakdown. It has a plasma half-life of 2 hours Most selective for β1 = β2 > α1/2

Answer 165

- Cardiogenic shock - Acute heart failure - Myocardial infarction Non-selective for β1 and β2. β2 activity causes a fall in venous blood pressure which results in a reflex tachycardia via the stimulation of baroreceptors

Answer 166

Used in cardiogenic shock- does not result in reflex tachycardia like Isoprenaline, but it is rapidly metabolised by COMT Most selective for β1 > β2 > α1/2

Answer 167

Used in the treatment of asthma (β2-relaxation of bronchial smooth muscle) and in treatment of threatened premature labour (β2-relaxation of uterine smooth muscle) Most selective for β2 > β1 > α1/2

Answer 168

Reflex tachycardia Tremor Blood sugar dysregulation

Answer 169

Low Doses- euphoria, excitement, increased motor activity | High Doses- activation of CTZ, CNS depression, respiratory failure, convulsions and death

Answer 170

Low Doses- tachycardia, vasoconstriction, raised blood pressure High Doses- ventricular fibrillation and cardiac arrest

Answer 171

A dietary amino acid | Found naturally in cheese, red wine and soy sauce

Answer 172

When taking MAO inhibitors tyramine competes with MAO which is required for the breakdown of NA Causes hypertensive crisis

Answer 173

Involved in receptor-mediated negative feedback of noradrenaline release

Answer 174

α1: Vasoconstriction, relaxation of GIT α2: Inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions β1: Increased cardac rate and force, relaxation of GIT, renin release from kidney β2: Bronchodilation, vasoconstriction, relaxation of visceral smooth muscle, hepatic glycogenolysis β3: Lipolysis

Answer 175

``` Non-selective (α1 + β1): Labetalol α1 + α2: Phentolamine α1: Prazosin β1 + β2: Propranolol β1: Atenolol ```

Answer 176

Hypertension Cardiac arrhythmias Angina Glaucoma

Answer 177

1) Sympathetic nerves that release the vasoconstrictor noradrenaline 2) Kidney- blood volume/ vasoconstriction 3) Heart 4) Arterioles- determine peripheral resistance 5) CNS- determines blood pressure set point and regulates some systems involved in blood pressure control and autonomic nervous system

Answer 178

1) Acts in CNS to reduce sympathetic tone 2) Heart: reduces heart rate and cardiac output but this effect disappears in chronic treatment 3) Kidney: reduces renin production. Common long-term feature in their anti-hypertensive action is a reduction in peripheral resistance

Answer 179

Involved in receptor-mediated positive feedback of noradrenaline

Answer 180

``` Bronchoconstriction Cardiac failure Hypoglycaemia Fatigue Cold extremities Bad dreams ```

Answer 181

Activation of β2 receptors cause bronchodilation so non-selective β-antagonists cause bronchoconstriction, In asthmatic patients this can be dramatic and life-threatening. Also clinically important in patients with obstructive lung disease (e.g. bronchitis)

Answer 182

Patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output, and removal of this by blocking β-receptors will produce a degree of cardiac failure

Answer 183

Use of β-antagonists mask the symptoms of hypoglycaemia (sweating, palpitations, tremor). Non-selective β-antagonists will also block the β2-receptor driven breakdown of glycogen

Answer 184

Due to reduced cardiac output and reduced muscle perfusion

Answer 185

Loss of β-receptor mediated vasodilation in cutaneous vessels

Answer 186

β1 and β2 (non-selective) adrenoceptor antagonist In a subject at rest propanolol causes very little change in heart rate, cardiac output or arterial pressure, but reduces the effect of exercise or stress on these variables

Answer 187

"Cardio-selective drugs" β1-selective: antagonises the effects of noradrenaline on the heart but will affect any tissue with β1 receptors (e.g. kidney) Less effect on the airways than non-selective drugs, but still not safe with asthmatic patients. Selectivity is concentration dependent

Answer 188

Dual acting β1 and α1 antagonist, higher ratio of β1 to α1 (4:1) This drug lowers blood pressure via a reduction in peripheral resistance Like β-blockers, labetalol induces a change in heart rate or cardiac output but this effect wanes with chronic use

Answer 189

1) Fall in arterial pressure 2) Postural hypotension 3) Cardiac output/ heart rate increases- reflex response to fall in arterial pressure (β-receptors) 4) Blood flow through cutaneous and splanchnic vascular beds increased, but effects on vascular smooth muscle are slight

Answer 190

Non-selective α-antagonist Causes vasodilation and a fall in blood pressure due to blockade of α1-receptors Blockade of α2-receptors tends to increase noradrenaline release (takes away negative feedback), enhances the reflex tachycardia that occurs with any blood pressure lowering agent Increased GIT motility, diarrhoea a common problem

Answer 191

Highly selective α1-antagonist Causes vasodilation and a fall in arterial pressure Less tachycardia than non-selective antagonists since they do not increase noradrenaline release from nerve terminals (no α2 actions) Cardiac output decreases, due to fall in venous pressure as a result of dilation of capitance vessels Hypotensive effect is dramatic

Answer 192

An antihypertensive agent taken up by noradrenergic neurons. Decarboxylated and hydroxylated to form false transmitter α-methyl-noradrenaline Not deaminated within neuron by MAO (Mono Amine Oxidase) and therefore tends to accumulate in larger quantities than noradrenaline, and displaces noradrenaline from synaptic vesicles

Answer 193

False transmitter released in the same way as noradrenaline but 1) Less active than noradrenaline on α1-receptors, less effective in causing vasoconstriction 2) More active on presynaptic (α2) receptors, auto-inhibitory feedback mechanism operates more strongly, reduces transmitter release below normal levels Some CNS effects; stimulates vasopressor centre in the brain stem to inhibit sympathetic outflow

Answer 194

Renal and CNS blood flow are well maintained, so widely used in hypertensive patients with renal insufficiency or cerebrovascular disease Recommended in hypertensive pregnant women, has no adverse effects on foetus despite crossing the blood-placenta barrier

Answer 195

Dry mouth Sedation Orthostatic hypotension Male sexual dysfunction

Answer 196

Increase in sympathetic drive to the heart via β1 can precipitate or aggrivate arrhythmias. Particularly after myocardial infarction there is an increase in sympathetic tone AV conductance depends critically on sympathetic activity. β-adrenoceptor antagonists increase the refractory period of the AV node, interfering wth AV conduction in atrial tachycardias, and slowng ventricular rate

Answer 197

Propanolol- a non-selective β-antagonist; effects mainly attributed to β1-antagonism

Answer 198

Stable: pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels (e.g. atheroma) Unstable: pain with less and less exertion, culminating with pain at rest. Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel. Risk of infarction Variable: occurs at rest, caused by coronary artery spasm, associated with atheromatous disease

Answer 199

Decrease heart rate Decrease systolic blood pressure Decrease cardiac contractile activity At low doses β1-selective agents (e.g. metoprolol) reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle Reduce the oxygen demand whilst maintaining the same degree or effort

Answer 200

Side effects: fatigue, insomnia, dizziness, sexual dysfunction, bronchospasm, bradycardia, heart block, hypotension, decreased myocardial contractility NOT USED: bradycardia (<55bpm), bronchospasm, hypotension (systolic <90mmHg), AV block or severe congestive heart failure

Answer 201

Non selective β1 and β2 antagonists e.g. carteolol hydrochloride, levobunolol hydrochloride, timolol maleate Reduce the rate of aqueous humour formation by blocking the receptors on ciliary body Selective β1 antagonists betaxolol hydrochloride also shown to be effective

Answer 202

Anxiety states- to control somatic symptoms associated with sympathetic over-reactivity, such as palpitations and tremor Migraine prophylaxis Benign essential tremor

Answer 203

Causes decreased pupil size as it enhances parasympathetic nervous system response which causes more contraction of sphincter pupilae muscle. Increased accommodation for near vision due to enhanced PNS leading to increased lens bulging and constriction of ciliary muscles. Loss of light reflex due to PNS causing maximal constriction. Used to treat glaucoma as it causes contraction of the sphincter pupilae which allows the canal of Schlemm to open and the intraocular fluid to drain. Has side effects so more selective drugs are used.

Answer 204

Causes increased pupil size due to inhibition of the PNS (antagonist) causing less constriction of the sphincter pupilae. Decreased accommodation for near vision due to decreased contraction of the ciliary muscles. Loss of light reflex due to loss of ability to constrict. Clinically tropicamide is used to allow visualisation of the retina

Answer 205

1) α2-receptors on dilator pupilae which means radial muscle constricts which dilates the pupil 2) Activity on β1-receptors on ciliary body which means aqueous humour production generated 3) Activity on α1-receptors on blood vessels which means vasoconstriction occurs

Answer 206

Dipivetrine causes vasoconstriction (main effect outweighs other sympathetic effects) Timolol also reduces blood flow

Answer 207

Eye is heavily vascularised- more gets into the blood vessels than into the eye (need a higher dose). If this is chronic treatment, over time it will leak into the systemic circulation With eye drops some of the drug is lost Use more selective drug to have less systemic effects Timolol is a β-blocker = more selective as an antagonist than dipivetrine as an agonist (prodrug for adrenaline)- acts on both α and β

Answer 208

Organophosphate and heroin both affect the PNS. Opiate receptors on GABA interneurones; respond to heroin which causes disinhibition. Heroin causes massive stimulation of cranial nerve 3 (the occulomotor nerve), which leads to pathognomic pupil constriction if given a toxic dose. If toxicity continues and asphyxia occurs loss of oxygen causes nerve damage and further dilation Organophosphate is an anticholinesterase so it causes increased ACh in the synapse BOTH CAUSE CONSTRICTION OF THE SPHINCTER PUPILAE

Answer 209

End result the same as pilocarpine. Gets into venous drainage channels (main action to break down collagen). Clear path within venous drainage channel means there is less resistance to flow and therefore improved drainage e.g. latanoprost

Answer 210

Ciliary body β- receptors are coupled to carbonic anhydrase (which generates bicarbonate). Inhibiting carbonic anhydrase means less bicarbonate is generated so not enough Na and bicarbonate are available to create aqueous humour.

Answer 211

Action potential is all or nothing (threshold to activate) | End-plates have a graded potential

Answer 212

Nicotinic (pentameric) receptors

Answer 213

It binds to the α-subunit. This means you need more than one ACh to stimulate the receptor

Answer 214

Spasmolytics e.g. Diazepam, baclofen They reduce the action potential propagation and reduce muscle contraction of skeletal muscle

Answer 215

Local anaesthetics Inhibit the influx of sodium by blocking the voltage-sensitive sodium channels, which reduces the generation of propagation of action potentials. Can also effect the motor neurones so avoid injecting near to motor neurones

Answer 216

Hemicholinium (Inhibits/slows down reuptake of choline so leads to depletion of ACh) Ca²⁺ entry blockers (interact with presynpatic Ca²⁺ channels to dampen down Ca²⁺ influx) Neurotoxins (e.g. cobra venoms and bacterial toxins. Inhibits release of ACh)

Answer 217

Tubocurarine | Suxamethonium

Answer 218

Spasmolytics e.g. Dantrolene Works by inhibiting the release of Ca²⁺ ions from the sarcoplasmic reticulum in skeletal muscle fibres

Answer 219

Postsynaptic action

Answer 220

Tubocurarine | Atracurium

Answer 221

Suxmethonium

Answer 222

Induces an extended end plate depolarisation which causes a depolarisation block (over stimulating the receptors) It is broken down much slower than ACh so they switch off due to overstimulation Phase 1 (depolarisation) block Causes fasciculations then flaccid paralysis

Answer 223

Administered intravenously Causes ∼5 minute paralysis Metabolised by pseudocholinesterase in liver and plasma

Answer 224

- Endotracheal intubation | - Muscle relaxant for electroconvulsive therapy (used to treat severe clinical depression- last resort)

Answer 225

1) Post-operative muscle pains (from fasciculations) 2) Bradycardia - direct muscarinic action on heart (can be blocked with atropine premeds) 3) Hyperkalaemia - soft tissue injury or burns damage cholinergic fibres so upregulates nicotinic receptors on surface (denervation super sensitivity) = exaggerated response to drug; ventricular arrhythmias / cardiac arrest 4) Increased intraocular pressure - avoid for eye injuries, glaucoma

Answer 226

``` A competitive nicotinic ACh antagonist 70-80% block necessary (to bring down the graded potential) Tubocurarine causes flaccid paralysis Administration causes paralysis of: 1) extrinsic eye muscles (double vision) 2) small muscles of the face, limbs, pharynx 3) Respiratory muscles (unblocked in reverse order) ```

Answer 227

1) Relaxation of skeletal muscles during surgical operations- particularly abdominal muscles (= less anaesthetic) 2) Permits artificial ventilation- causes relaxation of respiratory muscles

Answer 228

Administer anticholinesterases Increases the amount of ACh in the synaptic cleft e.g. Neostigmine (and atropine to reduce stimulation of muscarinic receptors (combined IV injection)

Answer 229

Administered intravenously (highly charged) Induces paralysis for 40-60 mins (long duration) Does not cross the BBB or placenta Is not metabolised Excreted: 70% urine; 30% bile

Answer 230

Atracurium | Has a 15 minute duration of action so is less dependent on rapid excretion.

Answer 231

Caused by ganglion block; histamine release 1) HYPOTENSION - Ganglion blockade = decreased TPR - Histamine release from mast cells 2) Tachycardia (can lead to arrhythmias) - reflex - blockade of vagal ganglia (reduces the firing rate of the heart) 3) BRONCHOSPASM 4) Excessive secretions (bronchial and salivary) 5) Apnoea (always assist respiration)

Answer 232

5) Respiration

Answer 233

4) A flaccid paralysis

Answer 234

C) Zero efficacy and moderate affinity Only agonists possess efficacy

Answer 235

Physiological antagonism

Answer 236

Barbiturates

Answer 237

A partial agonist | e.g. clonidine

Answer 238

It reduces reabsorption in the kidney

Answer 239

c) Increased secretions Blocks the action of acetylcholinesterase which causes a build up of ACh in the synapse and increases the action

Answer 240

They increase dopamine receptor activation

Answer 241

Antagonism of the actions of acetylcholine at nicotinic receptors

Answer 242

Electrical excitation of the cell from action potentials arises from the sino-atrial node which induces membrane depolarisation that promotes If (funny channels) to open and cause a small release of Ca²⁺ into the cytoplasm. The small Ca²⁺ current induces a release of Ca²⁺ from the SR (Ca-induced Ca-release) through It (transient) and Il (Long lasting) ryanodine receptors

Answer 243

Decrease If and and Ica which contractility

Answer 244

Decrease Ica

Answer 245

1) Rate slowing (Cardiac and smooth muscle actions) - Phenylalkylamines (e.g. Verapamil) - Bencothiazepines (e.g. Diltiazem) 2) Non-rate slowing (smooth muscle actions - more potent) - Dihydropyridines (e.g. amlodipine) Rate slowing have higher selectivity on the heart. Non-rate slowing have higher selectivity on the vasculature

Answer 246

Organic nitrates (directly supply NO) and potassium channel openers (tend to lead to hyperpolarisation) Both dilate coronary vessels and improve oxygen to the heart ↑ coronary blood flow Vasodilation = ↓ afterload Venodilation = ↓ preload

Answer 247

Increases heart rate

Answer 248

β-blocker or calcium antagonist as background anti-angina treatment Ivabradine is a newer treatment Nitrate as symptomatic treatment (short acting)- taken pre-exercise Other agents (e.g. potassium channel opener) if intolerant to other drugs

Answer 249

- Worsening of cardiac failure (CO reduction) - Bradycardia (heart block) (due to less conduction through AV node) - Bronchoconstriction (blockade of β2 in airways) - Hypoglycaemia (in diabetics on insulin) (decreased glycogenolysis/gluconeogenesis) - Cold extremities and worsening of peripheral arterial disease (blockade of β2 in skeletal muscle vessels) - Fatigue - Impotence (sexual dysfunction) - Depression - CNS effects (lipophilic agents) e.g. nightmares

Answer 250

Verapamil - Bradycardia and AV block - Constipation (25%) Dihydropyridines- 10-20% patients - Ankle oedema - Headache/flushing - Palpitations

Answer 251

- Reduce sudden death - Prevent stroke - Alleviate symptoms

Answer 252

- Supraventricular arrhythmias (e.g. amiodarone, verapamil) - Ventricular arrhythmias (e.g. flecainide, lidocaine) - Complex (supraventricular and ventricular arrhythmias) (e.g. disopyramide)

Answer 253

Class Mechanism of Action I Sodium channel blockade II β adrenergic blockade III Prolongation of repolarisation ('Membrane stabilisation' mainly due to potassium channel blockade) IV Calcium channel blockade

Answer 254

Used intravenously to terminate supraventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil Used for acute arrhythmias Couples with G causing reduced cAMP

Answer 255

Used for reduction of ventricular responsiveness to atrial arrhythmias Depresses SA automatically and subsequent AV node conduction

Answer 256

Used for superventricular and ventricular tachyarrhythmias- often due to reentry Has complex action probably involving multiple ion channel block Amiodarone accumulates in the body (half life- 10-100 days) Has a number of important adverse effects including: - photosensitive skin rashes - hypo- or hyper- thyroidism - pulmonary fibrosis

Answer 257

Causes inhibition of Na/K/ATPase which results in increased intracellular Ca²⁺ exchange= Positive inotropic effect Central vagal stimulation causes increased refractory period and reduced rate of conduction through AV node

Answer 258

Uses: - Atrial fibrillation and flutter lead to a rapid entricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output - Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV nodes. Fewer impulses reach the ventricles and ventricular rate falls Adverse effects: - Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity

Answer 259

It lowers the threshold for toxicity. Digoxin prevents K⁺ uptake into cells, so more K⁺ outside of cells. If you have lower K⁺ the effect of digoxin is enhanced because you have lower K⁺

Answer 260

Total peripheral resistance

Answer 261

Contraction ↓ radius ↑ resistance ↓ flow Relaxation ↑ radius ↓ resistance ↑ flow

Answer 262

140/90 mmHg

Answer 263

- Stroke (50% of ischaemic strokes) - ~25% of heart failure cases (70% in elderly) Major risk factor for myocardial infarction and chronic kidney disease

Answer 264

ACE inhibitor or angiotensin receptor blocker

Answer 265

Calcium channel blocker or thiazide-type diuretic

Answer 266

ACE inhibitor and calcium channel blocker OR ACE inhibitor and thiazide type diuretic

Answer 267

ACE inhibitor and calcium channel blocker and thiazide type diuretic

Answer 268

Consider low dose spironolactone | Consider β-blocker or α-blocker

Answer 269

Prevents the conversion of angiotensin I to angiotensin II | Also prevents the conversion of bradykinin to inactive metabolytes- this causes a cough

Answer 270

ACE inhibitors

Answer 271

Uses: - hypertension - heart failure - post-myocardial infarction - diabetic nephropathy - progressive renal insufficiency - patients at high risk of cardiovascular disease e. g. Enalapril

Answer 272

Starling's law

Answer 273

Antagonists or type I (AT₁) receptors for Ang II, preventing the renal and vascular actions of Ang II Uses: hypertension and heart failure

Answer 274

ACE inhibitors as there is lower incidence of stroke

Answer 275

Dihydropyridines (DHPs) - More selective for blood vessels - Amlodipine: does not cause any negative inotropy - Also licensed for prophylaxis or angina Non-DHPs (aka rate-limiting) - Verapamil: large negative inotropic effect (more likely to have an effect on the heart)

Answer 276

Amlodipine

Answer 277

DHPs inhibit Ca²⁺ entry into vascular smooth muscle cells | ↓TPR = ↓BP

Answer 278

Because they have a less severe side effect profile so patients are more likely to continue taking them

Answer 279

They have a low plasma renin activity. Need to utilise dual therapy with this ethnic group

Answer 280

α₁ causes vasoconstriction and are found on blood vessels so blocking these will prevent this. This will prevent IP₃ production which means no Ca²⁺ Reduced vasoconstriction but α₂ receptors are negative feedback (particularly in the brain) so you get an enhanced sympathetic response

Answer 281

Thiazide diuretic Increases salt excretion and therefore water causing blood pressure to decrease. It blocks water moving from lumen to blood; blood volume decreases; preload decreases (venous return decreases)

Answer 282

ACE inhibitor which blocks production of angiotensin II- a vasoconstrictor which also causes aldosterone secretion. Causes vasoconstriction and reduces fluid volume. Used as second line treatment as first diuretic will cause compensatory activation of RAAS, which is then targeted by the ACE inhibitor

Answer 283

It slows down the heart rate and increases contractility Heart rate is reduced because the Na/K pump is blocked- sodium then builds up inside the cell- calcium cannot therefore be removed from the cardiac muscle- this will impact contractility

Answer 284

Stable angina occurs after exercise; unstable angina can occur at any time

Answer 285

Blocks vitamin K reductase which prevents the production of clotting factors It prevents the carboxylate the glutamic acid which resides in the clotting factors which allows clotting Factors II, VII, IX, X

Answer 286

Nitric oxide donor. Causes vasodilation (cyclic GMP- interferes with smooth muscle contraction causing vessel relaxation

Answer 287

It is a HMG-CoA reductase inhibitor which is a rate limiting step in cholesterol synthesis

Answer 288

It is a cyclooxygenase inhibitor on platelets which prevents thromboxane synthesis. Thromboxane normally activates platelets and causes vasoconstriction

Answer 289

When the heart does not work efficiently to meet tissue demand Congestive means there is a backlog of blood (pooling) in the venous system

Answer 290

A loop diuretic. It blocks the Na/K/Cl cotransporter in the ascending limb, so water is not absorbed in the descending limb

Answer 291

They target the reward pathway in the brain. | Dopinergic neurons have cell bodies in the ventral tegmental area which project to the nucleus accumbens

Answer 292

- Intranasal - Oral - Inhalation - Intravenous

Answer 293

Inhalation Drug diffuses across alveoli and enters the pulmonary circulation. It then returns to the heart and immediately into the systemic circulation (to the brain)

Answer 294

- Narcotics/painkillers - opiate like drugs e.g. heroin - Depressants - 'downers' e.g. alcohol, benzodiazepines (valium), barbiturates - Stimulants - 'uppers' e.g. cocaine, amphetamine ('speed'), caffeine, metamphetamine ('crystal meth') Miscellaneous e.g. Cannabis, Ecstasy (MDMA)

Answer 295

1) Blood 2) Brain 3) High perfusion tissues 4) Low perfusion tissues 5) Fat

Answer 296

For 30 days in fat

Answer 297

There is a poor correlation

Answer 298

Converted to 11-hydroxy-THC | This is more potent

Answer 299

Liver → 11-hydroxy-THC GIT → 65% Bile → enterohepatic recycling Urine → 25%

Answer 300

CB₁ and CB₂ receptors

Answer 301

In the brain - Hippocampus - Cerebellum - Cerebral cortex - Basal ganglia

Answer 302

Immune cells

Answer 303

Cannabis binds to CB₁ receptors which decreases GABA firing to the ventral tegmental area. This then increases dopamine release to the nucleus accumbens (disinhibition)

Answer 304

The Anterior Cingulate Cortex has a major role in performance monitoring with behavioural adjustment in order to avoid losses (e.g. stop talking when driving requires more concentration) Heavy cannabis user experience hypoactivity in the ACC

Answer 305

1. Presynaptic inhibition of GABA (by cannabis binding to CB₁) increases MCH (melanin concentrating hormone) neuronal activity 2. Increased orexin production MHC and orexin stimulation makes you hungry

Answer 306

CB₂ receptors are found on immune cells - B cells - T cells - NK cells - Macrophages - Mast cells

Answer 307

Causes memory loss - Limbic regions (Amnestic effects / ↓ BDNF) BDNF = Brain derived neurotrophic factor

Answer 308

Low CB₁ receptor expression in the medulla which means it is very difficult (impossible) to fatally overdose on cannabis- no effect on CVS

Answer 309

Multiple sclerosis / pain / stroke - regulatory Fertility / obesity - pathology Up-regulation of CB₁ receptors in the adipose tissue of the genetically obese compared with lean mice

Answer 310

Cannabis based drug Used to treat nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type os nausea without good results. Used to treat loss of appetite and weight loss in people who have AIDS

Answer 311

Paste → 80% cocaine | Cocaine HCl → dissolve in acidic solution

Answer 312

Crack → precipitate with alkaline solution (e.g. baking soda) Freebase → dissolve in non-polar solvent )e.g. ammonia + ether)

Answer 313

pKa = 8.7 | Ionized in the GIT so it is absorbed slowly

Answer 314

Metabolised by cholinesterase in the liver and in the blood plasma

Answer 315

T½ = 20-90 minutes - Very quick breakdown means it will be taken again and again. - Very fast speed of onset which makes it more addiactive. - Inhaled - Cleared from the body very quickly

Answer 316

Local anaesthetic effect by blocking sodium channels

Answer 317

Cocaine is a monoamine reuptake inhibitor or neurotransmitters (e.g. seratonin, dopamine etc)

Answer 318

Cocaine has no effect on the affinity or efficacy of dopamine for the receptor. It causes a build up of dopamine in the synapse of the nucleus accumbens

Answer 319

- Mood amplifications (euphoria and dysphoria) - Heightened energy - Sleep disturbance - Motor excitement (restlessness) - Talkativeness - Increased sexual interest - Anger, verbal aggression - Mild to moderate anorexia

Answer 320

- Irritability, hostility, anxiety, fear, withdrawal - Extreme energy or exhaustion - Total insomnia - Compulsion - Rambling, incoherent speech - Decreased sexual interest - Possible extreme violence - Total anorexia - Delusions of grandiosity

Answer 321

- Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating sympathetic outflow and increasing the sensitivity of adrenergic nerve endings to noradrenaline. - Also acts like a class I antiarrhythmic agent (local anaesthetic) by blocking sodium and potassium channels which depresses cardiovascular parametres - Stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principle vasodilator produced by endothelial cells - Activates platelets, increasing platelet aggregation promoting thrombosis

Answer 322

- Nitrogen - Carbon monoxide/dioxide - Benzene - Hydrogen cyanide

Answer 323

- Alkaloids | - Tar

Answer 324

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

Answer 325

pKa of nicotine is 7.9 but cigarette smoke is acidic so it is not absorbed in the buccal cavity Absorption in alveoli independent of pH

Answer 326

70-80% is converted to Cotinine by Hepatic CYP2A6

Answer 327

T½ = 1-4 hours

Answer 328

Nicotine is an agonist on nicotinic receptors so has a profound effect on the nervous system - Nicotine binds to nicotinic ACh receptors on cell bodies in the ventral tegmental area - Stimulates release of dopamine in the nucleus accumbens

Answer 329

↑ sympathetic stimulation (CNS and adrenals) ↑ Heart rate and systolic volume Vasodilation of skeletal muscle arterioles ↑ lipolysis, FFA, VLDL ↓ HDL ↑ TXA₂ (platelet activation) ↓ NO No effect on lung function (only effect is due to components of smoke)

Answer 330

↑ metabolic rate | Nicotine is an appetite suppressant so reduces smokers weight

Answer 331

Nicotine is protective against neurodegenerative disorders

Answer 332

Nicotine increases brain CYPs which metabolise neurotoxins which cause Parkinson's disease

Answer 333

↓ β-amyloid toxicity | ↓ amyloid precursor protein

Answer 334

Caffeine is an adenosine (A1) receptor antagonist so it can induce euphoria by blocking the effects of adenosine - Caffeine increases dopamine release - Adenosine binds to A1 receptors- decreases the release of dopamine and decreases D1 receptor function

Answer 335

Units = [%ABV x volume(ml)] / 1000

Answer 336

Men and women ≤ 14 units / week

Answer 337

0.08% | 1 drink

Answer 338

Speed of onset ∝ Gastric emptying Drinking on a full stomach slows the speed of gastric emptying so the speed of onset of the alcohol is slower If you drink on a full stomach the alcohol is retained in the stomach for longer and it is not absorbed Fluid stimulates gastric emptying so on an empty stomach it would go straight into the duodenum and be absorbed

Answer 339

``` Alcohol → acetaldehyde (toxic) 1) 85% in the liver (first pass hepatic metabolism) Enzymes: - Alcohol dehydrogenase (75%) - Mixed function oxidase (25%) 2) 15% in the GIT Enzyme: - Alcohol dehydrogenase ```

Answer 340

Unmetabolised alcohol in your breath

Answer 341

Mixed function oxidase | It is upregulated in heavy alcohol consumption

Answer 342

♀ body water: 50% ♂ body water: 59% Alcohol is fairly water soluble. Men have more body water and women have more adipose tissue so alcohol is better distributed and dissolved in men Women also have less alcohol dehydrogenase

Answer 343

Acetaldehyde → Acetic acid Enzyme: - Aldehyde dehydrogenase

Answer 344

A polymorphism in aldehyde dehydrogenase

Answer 345

Disulfiram Causes acetaldehyde from breaking down acetaldehyde which is toxic, and therefore produces unwanted negative effects to be experienced

Answer 346

``` Depressant effect Degree of CNS excitability ↙︎ ↘︎ Environment Personality ↙︎ ↘︎ Non-social Social setting setting ```

Answer 347

1. GABAa receptor: positive effect on function by post-synaptic and pre-synaptic influence- increases production of steroid (allopregnenolone) 2. NMDA firing rate is reduced (enhances an excitatory transmitter) 3. Reduces neurotransmitter exocytosis (decrease Ca²⁺ channels)

Answer 348

Low potency Low selectivity Alcohol is a small straight forward molecule which binds to a lot of targets and influences a lot of symptoms (if large amount in the system) so it has large effects very easily

Answer 349

Minds to μ-receptors which decreases GABA firing. Not a selective agonist like opiates so does not have as powerful an effect as heroin

Answer 350

↓ Ca²⁺ entry ↑ Prostaglandins Though to be the effect of acetaldehyde

Answer 351

- Centrally mediated decrease in baroreceptor sensitivity leads to an acute increase in heart rate. - Alcohol diminishes the brains control of arteriole baroreceptors

Answer 352

``` Acetaldehyde has an effect on the posterior pituitary by preventing vasopressin secretion Less vasopressin (ADH) means more water excretion ```

Answer 353

``` 1) Dementia Cortical atrophy / ↓ volume cerebral white matter 2) Ataxia Cerebellar cortex degeneration 3) Wernicke-Korsakoff syndrome Thiamine deficiency 4) Wernicke's encephalopathy 3rd ventricle and aqueduct 5) Korsakoff's psychosis Dorsomedial thalamus ```

Answer 354

Neuropsychiatric condition characterised by the triad ophthalmoplegia, ataxia and confusion (only 10% experience all three) Caused by overwhelming metabolic demands on brain cells that have depleted intracellular thiamine (vit B1)

Answer 355

Associated with polyneuritis | Characterised by an impaired ability to acquire new information and substantial, irregular memory loss

Answer 356

Metabolism of alcohol uses NAD⁺ to produce NADH. This disrupts the dehydrogenase-related reactions in the cytoplasm and mitochondria (TCA and β-oxidation of fatty acids) thereby suppressing energy supply and fatty acid oxidation This also diverts NAD⁺ from normal functions such as glycolysis to alcohol metabolism. Acetyl CoA (unable to enter the citric acid cycle) are transformed to ketones

Answer 357

Mixed function oxidase enzyme generates free radicals. These free radicals generate an inflammatory stimulus, which if prolonged, releases cytokines This is reversible

Answer 358

After hepatitis is the alcohol consumption is prolonged the liver will get cirrhosis - Decreased hepatocyte regeneration - Increased fibroblasts - Decreased active liver tissue

Answer 359

↓ Mortality from coronary artery disese ↑ HDLs ↑ tPA levels / ↓ platelet aggregation Some evidence that it is specifically wine

Answer 360

Damage to gastric mucosa ∝ dose | Acetaldehyde could be carcinogenic

Answer 361

↑ ACTH secretion ↓ Testosterone secretion Effects sex steroid function

Answer 362

``` Negative symptoms occur when blood alcohol reaches 0 - Nausea: Irritant → Vagus → Vomiting centre - Headache Vasodilation - Fatigue Rebound excitation = poor sleep quality - Restlessness and muscle tremors 'Rebound' - Polyuria and polydipsia ↓ ADH secretion ```

Answer 363

- Prothrombin - Factors V, VII-XIII - Fibrinogen

Answer 364

- Plasminogen - TFPI (Tissue factor pathway inhibitor) - Proteins C & S - Antithrombin

Answer 365

A physiological process | - Blood coagulation prevents excessive loss of blood

Answer 366

A pathophysiological process | - Blood coagulates within blood vessel → obstructs blood flow

Answer 367

Venous thromboses | - High fibrin component

Answer 368

A pathophysiological process - thrombus forms within an atherosclerotic plaque Plaque rupture → thrombus released into lumen (ischaemia)

Answer 369

Arterial thromboses | - High platelet components

Answer 370

1. Rate of blood flow Blood flow is slow/stagnating → no replenishment of anticoagulant factors and balance adjusted in favour of coagulation 2. Consistency of blood Natural imbalance between procoagulation and anticoagulation factors e.g. Factor V leiden 3. Blood vessel wall integrity Damaged endothelia → blood exposed to procoagulation factors

Answer 371

1. Initiation Small scale production of thrombin 2. Amplification Large scale thrombin production on the surface of platelets 3. Propagation Thrombin mediated generation of fibrin strands

Answer 372

Small scale thrombin production 1. Tissue factor (TF) TF bearing cells activate factors X and V forming → prothrombinase complex 2. Prothrombinase complex This activates factor II (prothrombin) creating factor IIa (thrombin) 3. Antithrombin (AT-III) AT-III → initiates fIIa and fXa

Answer 373

Inhibits factor IIa | Oral

Answer 374

Factor Xa inhibitor | Oral

Answer 375

Activates AT-III (↓fIIa and ↓fXa) | IV or SC

Answer 376

A low-molecular weight heparin | Activates AT-III (↓fXa)

Answer 377

A vitamin K antagonist | Vitamin K is required for the generation of factors II, VII, IX and X

Answer 378

Venous thrombosis - Deep vein thrombosis and pulmonary embolism - Thrombosis surgery - Atrial fibrillation - prophylaxis of stroke

Answer 379

Rivaroxaban

Answer 380

Heparin | also Dalteparin

Answer 381

Dabigatran

Answer 382

``` Platelet activation and aggregation 1. Thrombin Factor IIa → activates platelets 2. Activated platelet - Changes shape - Becomes 'sticky' and attaches other platelets ```

Answer 383

- Thrombin binds to protease-activated receptor (PAR) on platelet surface - PAR activation → rise in intracellular Ca²⁺ - Ca²⁺ rise → exocytosis of adenosine diphosphate (ADP) from dense granules 1. ADP receptors - ADP activates P2Y₁₂ receptors → platelet activation / aggregation 2. Cyclo-oxygenase (COX) - PAR activation → liberates arachadonic acid (AA) - COX generates thromboxane A₂ (TXA₂) from AA 3. Glycoprotein IIb/IIIa receptor (GPIIb/IIIa) - TXA₂ activation → expression of GPIIb/IIIa integrin receptor on platelet surface - GPIIb/IIIa - involved in platelet aggregation

Answer 384

ADP (P2Y₁₂) receptor antagonist | Oral

Answer 385

Irreversible COX-1 inhibitor- inhibits production of TXA₂ | Oral

Answer 386

IV or SC | Only used by specialists

Answer 387

Arterial thrombosis - Acute coronary syndromes - myocardial infarction - Atrial fibrillation - prophylaxis of stroke

Answer 388

``` Generation of fibrin strands 1. Activated platelets Large-scale thrombin production 2. Thrombin Factor IIa → binds to fibrogen and convert to fibrin strands ```

Answer 389

Convert plasminogen → plasmin | Plasmin - protease degrades fibrin

Answer 390

Recombinant tissue type plasminogen activator (rt-PA) | IV

Answer 391

Arterial and venous thrombosis DO NOT remove preformed clots - Stroke - first-line treatment - ST- elevated MI

Answer 392

Red thrombus → deep vein of the leg (e.g. popliteal vein) Caused by: - ↓ rate of blood flow - Damage to endothelium thrombus detachment → pulmonary embolism (PE)

Answer 393

Restore balance between coagulants and anti-coaulants - ↓ levels of anticoaulant - Anticoagulants

Answer 394

Non-ST elevated myocardial infarction (MI) - 'White' thrombus → partially occluded coronary artery Caused by: - Damage to endothelium - Atheroma formation - Platelet aggregation

Answer 395

``` Reduce lipid accumulation Reduce platelet aggregation Prevent further arterial occlusion - ↓ platelet activation / aggregation - Anti-platelets ```

Answer 396

``` ST-elevated myocardial infarction - 'White' thrombus → fully occluded coronary artery Caused by: - Damage to endothelium - Atheroma formation - Platelet aggregation ```

Answer 397

``` Reduce lipid accumulation Reduce platelet aggregation Dissolve thrombus Prevent death - ↓ Platelet activation / aggregation - Dissolve clot - Anti-platelets and thrombolytics ```

Answer 398

Haemostasis is a physiological process preventing blood loss, whereas thrombosis is a pathophysiological process

Answer 399

Surface apoproteins (these allow the lipoproteins to circulate) HDL- Apoprotein A-1 LDL- Apoprotein B

Answer 400

Intestine- dietary triglycerides and cholesterol ↓ Chylomicron ↙︎ ↘︎ FFA Chylomicron remnant ↙︎ ↘︎ ↙︎ ↘︎ Skeletal Adipose Liver Atheroma muscle tissue

Answer 401

Hepatic lipase

Answer 402

Lipoprotein lipase

Answer 403

Macrophages | They get into the subepithelial space and are converted to foam cells, forming the core of the atheromatous plaque

Answer 404

1. LDL moves into the subendothelium 2. LDL is oxidised by macrophages and smooth muscle cells 3. Release of growth factors and cytokines which attract additional macrophages 4. Macrophages become foam cells which accumulate and smooth muscle cell proliferation result in the growth of the plaque

Answer 405

Increased endothelial permeability → Upregulation of endothelial adhesion molecules →Leukocyte adhesion → Migration of leukocytes into the artery wall Endothelium becomes leaky

Answer 406

- Adherence and entry of leukocytes - Migration of smooth muscle cells - Activation of T cells - Adherence and aggregation of platelets - Formation of foam cells

Answer 407

- Formation of the fibrous cap - Accumulation of macrophages - Formation of necrotic core

Answer 408

1. Coronary artery at lesion-prone location - Adaptive thickening (smooth muscle 2. Type II lesion - Macrophage foam cells 3. Type III (preatheroma) - Small pools of extracellular lipid 4. Type 4 (atheroma) - Core of extracellular lipid 5. Type V (fibroatheroma) - Fibrous thickening 6. Type VI (complicated lesion) - Thrombus - Fissure and haematoma

Answer 409

Familial hypercholesterolaemia

Answer 410

Remnant lipoproteins

Answer 411

In stable plaques the lumen and lipid core is separated by a thick layer of mostly collagen. This is not the case in vulnerable plaques which have a thin layer

Answer 412

Has a protective effect for risk of atherosclerosis and CHD | - The lower the HDL cholesterol level the higher the risk for atherosclerosis ad CHD

Answer 413

- Smoking - Obesity - Physical inactivity

Answer 414

- Block HMG-CoA reductase which prevents production of cholesterol from acetyl-CoA - Increases LDL receptors on hepatocytes, which then internalise LDL and break it down

Answer 415

Rosuvastatin

Answer 416

``` Inhibit the synthesis of prostanoids - Lipid mediators derived from arachidonic acid - Prostaglandins and thromboxanes - Receptor mediated NSAIDs inhibit Cyclo-oxygenases (COX-1 and -2) This inhibits production of PGH₂ which then produces - Prostacyclin -PGI₂ - PGE₂ - PGD₂ - PGF₂∝ - Thromboxane A₂ ```

Answer 417

Both COX-1 and COX-2

Answer 418

Inhibits COX-2 | e.g. celecoxib

Answer 419

- DP1, DP2 - EP1, EP2, EP3, EP4 - FP - IP1, IP2 - TP

Answer 420

G protein-coupled

Answer 421

EP1 EP2 EP3 EP4

Answer 422

- Increased pain perception* - Thermoregulation* - Acute inflammatory response* - Immune responses - Tumorigenesis - Inhibition of apoptosis * Targeted by NSAIDs

Answer 423

Stimulation of PG receptors sensitises the nociceptors which cause pain both acutely and chronically

Answer 424

PGE₂ stimulates hypothalamic neurones initiating a rise in body temperature

Answer 425

- Irritants stimulate keratinocytes to release PGE₂ | - PGE₂ binds to EP3 on mast cells which initiates a cascade resulting in histamine release and release of IL-6

Answer 426

- Gastroprotection - Renal salt and water homeostasis - Bronchodilation - Vasoregulation (dilation and constriction depending on receptor activated)

Answer 427

- Downregulates HCl secretion | - Stimulates mucus and bicarbonate secretion

Answer 428

COX-1 mediated | Less mucus production to protect the stomach plus increased HCl secretion

Answer 429

COX-1 and COX-2 control the glomerulus COX-2 controls reabsorption in the ascending limb of the loop of Henle COX-1 controls reabsorption in the collecting duct

Answer 430

- Constriction of afferent renal arteriole - Reduction in renal artery flow - Reduced glomerular filtration rate

Answer 431

- COX inhibitor. Blocks production of PGE₂ from arachidonic acid - PGE₂ is a bronchodilator - This causes increased production of leukotreines (using lipoxygenase enzyme) which is a bronchoconstrictor - PGE₂ inhibits lipoxygenase so reduces leukotreines - LT4 is the most prominent leukotreine in the lungs

Answer 432

- Vasoconstriction - Salt and water retention - Reduced effect of antihypertensives Increased risk of: - Hypertension - Myocardial infarction - Stroke

Answer 433

1. CVS - Stroke - MI 2. GI bleed

Answer 434

COX-2 inhibitors pose higher risk of CVD than conventional NSAIDs Mechanism is unclear - Enhanced probability of coronary atherothrombosis - Increased risk of heart failure - Increased long-term CV risk

Answer 435

- Topical application - Minimise NSAID use in patients with history of GI ulceration - Treat H. pylori if present - If NSAID is 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, anticoagulant or glucocorticoid steroid use)

Answer 436

Unique among NSAIDs - Selective for COX-1 - Binds irreversibly to COX enzymes - Has anti-inflammatory, analgesic and anti-pyretic actions - Reduces platelet aggregation

Answer 437

- Very high degree of COX-1 inhibition which effectively suppresses TXA₂ production by platelets - Covalent binding which permanently inhibits platelet COX-1 - Relatively low capacity to inhibit COX-2 - Need low dose to allow endothelial resynthesis of COX-2

Answer 438

- Gastric irritation and ulceration - Bronchospasm in sensitive asthmatics - Prolonged bleeding times - Nephrotoxicity - Side effects are more likely with aspirin than other NSAIDs because it inhibits COX covalently, rather than its selectivity for COX

Answer 439

Paracetamol forms a toxic metabolite (NAPQI) in overdose which is then converted to an inactive reduced form by Glutathione S-transferase - If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death - Will result in irreversible liver failure

Answer 440

- Add compound with -SH groups - Usually intravenous Acetylcysteine (in cases of attempted suicide) - Occassionally oral methionine - If not administered early enough, liver failure may be unpreventable

Answer 441

- Pack size restricted to 16 x 500mg tablets - No more then 2 packs per transaction - Illegal to sell more than 100 paracetamol in one transaction

Answer 442

Thromboxane A₂ synthase | - TXA₂ causes platelet aggregation, but not much else

Answer 443

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, because PGI₂ actually reduces platelet aggregation. It's te inhibition of thromboxane synthesis

Answer 444

Nicotinic receptors (receives signals from preganglionic neurons)

Answer 445

Receives signals from postganglionic M1→ Brain M2→ Heart M3→ Everything else

Answer 446

It is broken down by acetylcholinesterase after a few seconds

Answer 447

Vagus nerve

Answer 448

Resistance to the flow of air into the lungs due to surface area - Bronchoconstriction - Mucus secretion - Inflammatory response (histamine and cytokines promote oedema) - COPD (causes reduction in surface area) - Intubation - Parasympathetic nervous system contributes to airway resistance by stimulating bronchoconstriction

Answer 449

- Cigarette smoking causes inhalation of irritants into the lungs which stimulates the PNS to induce bronchoconstriction - PNS stimulates muscarinic receptors to induce bronchoconstriction. An antimuscarinic would prevent this - If you stop smoking the irritants will clear so the PNS stimulation will stop

Answer 450

- Constipation (interferes with gut activity and secretions) - Tachycardia - No sweating - Reduced secretions - Impaired vision - Dysregulation of bladder function

Answer 451

- Selective for M3 receptor - Administered by inhalation so low dose can be given straight to target tissue - Make drug less lipid soluble so it can diffuse across the alveoli

Answer 452

Because histamine is not the only contributor to asthma symptoms

Answer 453

- Histamine - Leukotreines - Antibody mediated (IgE) - Prostaglandins

Answer 454

- Take β2 agonist (e.g. Salbutamol) | - Warm up (exercise) prior to intense exercise

Answer 455

- Depends on the dose - Transdermal is the best route of administration- it has to be lipid soluble to be administered this way, and will diffuse readily into the blood stream - Oral administration has more barriers

Answer 456

- Stops bronchoconstriction - NSAID sensitive asthmatics have upregulated leukotreines so blocking this will prevent bronchoconstriction in the lungs

Answer 457

- A deep breath is taken, the glottis is closed and the larynx is raised to open the upper oesophageal sphincter. Also, the soft palate is elevated to close off the posterior nares. - The diaphragm is contracted sharply downward to create negative pressure in the thorax, which facilitates opening of the oesophagus and distal oesophageal sphincter - Simultaneously with downward movement of the diaphragm, the muscles of the abdominal wall are vigorously contracted, squeezing the stomach and thus elevating intragastric pressure. With the pylorus closed and the oesophagus relatively open, the route of exit is clear

Answer 458

- Dehydration - Loss of gastric H⁺ and Cl⁻ ions may lead to hypochloaemic metabolic alkalosis (↑ blood pH) - Contributes to a reduction in renal bicarbonate excretion and an increase in bicarbonate reabsorption; accompanied by increased Na⁺ reabsorption in exchange for K⁺, leading to hypokalaemia

Answer 459

- CNS - Vestibular system - Chemoreceptor trigger zone (area postrema) - Vomiting centre (nucleus of tractus solitarius) - GI tract and heart

Answer 460

- Cortex - Thalamus - Hypothalamus - Meninges

Answer 461

- H₁ receptor | - M₁ receptor

Answer 462

- Chemoreceptors - D₂ receptors - NK₁ receptor - (5-HT₃ receptor)

Answer 463

- Chemoreceptors - D₂ receptors - NK₁ receptor - (5-HT₃ receptor)

Answer 464

- Mechanoreceptors - Chemoreceptors - 5-HT₃ receptor

Answer 465

- Motion | - Labyrinth disorders

Answer 466

- Drugs - Metabolic products - Bacterial toxins

Answer 467

- Mechanical stretch (e.g GI obstruction or stasis) - GI mucosal injury (e.g. metastases, candida infection, GERD, radiation therapy, chemotherapy) - Local toxins and drugs

Answer 468

- Sensory input - Anxiety - Meningeal irritation - Increased intracranial pressure

Answer 469

Mixed receptor antagonists - Competitive antagonist at histaminergic (type H₁), cholinergic (muscarinic, M) and dopaminergic (type D₂) receptors - Order of potency of antagonistic activity: H₁>M>D₂ receptors - Acts centrally (vestibular nucleus, CTZ, vomiting centre) to block activation of vomiting centre

Answer 470

- Motion sickness - normally used prophylactically, but some benefit may be gained if it is taken after the onset of nausea and vomiting - Disorders of the labyrinth e.g. Meniere's disease - Hyperemesis gravidarum - Pre-and post-operatively (sedative and anti-muscarinic action are also useful)

Answer 471

- Administered orally - Onset of action 1-2 hours - Maximum effect circa 4 hours - Duration of action 24 hours

Answer 472

- Dizziness - Tinnitus - Fatigue - Sedation - Excitation in excess - Antimuscarinic sid-effects

Answer 473

- Metoclopramide | - Domperidone

Answer 474

- Acts centrally, especially at chemoreceptor trigger zone (CTZ) - Prokinetic effects in the GI tract by blocking the inhibitory effect of dopamine on myenteric motor neurons (which suppress intestinal motility) - Increases smooth muscle motility (from oesophagus to small intestine) - Accelerated gastric emptying - Accelerates transit of intestinal contents (from duodenum to ileo-coecal valve)

Answer 475

To treat nausea and vomiting associated with: - Uraemia (severe renal failure) - Radiation sickness - GI disorders - Cancer chemotherapy (high doses) e.g. cisplatin (intractable vomiting) - Parkinson's disease treatments with stimulate dopaminergic transmission in chemoreceptor trigger zone (e.g. L-DOPA, DA agonists) Not effective against motion sickness

Answer 476

- May be administered orally; rapidly absorbed; extensive first pass metabolism. May also be given I.V. - Metoclopramide crosses the BBB - Crosses the placenta

Answer 477

- Absorption and hence effectiveness of digoxin may be reduced - Nutrient supply may be compromised; especially important in conditions such as diabetes mellitus

Answer 478

No anti-psychotic actions - Drowsiness - Dizziness - Anxiety - Extrapyramidal reactions: children more susceptible than adults (Parkinsonian-like syndrome: rigidity, tremor, motor restlessness)

Answer 479

- Hyperprolactinaemia - Galactorrhoea - Disorders of menstruation

Answer 480

Acts centrally, especially in the vestibular nuclei and CTZ to block activation of vomiting centre

Answer 481

D₂ >> H₁ >>> Muscarinic receptors

Answer 482

Muscarinic >>> D₂ = H₁

Answer 483

- Prevention of motion sickness - Has little effects once nausea/emesis is established - In operative pre-medication

Answer 484

Can be administered orally (peak effect in 1-2 hours), intravenously or transdermally

Answer 485

Typical anti-muscarinic side effects: - Drowsiness - Dry mouth - Cycloplegia (paralysis of the ciliary muscle of the eye, loss of accommodation) - Mydriasis

Answer 486

Acts to block transmission in visceral afferents and CTZ

Answer 487

- Main use in preventing anticancer drug-induced vomiting, especially cisplatin - Radiotherapy-induced sickness - Post-operative nausea and vomiting

Answer 488

Administered orally, well absorbed, excreted in urine

Answer 489

- Headache - Sensation of flushing and warmth - Increased large bowel transit time (constipation)

Answer 490

Used alone the efficacy may wear off - 5-HT₃ receptor antagonists may be used for low emetogenic chemotherapy - Corticosteroids, such as dexamethasone, may be used in combination with 5-HT₃ receptor antagonists for high or moderately high emetogenic chemotherapy - Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids

Answer 491

- δ9-tetrahydrocannacinol (THC) isolated from marijuana or the synthetic agent Nabilone - Effective at treating emesis from anti-cancer drugs which other antiemetic's are not very effective against e.g. Cisplatin - Act at a number of cited within the CNS via the CB1 receptors which are located pre-synaptically and decrease the release of neurotransmitters associated with triggering the vomiting process - Also inhibit prostaglandin synthesis which has been implicated in emesis from anti-cancer drugs

Answer 492

1. Genetic predisposition - People of white European origin most susceptible 2. Environmental factors which could include: - Smoking (especially CD) - Diet / obesity (diseases of affluence) - Gut microbiome 3. Obesity is a risk factor for CD, but not UC

Answer 493

Complex interplay between host and microbes ↓ Disrupted innate immunity and impaired clearance ↓ Prof-inflammatory compensatory responses ↓ Granuloma formation and physical damage

Answer 494

Th1-mediated e.g. IFNγ, TNFα, IL-17, IL-23 Florid T cell expansion Defective T cell apoptosis

Answer 495

Th2-mediated e.g. IL-5, IL-13 Limited clonal expansion Normal T cell apoptosis

Answer 496

CD: All layers; any part of the gut (patchy) UC: Mucosa/submucosa; rectum, spreading proximally (continuous)

Answer 497

- Fluid/electrolyte replacement - Blood transfusion/oral iron - Nutritional support (malnutrition common)

Answer 498

``` Ulcerative Colitis - First line in inducing and maintaining remission - Good evidence base Crohn's Disease - Literature unclear - Ineffective in inducing remission - Less clear cut than utility in UC ```

Answer 499

- Mesalazine: 5-aminosalicylic acid (5-ASA) - Olsalazine (2 linked 5-ASA molecules) - Anti-inflammatory

Answer 500

- Inhibition of IL-1, TNF-α and platelet activating factor (PAF) - Decreased antibody secretion - Non-specific cytokine inhibition - Reduced cell migration (macrophages) - Localised inhibition of immune responses

Answer 501

``` Mesalazine: - Absorbed in the small bowel and colon Olsalazine - Metabolised by colonic flora - Absorbed in the colon ```

Answer 502

- More effective than a placebo - Safe drug - Superior to topical steroids in inducing remission in ulcerative colitis

Answer 503

Ulcerative Colitis: - Use of glucocorticoids in decline - Can be used topically (enema) or I.V. if very severe - Evidence that aminosalicylates superior Crohn's Disease - GCs remain drugs of choice for inducing remission - Likely to get side effects if used to maintain remission

Answer 504

Powerful anti-inflammatory and immunosuppressive drugs Derived from cortisol Activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors e.g. Prednisolone, fluticasone, budesonide

Answer 505

- Administer topically - fluid or foam enemas or suppositories - Use a low dose in combination with another drug - Use an oral or topically administered drug with high hepatic first pass metabolsim (e.g. Budesonide) so little escapes into the systemic circulation (used in mild cases as budesonide worse at inducing remission in active CD)

Answer 506

``` Azathioprine and 6-mercaptopurine - No advantage over placebo in active CD - Some success in UC Methotrexate - Efficacy in some IBD patients Cyclosporin - In severe UC only ```

Answer 507

- Immunosuppressive - Mainly used to maintain remission in CD (allows reduction in glucocorticoids) - Slow onset- 3-4 months treatment for clinical benefit

Answer 508

It is a prodrug - Activated by gut flora to 6-mercaptopurine - Give 6-mercaptopurine directly - Purine antagonist

Answer 509

It impairs: - Cell- and antibody-mediated immune responses - Lymphocyte proliferation - Mononuclear cell infiltration - Synthesis of antibodies It enhances: - T cell apoptosis

Answer 510

- Nearly 10% of patients have to stop treatment because of side effects - Pancreatitis - Bone marrow suppression - Hepatotoxicity - Increased risk (~4 fold) of lymphoma and skin cancer

Answer 511

Allopurinol treats gout. It inhibits Xanthine oxidase involved in metabolism of 6-MP (from azathioprine) which diverts metabolism down other pathways, increasing associated side effects

Answer 512

- Induces and maintains remission - Acts as a folate antagonist - Reduces synthesis of thymidine and other purines - Not widely used as monotherapy significant unwanted effects

Answer 513

1. Manipulation of the microbiome 2. Biologic therapies - Anti-TNFα (e.g. Infliximab) - Anti-α-4-integrin (e.g. Natalizumab)

Answer 514

1. Nutrition-based therapies - No evidence for probiotics in CD - Evidence for maintenance of remission in UC 2. Faecal microbiota replacement (FMT) therapies - Insufficient evidence for FMT - More studies needed 3. Antibiotic Treatment (Rifaximin) - Interferes with bacterial transcription by binding to RNA polymerase - Induces and sustains remission in moderate CD - May be beneficial in UC - May be microbiome modulator

Answer 515

- Used successfully in the treatment of CD - 60% patients respond within 6 weeks - Potentially curative - Successful in some patients with refractory disease and fistulae - Some evidence of effectiveness in UC

Answer 516

- Reduces activation of TNFα receptors in the gut - Reduces downstream inflammatory events - Also binds to membrane associated TNFα - Induces cytolysis of cell expressing TNFα - Promotes apoptosis of activated T cells

Answer 517

- Give I.V. - Very long half-life (9.5 days) - Benefits can last for 30 weeks after a single infusion - Most patients relapse after 8-12 weeks - Therefore repeat infusion every 8 weeks

Answer 518

- Emerging evidence that up to 50% of responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance - Attempts being made to optimise dosing regimens

Answer 519

- 4x-5x increase in incidence of TB - Also risk of reactivating dormant TB - Increased risk of septicaemia - Worsening of heart failure - Increased risk of demyelinating disease - Increased risk of malignancy - Can be immunogenic- azathioprine reduces risk, but raises TB/malignancy risk

Answer 520

It is metabolised and inactivated locally

Answer 521

1. Antibiotics 2. Inhibitors of gastric acid secretion 3. Cytoprotective drugs 4. Antacids 5. Triple therapy

Answer 522

Area of damage to the inner lining of - the stomach (gastric ulcer) OR - Upper part of the duodenum (duodenal ulcer)

Answer 523

Gastric ulcer: Pain at mealtimes when gastric acid is secreted Duodenal ulcer: Pain relieved by a meal as pyloric sphincter closes; pain 2-3 hours after a meal Occurrence: duodenal:gastric 4:1

Answer 524

Lubricate ingested food and protect the stomach and duodenum from attack by acid and enzymes: 1. Mucous from gastric mucosa creates gastrointestinal mucosal barrier 2. HCO₃⁻ ions trapped in mucous generate a pH or 6-7 at mucosal surface 3. Locally produced prostaglandins stimulate mucous and bicarbonate production (paracrine action) and inhibit gastric acid secretion

Answer 525

1. Acid secretion from parietal cells of the oxyntic glands in the gastric mucosa 2. Pepsinogens from chief cells which can erode the mucous layer

Answer 526

- Increased acid and/or decreased bicarbonate production - Decreased thickness of mucosal layer - Increase in pepsin type I - Decreased mucosal blood flow - Infections with Helicobacter pylori may also play a role in pathogenesis of gastric cancer

Answer 527

Risk factors: - Genetic predisposition - Stress - Diet, alcohol, smoking Prevalence: 1:10 of the population in developed countries

Answer 528

Patients swallow urea labelled with an uncommon isotope, either radioactive carbon-14 or non-radioactive carbon-13. In the subsequent 10-30 minutes the detection of isotope-labelled carbon dioxide in exhaled breath indicates that urea was split; this indicates that urease (which H. pylori uses to metabolise urea) is present in the stomach, so hence there is H. pylori present

Answer 529

- 50-80% are chronically infected - 10-20% will go on to develop peptic ulcer disease or neoplasm - Almost 100% of patients with duodenal ulcer and 80-90% with gastric ulcer are infected - Current therapy aims for 90% eradication within 7-14 days

Answer 530

Uncertain: - Socioeconomic conditions - Contact with animals and contaminated faeces

Answer 531

Triple therapy: 1. Antibiotics (a single antibiotic is not sufficiently effective) 2. Drugs which reduce gastric acid secretion 3. Drugs which promote healing

Answer 532

- Proton pump inhibitors - Histamine type 2 (H₂) receptors - Anti-muscarinics

Answer 533

Parietal cells secrete HCl (pH < 1). The principle stimuli on parietal cells are: 1. Acetylcholine from the vagal nerve of PANS 2. Gastrin, stimulatory hormone produced in the antrum in response to food and vagal PANS, gastrin then releases histamine from the H cells which acts on the parietal cells 3. Prostaglandins E2 and I2 are local hormones that inhibit acid production and promote a good blood supply. Gastrin also indirectly increases pepsinogen secretion, stimulates blood flow and increases gastric motility. Secretin regulates water homeostasis and the pH of the duodenum Somatostatin inhibits release of gastrin from G cells and histamine from H cells Inhibitors of gastric acid production: - Secretin - GIP (gastric inhibitory peptide)

Answer 534

e.g. Omeprazole Inhibits the basal and stimulated gastric acid secretion from the parietal cells by >90% Mechanism of action: - Irreversible inhibitors of the H⁺/K⁺ATPase - Inactive at neutral pH - As it is a weak base it accumulates in the cannaliculi of parietal cells; this concentrates its action there and prolongs its duration of action (2-3 days) and minimises its effect on ion pumps elsewhere in the body

Answer 535

- Peptic ulcers which are resistant to H₂ antagonists - Component of triple therapy - Gastroesophageal reflux disease (GERD), oesophagitis - Prophylaxis of peptic ulcers in the intensive care setting, and among high-risk patients prescribed aspirin, NSAIDs, as antiplatelets and anticoagulants

Answer 536

Orally active; administered as an enteric coated slow-release formulation

Answer 537

Rare (short term use) Long-term and/or high-dose administration associated with several potential side effects e.g. enteric infections (Clostridium difficile), community acquired pneumonia, and hip fracture

Answer 538

Inhibits gastric acid secretion from the parietal cells by ~60% and are less effective at healing ulcers than PPIs Mechanism of action: - Competitive antagonism of H₂ histamine receptors e.g. Cimetidine, ranitidine

Answer 539

Orally administered, well absorbed Ranitidine is longer acting than cimetidine

Answer 540

Rare (dizziness, headache) Fewer side effects with Ranitidine (Zantac, available OTC) Relapses likely after withdrawal of treatment, >90% recurrence within 1 year after initial healing

Answer 541

- Little use as anti-ulcer drugs alone | - More effective combination therapies

Answer 542

These drugs enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer E.g. - Sucralfate - Bismuth chelate - Misoprostol

Answer 543

It is a polymer containing aluminium hydroxide and sucrose octa-sulphate Mechanism: - Acquires a strong negative charge in an acid environment - Binds to positively charged groups in large molecules (proteins, glycoproteins) resulting in gel-like complexes, these coat and protect the ulcer, limit H⁺ diffusion and pepsin degradation of mucus - Increases prostaglandin, mucous and HCO₃⁻ secretion and reduces the number of H. pylori

Answer 544

Most of the orally administered Sucralfate remains in the GIT which may cause constipation or reduced absorption of some other drugs (e.g. antibiotics and digoxin)

Answer 545

- Acts like sucralfate - Used in triple therapy (in cases where resistance to drugs has been shown) - Anti-inflammatory actions in the stomach - Weak antibiotic and antacid properties

Answer 546

It is a stable prostaglandin analogue. Orally administered Mechanism: Mimics the action of locally produced prostaglandin to maintain the gastroduodenal mucosal barrier

Answer 547

May be co-prescribed with oral non-steroidal anti-inflammatory drugs (NSAIDs) when used chronically NSAIDs block the COX enzyme required for prostaglandin synthesis from arachidonic acid Therefore, there is a reduction in the natural factors that inhibit gastric acid secretion and stimulate mucus and HCO₃⁻ production

Answer 548

- Diarrhoea - Abdominal cramps - Uterine contractions (not to be given during pregnancy)

Answer 549

Mainly salts of Na⁺, Al₃⁺ and Mg₂⁺ - Sodium bicarbonate has rapid effects - Aluminium hydroxide and magnesium trisilicate have slower actions Taken orally; primarily used for non-ulcer dyspepsia (OTC)

Answer 550

- Neutralise acid, raises gastric pH, reduces pepsin activity - May be effective in reducing duodenal ulcer recurrence rates

Answer 551

- Compliance - Resistance to antibiotics (may be superseeded by vaccination) - Adverse response to alcohol (metronidazole interferes with alcohol metabolism)

Answer 552

Stomach and duodenal contents reflux into the oesophagus (oesophagitis) - occasional and uncomplicated GERD - heartburn, may treat by self medication with antacids and H₂ antagonists (OTC) - chronically may progress to pre-malignant mucosal cells and potentially oesophageal adenocarcinoma

Answer 553

PPIs (drug of choice) or H₂ antagonists (less effective) Combine with drugs that increase gastric motility and emptying of the stomach e.g. Dopamine D2 receptor antagonist (metoclopramise)

Answer 554

30% to 60%

Answer 555

- Onset - Severity - Type

Answer 556

``` Acute - Within 1 hour Sub-acute - 1 to 24 hours Latent - > 2 days ```

Answer 557

``` Mild - requires no change in therapy Moderate - requires change in therapy, additional treatment, hospitalisation Severe - disabling or life-threatening ```

Answer 558

- Results in death - Life-threatening - Requires or prolongs hospitilisation - Causes disability - Causes congenital anomalies - Requires intervention to prevent permanent injury

Answer 559

- Extension of pharmacological effect - Usually predictable and dose dependent - Responsible for at least two-thirds of ADRs - e.g. atenolol and heart block, anticholinergics and dry mouth, NSAIDs and peptic ulcer; paracetamol; digoxin

Answer 560

- Idiosyncratic or immunologic reactions - Includes allergy and "pseudoallergy" - Rare (even very rare) and unpredictable - 1/10,000 people: irreversible and mostly fatal - e.g. chloramphenicol and aplastic anaemia, ACE inhibitors and angiodema

Answer 561

- Associated with long-term use - Involves dose accumulation - e.g. methotrexate and liver fibrosis, antimalarials and ocular toxicity

Answer 562

- Delayed effects (sometimes dose independent) - Carcinogenicity (e.g. immunosuppressants) - Teratogenicity (e.g. thalidomide)

Answer 563

Withdrawal reactions - Opitates, bencodiazepines, corticosteroids Rebound reactions - Clonidine, β-blockers, corticosteroids "Adaptive" reactions - Neuroleptics (major tranquillisers)

Answer 564

A potent antihypertensive. Makes you drowsy and tired Missed doses will cause the blood pressure to suddenly increase causing strokes or death in some cases Usually given in long acting preparations to prevent this from happening

Answer 565

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

Answer 566

``` Type I - immediate, anaphylactic (IgE) - e.g. anaphylaxis with penicillins Type II - cytotoxic antibody (IgG, IgM) - e.g. methyldopa and haemolytic anaemia 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 567

Aspirin/NSAIDs - bronchospasm - bronchospasm affects mainly asthmatics - blocking cyclooxygenase pathways which usually makes prostaglandins- AA is converted to leukotreines ACE inhibitors - cough/angioedema - ACE inhibitors stop the breakdown of inflammatory proteins (bradykinin) which irritate sensory nerves in the lungs and cause a cough

Answer 568

- Antibiotics - Antineoplastics* - Anticoagulants - Cardiovascular drugs* - Hypoglycemics - Antihypertensives - NSAID/Analgesics* - CNS drugs* *account for ⅔ of fatal ADRs

Answer 569

Polypharmacy increases adverse drug reactions The higher the number of drugs the higher the frequency of adverse drug reaction

Answer 570

``` Subjective report - patient complaint Objective report - direct observation of event - abnormal findings • physical examination • laboratory test • diagnostic procedure ```

Answer 571

- Introduced in 1964 after thalidomide - Run by the Committee on Safety of Medicines (part of the Medicines Control Agency) - Entirely voluntary - Can be used by doctors, dentists, nurses, coroners and pharmacists - Includes blood products, vaccines, contrast media - For established drugs only report SERIOUS adverse reactions (fatal, life-threatening, needing hospital admission, disabling) - For "black triangle" drugs ∇ (newly licensed, usually <2 years) report any suspected adverse reaction

Answer 572

Drugs interacting outside the body (mostly IV infusions)

Answer 573

Additive, synergistic or antagonistic effects from co-adminitration of two or more drugs - Synergistic actions of antibiotics - Overlapping toxicities - ethanol and benzodiazepines - Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)

Answer 574

- Alteration in absorption - Proteins binding effects - Changes in drug metabolism - Alteration in elimination

Answer 575

Chelation - Irreversible binding of drugs in the GI tract (stops absorption of the drug and prevents entry into the circulation) - Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe²⁺), antacids (Al³⁺, Ca²⁺, Mg²⁺), dairy products (Ca²⁺)

Answer 576

Competition between drugs for protein or tissue binding sites - Increase in free (unbound) concentration may lead to enhanced pharmacological effect Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions PB interactions are not usually clinically significant but a few are (mostly with warfarin)

Answer 577

1. Drug excreted unchanged by the kidney 2. Phase 1 - original drug altered but then cleared by the liver or kidney 3. Drug altered once then altered again before being excreted by the kidney (Drug converted from lipid to water soluble so it is easier to excrete in the kidney)

Answer 578

- Oxidation - Reduction - Hydrolysis

Answer 579

Conjugation - Glucuronidation - Sulphation - Acetylation

Answer 580

Drug metabolism is inhibited or enhanced by coadministration of other drugs - CYP 450 system has been most extensively studied Phase 2 metabolic interactions (glucoronidation, etc) occur, research in this area is increasing

Answer 581

Metabolism by a single isozyme (predominantly) - few examples of clinically used drugs - examples of drugs used primarliy in research on drug interactions Metabolism by multiple isozymes - Most drugs metabolised by more than one isozyme • Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19 - If co-administered with CYP450 inhibitor, some isozymes may "pick up slack" for inhibited isozyme

Answer 582

- Cimetidine - Erythromycin and related antibiotics - Ketoconazole etc - Ciprofloxacin and related antibiotics - Ritonavir and other HIV drugs - Fluoxetine ad other SSRIs - Grapefruit juice (Many HIV drugs are potent inhibitors of CYP 450)

Answer 583

- Rifampicin - Carbamazepine - (Phenobarbitone) - (Phenytoin) - St John's wort (hypericin)

Answer 584

Almost always in renal tubule - Probenecid + penicillin (Good- induces elimination of penacillin) - Lithium + thiazides (Bad- Causes toxic accumulation in the blood as thiazides reduce clearance of the drug. Toxic and potentially lethal)

Answer 585

Levodopa + carbidopa - Allows lower doses to be used because not broken down in the periphery ACE inhibitors + thiazides - Enhance each other's antihypertensive effects Penicillins + gentamycin - Due to severe staphylococcal infections Salbutamol + ipratropium - Treatment of asthma and COPD

Answer 586

- Tertiary nitrogen: Important to anchor the drug to the receptor; also determines if the drug is an agonist or an antagonist - Two hydroxyl groups which prevent the drug from easily passing through lipid membranes

Answer 587

The two hydroxyl side chains in morphine have been acetylated in heroin. This makes the drug pass through lipid membranes easily

Answer 588

The 3 position hydroxyl group in morphine is converted to CH₃OH in codeine. It is effectively methyl codeine Decreases the potency of the drug, as it changes the metabolism

Answer 589

In methadone there is only a tertiary nitrogen but the phenyl group and quaternary carbon remain

Answer 590

Very powerful but it only has a tertiary carbon

Answer 591

Given orally; it is ionised in the stomach (pKa>8); relatively well absorbed in the small intestine. Heavily metabolised in the liver- extensive first pass metabolism. Only ~20% opioids get into the blood. The solution if to inject the drug- But still enters the brain relatively slowly

Answer 592

They are far more lipid soluble than morphine Fentanyl cay be given as a patch- will cross the skin It is very addictive; can be administered sub-lingually

Answer 593

Methadone and fentanyl are more lipid soluble than heroin and therefore more potent. Fentanyl has fast metabolism and so would wear off quickly whereas methadone has slow metabolism so is long lasting.

Answer 594

- Endorphins (μ or δ) - Enkephalins (δ) - Dynorphins/neoendorphins (κ)

Answer 595

- Thalamus - Amygdala - Nucleus accumbens - PAG Pain/mood/CVS

Answer 596

- Nucleus accumbens - Cerebral cortex - Amygdala Pain/mood/CVS

Answer 597

- Hypothalamus Appetite

Answer 598

They depress the CNS. Three basic mechanisms 1. Hyperpolarisation (increase K efflux) 2. Decrease Ca inward current 3. Decrease adenylate cyclase activity (causing a general decrease in cellular activity)

Answer 599

- Analgesia* - Euphoria* - Depression of cough centre (anti-tussive)* - Depression of respiration (medulla) - Stimulation of chemoreceptor trigger zone (nausea/vomiting) - Pupillary constriction - G.I. effects

Answer 600

- Decrease pain perception | - Increase pain tolerance

Answer 601

Recognise - Pain sensed in the periphery - Relayed to dorsal horn - Spinothalamic tracts relay to thalamus - Sent to cortex to add emotional input (exaccerbate pain Depress (pain tolerence pathway) - PAG (peri aquaductal grey region): integrating centre for pain tolerance (signals from thalamus and cortex) - NRM (nucleus raffae magnus): initiating point of effecting arm (signal from PAG) - NRM depresses pain from dorsal horn - LC (locus correliois): sympathetic nervous system reduces pain signalling (acts on dorsal horn) - NRPG (nucleus reticularis paragigantocellularis): INDEPENDENT. Automatically regulates pain tolerence before rest of brain (reflex) by activating NRM

Answer 602

Regulates PAG response based on health

Answer 603

1. Automatically depresses signal from the dorsal horn (not processed) 2. Activates the substantia gelatinosa (mini brain of spinal cord) for further processing of signals- which then acts on dorsal horn

Answer 604

- Periphery - Dorsal horn - NRPG - PAG

Answer 605

- Opiates act on μ receptor - This reduces GABA firing (GABA inhibits VTA (ventral tegmental area) - Reduced firing stops inhibition which causes release of dopamine = EUPHORIA

Answer 606

1. Stimulation of mechanoreceptors or chemoreceptors (throat, respiratory pathway or stretch receptors in lungs) 2. Afferent impulses to cough centre (medulla) 3. Efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung 4. Increased contraction of diaphragmatic, abdominal and intercostal muscles = cough

Answer 607

1. Prevent relay of sensory via Ach/NK C-fibres info to vagus 2. Act directly on cough centre 3. Inhibit 5HT¹ᴬ receptors

Answer 608

They interfere with central chemoreceptors so control centre can't respond to change in blood CO2 Act on respiratory centre which generates breathing rhythm

Answer 609

Act on chemoreceptor trigger zone which induces nausea (probably interference with GABA)

Answer 610

μ receptor on Edinger-Westphal nucleus in the preganglionic parasympathetic neurones to the eye. This is stimulates by opioids Essential to diagnose heroin overdose if the patient is unconscious with pin-point pupils

Answer 611

μ and κ receptors are everywhere in the enteric nervous system and opioids activate them

Answer 612

Looks like an allergic reaction to opioids. Not fully understood. Opioids induce histamine release (in some patients)- not receptor mediated Influences pKA 6 position hydroxyl group has to be present to induce this response- SOLUTION switch the drug

Answer 613

Not pharmacokinetic Chronic opioid use upregulates arrestin which causes over-intenalisation of opioid receptors which increases tolerence of opioids

Answer 614

All recreational drugs have psycological dependence but only a few have physical dependence - Cells upregulate adenylate cyclase to compensate for drug action - When you withdraw this disrupts cell metabolism (for 1-2 weeks)

Answer 615

Naloxone Same structure as morphine but with long side chain on tertiary nitrogen group preventing it from activating the receptor (antagonist effect)

Answer 616

1. Error in prescription or dispensing 2. Patient non compliance 3. Drug formulation

Answer 617

1. Environmental exposure to chemical, inducing other drugs - Enzyme induction - Enzyme inhibition 2. Food intake - Drugs may interact chemically with components of food; this may alter their absorption - Foods delay gastric emptying and alter gastric pH 3. Fluid intake - Most drugs are better absorbed if taken with water (e.g. may dissolve better) - Fluids may stimulate gastric emptying 4. Age 5. Disease

Answer 618

Newborn infants have: - more body water than adults - poorer renal function, with immature tubular secretion - an immature BBB - lower capacity for drug metabolism They elderly have an overall deterioration in many physiological functions that may affect: 1. Drug absorption: decreased absorptive surface of small intestine - Altered gastric and gut motility - Increased rate of gastric emptying 2. Drug distribution: reduced lean body mass and body water, relative increase in fat - Lipid soluble drugs have increased Vd and decreased blood levels - Water soluble drugs have decreased Vd and increased blood levels - Reduced plasma albumin, so fewer plasma protein binding sites 3. Drug metabolism - Splanchnic and hepatic blood flow decrease by 0.3-1.5%/year - Liver size and hepatocyte number decrease - Hepatic enzyme activity and induction capacity decrease 4. Drug excretion: changes in renal function are probably the most important factors affecting drug handling in the elderly. With age there is a steady decline in the following factors: - Reduced renal mass - Reduced renal perfusion - Reduced glomerular filtration rate - Reduced tubular excretion These changes are normal, may be compounded if the patient has renal disease 5. Organ sensitivity: the elderly tend to be more sensitive to CNS active drugs

Answer 619

1. General nutritional status - Unbalanced diets may lead to deficiency states and enzyme abnormalities - Starvation: decreased plasma protein binding and metabolism - Obesity: increased lipid fraction 2. GI disorders e.g. achlorhydria, coeliac disease, Crohn's disease - Altered drug metabolism 3. Congestive heart failure (especially in the elderly) may lead to: - Reduced splanchnic blood flow - Intestinal mucosal oedema - Reduced hepatic clearance 4. Kidney failure (especially in the elderly) may lead to: - Decreased drug excretion leading to toxicity - Water overload leading to changes in drug concentration in different body fluid compartments 5. Liver failure may lead to: - Reduced metabolism - Reduced first pass metabolism (hence increased bioavailability) - Decreased biliary secretion and hence decreased removal - Decreased albumin synthesis and hence reduced plasma protein binding 6. Other acute or chronic disease states

Answer 620

Warfarin and clarithromycin are metabolised by the same liver enzymes, so co-administration causes them to compete and means there is more active drug in the system for longer Other drugs: PPIs (e.g. omeprazole)

Answer 621

St Johns wort increases induction of liver enzymes and therefore increases metabolism of warfarin, reducing the amount of active drug in the system St John's wort is an antidepressant Other drugs: barbiturates

Answer 622

Digoxin acts on the K⁺ binding site of the Na⁺K⁺ATPase to decrease heart rate so the blood K⁺ level must be monitored To ensure the correct dose of digoxin you can measure the level of digoxin in the blood

Answer 623

Temazepam is relatively water soluble. The percentage of body fat is higher in the elderly therefore water soluble drugs will be more effective

Answer 624

- Warfarin is >90% plasma protein bound so weight loss (muscle/protein loss) will decrease the plasma proteins and therefore increase the amount of active Warfarin in the system - Liver enzymes are also very dependent on nutritional status, so poor nutrition means there is decreased metabolism, so more drug remains in the blood and has greater effects.

Answer 625

H₂O and Na⁺ move down the concentration gradient (into the interstitium). Na⁺K⁺ATPase on basal membrane to actively pump Na⁺ out of cell to maintain the concentration gradient Carbonic anhydrase converts HCO₃⁻+H⁺→CO₂+H₂O to be moved into the cell, then converted back to HCO₃⁻+H⁺ and is them pumped out of cell into the interstitium with Na⁺ cotransporter; H⁺/Na⁺ exchanger (into tubule lumen from cell) is coupled to Glucose/AA transport

Answer 626

Occurs in the ascending limb of the loop of Henle On apical membrane Na⁺2Cl⁻K⁺ co transporter moves ions into the cell and Na⁺K⁺ exchanger and K⁺Cl⁻ cotransporter move ions into the interstitium

Answer 627

Na⁺Cl⁻ cotransporter from tubule into cell | Na⁺K⁺ exchanger and Cl⁻K⁺ cotransporter into interstitium

Answer 628

Aldosterone in the cell drives Na⁺ reuptake ( delivered in the blood and diffuses into the cell) Binds to mineralocorticoid receptor (to nucleus) increases production of Na⁺ channels and Na⁺K⁺ATPase Vasopressin induces AQP2 to increase water resorption

Answer 629

1. Osmotic diuretics 2. Carbonic anhydrase inhibitors 3. Loop diuretics 4. Thiazides 5. Potassium sparing diuretics

Answer 630

They are pharmacologically inert. Injected into the blood stream, they are filtered by the glomerulus but NOT reabsorbed No effect on Na⁺ reabsorption Increase the osmolarity of tubular fluid Decrease H₂O reabsorption where the nephron is permeable to water (i.e. proximal tubule, descending loop of Henle, collecting duct) e.g. Mannitol

Answer 631

Act in the proximal convoluted tubule. Block carbonic anhydrase in the cell and on the apical membrane. Inhibit Na⁺ and HCO₃⁻ reabsorption in proximal tubule (increased retention in the urine). ↑ tubular fluid osmolarity/↓ osmolarity of medullary interstitium = ↓ H₂O reabsorption in the collecting duct Other effects: ↑ delivery of HCO₃⁻ to distal tubule, ↑ K⁺ loss e.g. acetazolamide

Answer 632

Act on the Na⁺2CL⁻K⁺ cotransporter to effect the countercurrent mechanism ↑ tubular fuid osmolarity/↓osmolarity of meduallary interstitium = H₂O reabsorption in the collecting duct ↑ delivery of Na⁺ to distal tubule ↑ K⁺ loss (↑ Na+/K⁺exchange Lose Na⁺, Ca²⁺ and Mg²⁺ because there is a small leak of pottassium by blocking the cotransporter you are adjusting the membrane potential which means less reabsorption of Ca²⁺ and Mg²⁺ Causes up to 30% fluid loss e.g. furosemide

Answer 633

Acts in the distal convoluted tubule to block to the Na⁺Cl⁻ cotransporter which prevents NaCl reuptake which also reduces water reabsorption by increasing tubular fluid osmolarity Also ↑ delivery of Na⁺ to distal tubule and ↑ K⁺ loss (↑Na⁺K⁺ exchange) ↑ Mg²⁺ loss and ↑ Ca²⁺ reabsorption e.g. bendroflumethiazide

Answer 634

Chronic diuretic use (especially loop diuretics and thiazides) will result in resistance - Blood Na⁺ level will fall - Renin will be released in response to low Na⁺ entering the macula densa cell which will counter the effects of the diuretics

Answer 635

- Aldosterone receptor antagonists (e.g. spironolactone) | - Inhibitors of aldosterone-sensitive Na⁺ channels (e.g. amiloride)

Answer 636

- Aldosterone receptor antagonists block the action of aldosterone on the mineralocorticoid receptor which reduces Na⁺ channels and Na⁺K⁺ATPase - Na⁺ channel inhibitors block the Na⁺ channels which prevents Na⁺ entry into the cell Increase tubular fluid osmolarity ↑ H⁺ retention Only 5% decrease in fluid output

Answer 637

Loop diuretics and Thiazides: - Hypovolaemia: ↑ NaCl in the tubule = ↑ water in the tubule (30% LD; 10% T) - Hyponatremia: ↑Na⁺ excretion (30% LD; 10% T) - Metabolic alkalosis: due to Cl⁻ excretion - Hypokalemia: Na⁺K⁺ exchange- Na⁺ passed to later parts of the nephron and then exchanged with K⁺ so large volumes are lost. - Hyperuricemia: drugs acting on different parts of the kidney are excreted across the cell to be excreted in the urine (different mechanisms across the kidney; usually by different transporters) e.g. Organic anion transporter clears uric acid in the blood, diuretics are also transported using this, so they compete. Carbonic anhydrase inhibitors - Metabolic acidosis: due to HCO₃⁻ loss Potassium sparing diuretics - Hyperkalaemia: Less Na⁺K⁺ exchange

Answer 638

Thiazides 1st line treatment in most countries Particularly useful for salt sensitive hypertension - Initial response (4-6 weeks) due to ↓ plasma volume - After 4-6 weeks plasma volume restored - Chronic thiazides: ↓TPR - Activation of eNOS (endothelium), Ca²⁺ channel antagonism, opening of K(Ca) channel (smooth muscle

Answer 639

- Hypertension | - Heart failure

Answer 640

- Heart failure = ↓ CO - Body responds to ↓ CO by activating sympathetic nervous system and RAAS - which worsens the heart failure (by ↑ water retention + vasoconstriction) - Loop diuretics - 30% Na⁺ load- acute reduction in congestion - Chronic use associated with resistance as eventually RAAS will activate in response - Now add potassium sparing diuretics which tries to block rebound RAAS activation

Answer 641

Negative feedback in response to high GABA concentrations

Answer 642

``` GABA ↓ GABA T (GABA Transaminase) Succinic Semialdehyde (SSA) ↓ SSDH (Succinic semialdehyde dehydrogenase) Succinic Acid ``` Mitochondrial enzymes

Answer 643

1. Sodium valproate (Epilim) 2. Vigabatrin (Sabril) Both anticonvulsant drugs used to treat epilepsy Cause a large ↑ in brain GABA

Answer 644

Made up of 4 proteins 1. GABA receptor protein (GABA-R) 2. Benzodiazepine receptor protein (BDZ-R) 3. Barbiturates receptor protein (BARB-R) 4. GABA modulin GABA binds to the GABA-R and opens the Cl⁻ channel. GABA-R is linked to BDZ-R; binding BZD facilitates GABA action and enhances affinity of GABA-R for GABA. This is a reciprocated relationship Barbiturates bind to BARB-R and increase GABA action and binding but this relationship is not reciprocated

Answer 645

Bicuculline: Competitive GABA antagonist Flumazenil: Competitive benzodiazepine antagonist

Answer 646

``` Allosteric action (need GABA to act on receptor) Benzodiazepines increase the frequency of Cl⁻ channel opening Barbiturates increase the duration of Cl⁻ channel opening Barbiturates are less selective than benzodiazepines (↓ excitatory transmission) ```

Answer 647

- Anaesthetics (barbiturates only: Thiopentone) - Anticonvulsants (Diazepam; Clonazepam; Phenobarbital) - Anti-spastics (Diazepam) - Anxiolytics - Sedatives / Hypnotics

Answer 648

Removes anxiety without impairing mental or physical activity ("Minor tranquillisers)

Answer 649

Reduces mental and physical activity without producing loss of consciousness

Answer 650

Induces sleep

Answer 651

Sedative/hypnotic - Amobarbital for severe intractable insomnia (t½ 20-25h) Unwanted effects (not drugs of 1st choice) - Low safety margins (depress respiration, overdosing lethal) - Alter natural sleep (↓REM) = hangovers/irritability - Enzyme inducers - Potentiate effect of other CNS depressants (e.g. alcohol) - Causes tolerance - Dependence: withdrawal symdrome (insomnia, anxiety, tremor, convulsions, death)

Answer 652

``` Administration: - Well absorbed (orally) - Peak [plasma] ≈ 1h - IV vs status epilepticus (IV administration used to treat prolonged seizures) Distribution - Bind plasma proteins strongly - Highly lipid soluble (wide distribution) Metabolism - Usually extensive (liver) Excretion - Urine; glucuronide conjugates Duration of action (varies greatly) - Short - Long acting slow metabolism and/or active metabolites ``` e.g. Diazepam (t½ 32h) Oxazepam (t½ 8h) Temazepam (t½ 8 hours)

Answer 653

(Long-acting) - Diazepam (Valium) - Chlordiazepoxide (Librium) - Nitrazepam Oxazepam is considered long-acting in cases of hepatic impairment as it is metabolised slowly

Answer 654

- Temazepam - Oxazepam Nitrazepam will aid sleep at night and have an anxyolytic effect during the day; or used to treat people who sleep at night but wake up very early in the morning

Answer 655

Wide margin of safety: - Overdose→prolonged sleep (rousable) - Give flumazenil (shorter half life so need 2 doses) - Does not induce liver enzymes

Answer 656

- Sedation, confusion, amnesia, ataxia (impaired manual skills) - Potentiate other CNS depressants (alcohol, barbs) - Tolerance (less that barbs; 'tissue' only) Dependence - withdrawal syndrome similar to barbs (less intense - Withdrawal slowly - Free [plasma] ↑ by coadministration e.g. aspirin, heparin

Answer 657

- A short acting sedative/hyponotic (t½ ≈5g) -Acts at BZD receptors (cyclopyrrolong) Similar efficacy to BZ - Minimal hangover effects BUT dependency still a problem

Answer 658

Some antidepressant drugs: - SSRIs - Effective/delayed response/popular Some antiepileptic drugs - e.g. Valproate, Tiagabine Some antipsychotic drugs - e.g. olanzapine, quetiapine - Marked side effects Propanolol - Improves physical symptoms (tachycardia: β₁; tremor: β₂) Buspirone - 5HT₁ᴬ agonist - Fewer side-effects (

Answer 659

Enhancement of the action of GABA at GABA-A receptors

Answer 660

5. Temazepam

Answer 661

Parkinson's is not enough dopamine | Schizophrenia is too much dopamine

Answer 662

Control of movement Cell bodies originate in the substantia nigra zona compacta and project to the striatum Affected in Parkinson's

Answer 663

Involved in emotion Cell bodies originate in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule Affected in Schizophrenia

Answer 664

Regulates hormone secretion | Short neurones running from the arcuate nucleus of the hypothalamus to the medial eminance and pituitary gland

Answer 665

D1: D1 and D5 D2: D2, D3 and D4

Answer 666

Tyrosine in the diet

Answer 667

``` 1/1000 - general population 1/100 - > 60 years Mean age of onset is 65 Male:Female 4:1 ~8% of cases are familial Parkinson's disease 92% are Idiopathic Parkinson's disease: - environmental - oxidative stress - altered protein metabolism - risk gene ```

Answer 668

- Resting tremor - Rigidity (stiffness, limbs feel heavy/weak) - Bradykinesia (slow movement) - Postural abnormality - Unilateral onset - Spreads to bot sides of the body

Answer 669

- Pill-rolling rest tremor - Difficulty with fine movements - micrographia - Poverty of blinking - Impassive face - Monotomy of speech and loss of volume of voice (lack of diaphragm control and loss of tone around vocal cords) - Disorders of posture - flexion of the neck and trunk - Lack of arm swing - Loss of balance - lack of righting reflex, retropulsion - Short steps, shuffling gait - Unilateral onset (does spread to both sides and worsen)

Answer 670

- Depression - Sleep disturbance - Pain - Taste and smell disturbances - Cognitive decline/Dementia Autonomic dysfunction - Constipation - Postural hypotension - Urinary frequency/urgency - Impotence - Increased sweating

Answer 671

- Principally affected area- Substantia nigra (cell loss) - Putamen-projecting pathways degenerate significantly - Lewy bodies are present (defensive mechanism to protect against toxic altered proteins; eventually they spill out and cause toxicity) - Cell loss in locus coruleus - Other affected areas: dorsal vagus nucleus, nucleus basalis of mynert

Answer 672

``` Lose 80-85% of dopaminergic neurons and deplete 70% of the striatal dopamine bfore symptoms appear Compensatory mechanisms (e.g. neuron overactivity and upregulation of DA receptors) prevent appearance of symptoms ```

Answer 673

``` Stages describe the affected areas Stage 1-2 - Dorsal motor nucleus of vagus - Raphe nucleus - Locus coerulus Stage 3: - Substantia nigra pars compacta Stage 4 - Amydala - Nucleus of Meynert - Hippocampus Stage 5-6 - Cingulate cortex - Temporal cortex - Frontal cortex - Parietal cortex - Occipital cortex ```

Answer 674

L-DOPA - DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme DOPA decarboxylase (DD) - DD is also present in peripheral tissues and 95% would be converted in the periphery causing nausea and vomiting - Inhibitors cannot cross the BBB so DOPA can be converted to dopamine in the brain Drug: Peripheral DOPA decarboxylase inhibitor + L-DOPA

Answer 675

Treats hypokinesia, rigidity and tremor | effectiveness declines with time

Answer 676

Acute - Nausea (prevented by Doperidone: peripheral acting antagonist) - Hypotension - Psychological effects - confusion, disorientation and nightmares Chronic - Dyskinesias: (abnormal limb and face movements) can occur within 2 years of treatment. - "On-Off" effects: rapid fluctuation in clinical state. Off periods last from minutes to hours

Answer 677

Can only synthesise drugs which act on D2 receptors. | Drugs targeting D1 do not enter the brain

Answer 678

- Act on D2 receptors - Bromocriptine, Pergolide, Ropinerol - Longer duration of action than L-DOPA - Smoother and more sustained response - Actions independent of dopaminergic neurones - Incidence of dyskinesia is less - Can be used in conjunction with L-DOPA

Answer 679

``` Common: confusion, dizziness, nausea/vomiting, hallucinations Rare: constipation, headache, kyskinesia Ergot structure (within chemical structure): causes a problem with heart valves Non-ergot structure: causes addictive behaviours (OCD, gambling etc) ```

Answer 680

MAO inhibitor - Selective for MAO-B, predominates in dopaminergic areas of CNS. Actions are without peripheral side effects of none-selective MAO-I's - Can be given alone in the early stages of disease - Or in combination with L-DOPA, reduce the dose of L-DOPA by 30-50% - Side effects are rare: hypotension, nausea/vomiting. confusion and agitation

Answer 681

MAO inhibitor Shown to have neuroprotective properties by inhibiting apoptosis - promotes anti-apoptosis genes. Early clinical trials suggest that this drug may slow the disease down but subsequent studies not so positive

Answer 682

Catechol-O-methyl transferase CNS- Breaks down catecholamines (e.g. dopamine) in the brain Periphery- Converts L-DOPA to 3-OMD which compete for the same transport system across the BBB

Answer 683

CNS- Prevents the breakdown of dopamine in the brain Peripheral- Stop 3-OMD formation and thus increasing the penetration of L-DOPA across the BBB thus increasing brain concentrations, where it is converted to dopamine. Allows L-DOPA dose reduction Side effects: cardiovascular complications (can cause heart attack)

Answer 684

``` Positive symptoms: - Hallucinations - Delusions - Disorganised thoughts Negative symptoms: - Reduced speech - Lack of emotion and facial expression - Diminished ability to begin and sustain activities - Diminished ability to find pleasure - Social withdrawal Cognitive deficits: - Memory - Attention - Planning - Decision making ```

Answer 685

Strong genetic tendency 1st degree relatives: 50% 2nd degree relatives: 25% 3rd degree relatives: 12.5%

Answer 686

1. Resolves completely, with/without treatment and never returns: 10-20% 2. Recurs repeatedly; full recovery after each episode: 30-35% 3. Recurs repeatedly; incomplete recovery; persistent defective state develops becoming more pronounced each time: 30-35% 4. Persues a downhill course: 10-20%

Answer 687

Excessive dopamine transmission in the mesolimbic system and striatal region leading to positive symptoms - mediated through D2 receptors Whilst dopamine deficit in pre-frontal region, mediated by D1 receptors leads to negative symptoms

Answer 688

- NMDA receptor antagonists produce psychotic symptoms - Glutamate and dopamine exert excitatory and inhibitory effects respectively on GABA-ergic striatal neurons, which project to the thalamus and constitute a 'sensory gate'. Too little glutamate or too much dopamine disables the gate, allowing uninhibited sensory input to reach the cortex (causes patient to overanalyse normal situations)

Answer 689

- Gene for neuregulin-1-synaptic development and plasticity effects NMDA receptor expression causeing schizophrenia phenotype

Answer 690

- All neuroleptic drugs are antagonistic at dopamine "D2 like" receptors - Most neuroleptics block other receptors (e.g. 5-HT) thus accounting for some of their effects - Drugs treat positive symptoms but not the negative ones - Takes weeks to work, initially neuroleptics induce an increase in DA synthesis and neuronal activity (declines with time)

Answer 691

- Anti-emetic effect - Blocking dopamine receptors in the chemoreceptor trigger zone. Neuroleptic Phenothiazine, effective at controlling vomiting and nausea induced by drugs (e.g. chemotherapy), renal failure - Many neuroleptics also have blocking action at histamine receptors. Effective at controlling motion sickness

Answer 692

Extrapyramidal side effects - blockade of dopamine receptors in the nigrostriatal system can induce "Parkinson" like side effects - Acute dystonia: involuntary movements - muscle spasm, protuding tongue, fixed upward gaze, neck spasms etc often accompanied by Parkinson's features. Occur in the first few weeks, often declining with ongoing therapy. Reversible on drug withdrawal or anti-cholinergic Tardive dyskinesias: Involuntary movements, often involving the face and tongue, but also limb and trunk (20% of patients after several months or years). More associated with typical antipsychotics. Made worse by drug withdrawal or anticholinergics. May be related to proliferation in pre-synaptic DA D2 receptors or glutamate excitotoxic striatal neurodegeneration - Endocrine effects: dopamine is involved in the tuberoinfundibular system and acts to inhibit prolactin secretion via the D2 receptors. Antipsychotics increase serum prolactin concentrations which can lead to breast swelling (men and women) and sometimes lactation in women - Blocking α-adrenoceptors: causes orthostatic hypotension - Blocking 5-HT receptors: weight gain - Blockade of cholinergic muscarinic receptors: typical peripheral anti-muscarinic side effect (e.g. blurring of vision, increased intraocular pressure, dry mouth, constipation, urinary retention)

Answer 693

- Loss of consciousness (at low concentration) - Suppression of reflex responses (at high concentration) - Relief of pain (analgesia) - Muscle relaxation - Amnesia

Answer 694

Gaseous/Inhalation - Nitrous oxide - Diethyl ether - Halothane - Enflurane Intravenous - Propofol - Etomidate

Answer 695

Anaesthetic potency increases in direct proportion with oil/water partition coefficient (The more lipid soluble it is the better the anaesthetic)

Answer 696

Alter synaptic function Enhance GABA (inhibitory) β₃ - suppression of reflex responses α₅ - amnesia

Answer 697

Alter synaptic function Enhance GABA / compete with glycine, so prevents receptor activation α₁ - suppression of reflex responses Nitrous oxide - blocks NMDA-type glutamate receptors Not as powerful as IV

Answer 698

Increase in administration of inhalational anaesthetic causes a decrease in firing of nACh receptors

Answer 699

Enhancement of TREK (background leak) K⁺channels | - increases duration of hyperpolarisation so they are more difficult to excite

Answer 700

Intravenous agents are more specific and inhalational agents are active at more sites

Answer 701

Depress excitability of thalamocortical neurones Influences reticular activating neurones (major consciousness centre in the brain) RAN: sensory signals sent here increases consciousness GABA and background leak K⁺ channels decrease the link between the cortex and the RAN nAChR agents decrease the link between the thalamus and the RAN

Answer 702

Cause depression of reflex pathways in the spinal cord

Answer 703

Cause decreased synaptic transmission in the hippocampus/amygdala - There are a larger number of GABA with α₅ subunits in the hippocampus Means you lose the ability to form memories

Answer 704

IV into the blood, they then have free access to the brain | The liver metabolises the agent to return consciousness

Answer 705

Won't dissolve in the blood very well therefore it will be more available to the brain

Answer 706

Less lipid soluble so dissolves in the blood and therefore has slow transfer to the brain

Answer 707

The process is very controllable | Process reverses very quickly if you stop administering the agent

Answer 708

``` Inhalation: - Rapidly eliminated - Rapid control of the depth of anaesthesia Intravenous: - Fast induction - Less coughing / excitatory phenomena ```

Answer 709

``` Induction: Propofol (IV) Maintenance: Enflurane (inhalation) Relief of pain: Opioid Muscle relaxation: Neuromuscular blocking drugs Amnesia: Benzodiazepines ```

Answer 710

Resting membrane potential -70mV 1. Resting Na⁺ channels open; Na⁺ enters cells 2. Na⁺ channels close (inactivation); K⁺ channels open, K⁺ leaves the cell 3. Na⁺ channels restored to resting state but K⁺ channels still open therefore cell refractory 4. Hyperpolarisation 5. Na⁺ and K⁺ channels restored to resting state therefore cell will respond normally to further depolarising stimulus

Answer 711

Aromatic region: important for action and metabolism Basic amine side chain: (tertiary amine) hydrophilic Ester or amide bond: bridges between other two groups Exception- Benzocaine: has alcarve chain not an amino (weak LA)

Answer 712

Cocaine- ester | Lidocaine- amide

Answer 713

- LA will be in ionised form - Non-ionised form passes through neurone sheath and into an axon where it is then converted back into ionised (cationic) form - It is the cationic form which acts as a LA - Binds to the inside of voltage-sensitive Na⁺ channels and blocks the channels - This reduces the propagation of an action potential

Answer 714

As the nerve is stimulated the channels open, the faster the channels open the more LA can get into the channel to block the firing

Answer 715

Non-ionised drug passes into the membrane, and can move into the Na⁺ channel whilst in the membrane

Answer 716

They: 1. Prevent generation and conduction of action potentials 2. Do NOT influence resting membrane potential 3. May also influence - Channel gating - Surface tension 4. Selectively block - Small diameter fibres - Non-myelinated fibres LAs are weak bases (pKa 8-9)

Answer 717

In infected tissue more of the LA is ionized so it is less effective

Answer 718

1. Surface anaesthesia - Mucosal surface (mouth, bronchial tree) - Spray (or powder) - High concentrations → systemic toxicity 2. Infiltration anaesthesia - Directly into tissues → sensory nerve terminals - Minor surgery - Adrenaline co-injection (NOT extremities) 3. Intravenous regional anaesthesia - IV distal to pressure cuff - Limb surgery - Systemic toxicity of premature cuff release 4. Nerve block anaesthesia - Close to nerve trunks e.g. dental nerves - Widely used - low doses - slow onset - Vasoconstrictor co-injection (adrenaline and phalopressin) 5. Spinal anaesthesia (into CSF- intrathecal) - Sub-arachnoid space - spinal roots - Abdominal, pelvic, lower limb surgery - ↓BP; prolonged headache - Glucose (↑ specific gravity) 6. Epidural anaesthesia (outside of dural membrane) - Fatty tissue of epidural space - spinal roots - Uses as for 5 and painless childbirth - Slower onset - higher doses - More restricted action - less effect on BP

Answer 719

Absorption (mucous membranes): Good Plasma protein binding: 70% Metabolism: Hepatic N-dealkylation Plasma half-life: 2 hours

Answer 720

Absorption (mucous membranes): Good Plasma protein binding: 90% Metabolism: Liver and plasma, non-specific esterases Plasma half-life: 1 hour

Answer 721

``` CNS (paradoxical) - stimulation - restlessness, confusion - tremor CVS (Na⁺ channel blockade) - myocardial depression - vasodilation - ↓ BP ```

Answer 722

``` CNS - euphoria, excitation CVS - ↑CO - vasoconstriction - ↑BP (all sympathetic actions) ```

Answer 723

``` Emotional (psychological) - Misery, apathy, pessimism - Low self-esteem - Loss of motivation - Anhedonia Biological (Somatic) - Slowing of thought and action - Loss of libido - Loss of appetite, sleep disturbance ```

Answer 724

- Mood swings in same direction - Relatively late onset Reactive depression - stressful life events - non-familial Endogenous depression - unrelated to external stressors - familial pattern - Drug treatment

Answer 725

- Oscillating depression/mania - Less common : early adult onset - Strong hereditary tendency - Drug treatment (Lithium carbonate)

Answer 726

Depression = functional deficit of central MA transmission : mania = functional excess Monoamines = NA and 5-HT (serotonin) - Delayed onset of clinical effect of drugs - Down regulation: α2, β, 5-HT receptors - HPA axis (↑CRH level) - Hippocampal neurodegeneration

Answer 727

``` - Neuronal monoamine re-uptake inhibitors NA = 5-HT >> DA Other receptor actions - α₂ - mAChRs - Histamine - 5-HT Delayed down-regulation of β-adrenoceptors and 5-HT₂ receptors ```

Answer 728

- Rapid oral absorption - Highly PPB (90-95%) - Hepatic metabolism - active metabolites - renal excretion (glucuronide conjugates) - Plasma half-life: 10-20 hours

Answer 729

At therapeutic dosage: - Atropine-like effects (amitriptyline) - Postural hypotension (vasomotor centre) - Sedation (H1 antagonism) Acute toxicity (overdose) - CNS: excitement, delirium, seizures → coma, respiratory depression - CVS: cardiac dysrhythmias → ventricular fibrillation/sudden death - Care- attempted suicide

Answer 730

- Plasma protein binding: ↑ TCA effects (aspirin phenytoin) - Hepatic microsomal enzymes: ↑ TCA effects as they compete with TCAs (neuroleptics : oral contraceptives) - Potentiation of CNS depressants (alcohol) - Antihypertensive drugs (monitor closely): can sometimes increase and sometimes decrease

Answer 731

MAO-A : NA and 5-HT MAO-B : DA - Most are non-selective MAOIs - Irreversible inhibition → long duration of action - Rapid effects : ↑ cytoplasmic NA and 5-HT - Delayed effects: clinical response - down-regulation of β-adrenoceptors and 5-HT*2 receptors - Inhibition of other enzymes

Answer 732

- Rapid oral absorption - Short plasma half-life (few hours) but longer duration of action - Metabolised in the liver: excreted in urine

Answer 733

- Atropine-like effects (

Answer 734

Serious problem - 'Cheese reaction' : Tyramine-containing foods + MAOI → hypertensive crisis (throbbing headache, ↑BP, intracranial haemorrhage) - MAOIs + TCAs → hypertensive episodes (avoid) - MAOIs + pethidine → hyperpyrexia, restlessness, come and hypotension Moclobemide: reversible MAO-A inhibitor (RIMA), ↓ drug interactions, ↓ duration of action

Answer 735

- Selective 5-HT re-uptake inhibition - Less troublesome side-effects: safer in overdose - But less effective in severe depression

Answer 736

- Oral administration - Half life: 18-24 hours - Delayed onset of action (2-4 weeks) - Fluoxetine competes with TCAs for hepatic enzymes (avoid coadministration)

Answer 737

- Nausea, diarrhoea, insomnia and loss of libido - Interact with MAOIs (avoid coadministration) - ↑ suicidality (<18 years old) - Fewer than TCA/MAOIs

Answer 738

Dose-dependent reuptake inhibitor 5-HT > NA > DA 2nd line treatment for severe depression

Answer 739

α2 receptor antagonist ↑ NA and 5-HT release Other receptor interactions (sedative) Useful in SSRI-intolerant patients

Answer 740

Early onset = <55 years old - Genetically linked - Less that 10% of people with Parkinson's disease are <55 years - Loss of dopaminergic neurons which originate in the substantial nigra and project to the striatum (caudate putamen) causing loss of fine motor skills - D2 receptors are found in the brain - Must lose 80% of neutrons before you see effects

Answer 741

- Postural abnormalities - Tremor - Bradykinesia - Rigidity, muscle stiffness

Answer 742

- Tyrosine from the diet enters the brain through amino acid transporters - Tyrosine is converted to L-DOPA (Tyrosine hydroxylase) - DOPA is converted to dopamine (DOPA decarboxylase)

Answer 743

Dopamine is hydrophilic so it can't cross the the BBB, also there are very low levels of dopamine transporter in BBB so it cannot penetrate the brain L-DOPA uses the same transporter as tyrosine so it can get into the brain Tyrosine hydroxylase is the rate limiting step so it is better to use L-DOPA instead of tyrosine

Answer 744

A DOPA decarboxylase inhibitor - It cannot cross the BBB - It prevents the conversion of L-DOPA to dopamine peripherally so when used with L-DOPA more is converted in the brain and it also prevents the nausea and vomiting associated with dopamine stimulating the chemotactic trigger zone where there are fewer tight junctions than in the brain

Answer 745

They occur as Parkinson's progresses when pulses of dopamine are released and so the stores are depleted. This can be prevented by splitting the dose across more administration or increasing the initial dose. MAO and COMT break down dopamine so if you inhibit these then the life of dopamine in the synapse can be prolonged. The most commonly used is a COMT inhibitor (Entacapone)

Answer 746

A dopamine receptor agonist It causes nausea by binding to dopamine receptors in the chemoreceptor trigger zone Treated using domperidone (peripherally acting D2 receptor antagonist)

Answer 747

Dyskinesia. D2 agonists don't cause dyskinesia to the same extent

Answer 748

D2 antagonist (anti-psychotics/neuroleptics

Answer 749

Tardive dyskinesias (brain over-sensitised to dopamine) The brain is trying to compensate by upregulating dopamine receptors in that part of the brain (it is reversible) Other uses: - Anti-emetics - Increases prolactin secretion = galactorrhoea, lactation, inhibits fertility, amenorrhoea

Answer 750

``` Age Mostly sporadic (92%) remaining is genetic ```

Answer 751

1. Memory loss- especially recently acquired information 2. Disorientation/confusion- forgetting where they are 3. Language problems- stopping in the middle of a conversation 4. Personality changes- becoming confused, fearful, anxious 5. Poor judgement- such as when dealing with money

Answer 752

In a healthy individual γ-secretase, α-secretase and amyloid precursor protein (APP) are present in the membrane of neuronal cells. APP is cleaved by α-secretase and then cleaved by γ-secretase 1. APP is cleaved by α-secretase 2. sAPPα is released - C83 fragment remains 3. C83 → digested by γ-secretase 4. Products removed Pathological process APP is instead cleaved by β-secretase and then by γ-secretase 1. APP cleaved by β-secretase 2. sAPPβ released - C99 fragment remains 3. C99 → digested by γ-secretase releasing β-amyloid (Aβ) protein These β-amyloid (Aβ) proteins activate together and forms plaques which are deposited on the surface of neuronal cells

Answer 753

- Soluble protein present in axons - Important for assembly and stability of microtubule In Alzheimer's disease hyperphosphorylated tau is insoluble → self-aggregates to form neurofibrillary tangles Tau are neurotoxin This also results in microtuule instability

Answer 754

Microglia are specialised CNS immune cells - similar to macrophages - ↑ release of inflammatory mediators and cytotoxic proteins - ↑ phagocytosis - ↓ levels of neuroprotective proteins

Answer 755

All drugs treat the symptoms. None treat the underlying pathology. Only last for 2-3 years and then the drugs are not that effective. Only prescribed for mild to moderate Alzheimer's disease 1. Donepezil 2. Rivastigmine 3. Galantamine

Answer 756

Gold-standard. First line treatment Anticholinesterase - Reversible cholinesterase inhibitor - Long plasma half life (can be given once a day)

Answer 757

- Pseudo-reversible AChE and BChE (buteryl cholinesterase enzyme) inhibitor - 8 hour half-life - Reformulated as a transdermal patch - Causes liver problems as it inhibits BChE

Answer 758

- Reversible cholinesterase inhibitor - 7-8 hour half-life - α7 nAChR agonist

Answer 759

NMDA receptor blocker. Only licensed for moderate to severe Alzheimer's Memantine - Use-dependent non-competitive NMDA receptor blocker with low channel affinity - Long plasma half-life (administered once a day)

Answer 760

M. tuberculosis | The call wall of the bacteria has a layer of peptidoglycan surrounded by mycolic acid

Answer 761

Gram +ve have a prominent, thick peptidoglycan cell wall Gram -ve have a thin pedptidoglycan layer surrounded by an outer membrane with lipopolysaccharides making up the cell wall

Answer 762

1. Nucleic acid synthesis - Dihydropterate (DHOp) is produced from paraaminobenzoate (PABA) and then converted into dihydrofolate (DHF). - DHF is converted to tetrahydrofolate (THF) by DHF reductase. THF is important in DNA synthesis 2. DNA replication DNA gyrase (topoisomerase) releases tension in the DNA strand 3. RNA synthesis RNA polymerase produces RNA from DNA template 4. Protein synthesis Ribosomes (30s and 60s) produce protein from RNA templates

Answer 763

Sulphonamides Inhibit dihydropterate synthase Trimethoprim Inhibits dihydrofolate reductase

Answer 764

Fluroquinolones (e.g. Ciprofloxacin) | Inhibits DNA gyrase and topoisomerase IV

Answer 765

Rifamycons (e.g. Rifampicin) | Inhibits bacterial RNA polymerase

Answer 766

Inhibits ribosomes: - Aminoglycosides (e.g. Gentamycin) - Chloramphenicol - Macrolides (e.g. Erythromycin) - Tetracyclines

Answer 767

1. Peptidoglycan (PtG) synthesis - A pentapeptide is created on N-acetyl muramic acid (NAM). - N-acetyl glucosamine (NAG) associates with NAM forming PtG 2. PtG transportation PtG is transported across the membrane by bactoprenol 3. PtG incorporation PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides

Answer 768

Glycopeptides (e.g. Vancomycin) | Binds to the pentapeptide preventing PtG synthesis

Answer 769

Bacitracin | Inhibits bactoprenol regeneration preventing PtG transportation

Answer 770

``` β-lactams Bind covalently to transpeptidase inhibiting PtG incorporation into cell wall Includes: - Carbapenems - Cephalosporins - Penicillins ```

Answer 771

Lipopeptide (e.g. Daptomycin) Disrups Gram +ve cell walls Polymyxins Binds to LPS and disrupts Gram -ve cell membranes

Answer 772

- Unnecessary prescription - Livestock farming - Lack of regulation - Lack of development

Answer 773

1. Additional target production Bacteria produce another target that is unaffected by the drug (e.g. E. coli produce another DHF reductase enzyme making them resistant to trimethoprim) 2. Hyperproduction of enzyme Bacteria significantly increase levels of DHF reductase (e.g. E.coli produce additional DHF reductase enzymes making trimethoprim less effective) 3. Alterations in target enzymes Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective (e.g. S. aureus mutation in the ParC region of topoisomerase IV confers resistance to quinolones) 4. Alterations in drug permeation Reductions in aquaporins and increased efflux systems (e.g. Primarily of importance in Gram -ve bacteria) 5. Production of destruction enzymes β-lactamases hydrolyse C-N bond of the β-lactam ring (e.g. Flucloxacillin is β-lactamase resistant; Amoxicillin is broad spectrum)

Answer 774

1. Superficial - Outermost layers of skin 2. Dermatophyte - skin, hair or nails 3. Subcutaneous - innermost skin layers 4. Systemic - primarily respiratory tract

Answer 775

1. Azoles: Fluconazole | 2. Polyenes: Amphotericin

Answer 776

- Inhibits cytochrome P450-dependent enzymes involved in membrane sterol synthesis - Fluconazole (oral) used for candidiasis and systemic infections

Answer 777

- Interact with cell membrane sterols forming membrane channels - Amphotericin (IV) for systemic infections

Answer 778

Hepatitis B and C

Answer 779

Tenofovir | Nucleotide analogue, givent sometimes with Peginterferon α

Answer 780

Ribavirin and Peginterferon α Ribavirin: nucleoside analogue prevents viral RNA synthesis Boceprevir: protease inhibitor most effective against Hep C genotype 1

Answer 781

1. Attachment and entry - HIV GP120 attaches to CD$ receptor - GP120 also binds to either CCr5 or CXCR4 - GP41 penetrates host cell membrane and viral capsid is endocytosed 2. Replication and integration - Within cytoplasm - reverse transcriptase enzyme converts viral RNA → DNA - DNA transported into nucleus and integrated into host DNA 3. Assembly and release - Host cell's 'machinery' utilised to produce viral RNA and essential proteins - - Gag precursor encodes all viral structural proteins - HIV protease cleaves Gag precursor protein - Virus is assembles within cells → mature virion is released

Answer 782

- HCV genotype - Viral load - Past treatment experience - Degree of liver damage - Ability to tolerate the prescribed treatment - Need for liver transplant

Answer 783

Enfuvirtide - Binds to HIV GP41 transmembrane glycoprotein Maraviroc - Block CCR5 chemokine receptor

Answer 784

1. Nucleoside reverse transcriptase inhibitors - Activated by 3-step phosphorylation process e. g. Zidovudine 2. Nucleotide reverse transcriptase inhibitors - Fewer phosphorylation steps required e. g. Tenofovir 3. Non-nucleoside reverse transcriptase inhibitors - No phosphorylation required - Not incorporated into viral DNA e. g. Efavirenz

Answer 785

Raltegravir

Answer 786

Saquinavir (1st generation PI) Co-administered with Ritonavir which reduced PI metabolism (by inhibiting cytochrome P450) - co-administered to boost Squinavir concentrations in the body

Answer 787

Double stranded DNA virus, surrounded by tegument and enclosed in a lipid bilayer Treatment: Acyclovir (nucleoside analogue)

Answer 788

Multipartite single stranded RNA virus. Envelope protein neuraminidase → release Tropism: nose, throat, bronchi Treatment: Oseltamivir (Tamiflu) a neuraminidase inhibitor

Answer 789

Begins simultaneously in both hemispheres of the brain - Tonic-clonic seizures - Absence seizures - Myoclonic seizures

Answer 790

Begins within a particular area of the brain and may spread out (may be the result of injury of insult to the brain) - Simple/complex partial - Temporal lobe epilepsy

Answer 791

- Electroencephalography - Magnetoencephalography (MEG) - Functional magnetic resonance imaging (fMRI)

Answer 792

Regular activity: Distinctive firing patterns associated with certain activities (high to low Hz) - Gamma: awareness - hyperactive - Beta: awareness - thinking - Alpha: awareness - relaxed - Theta: drowsiness, meditation - Delta: deep sleep During a seizure there is irregular/asynchronous firing patterns due to neuronal over-activity

Answer 793

Excitatory post-synaptic receptors: - NMDA - AMPA - Kainate

Answer 794

Voltage-gated Na channel blocker - Drug of choice for partial seizures and tonic-clonic seizures - Stabilises inactive state of channel - Induces expression of hepatic enzymes - 16-30 hour half-life - Dangerous in individuals with HLA-B*1502 allele

Answer 795

Voltage-gated Na channel blocker - Indicated for most forms of epilepsy (not absence) - Class 1b channel blocker - Fast onset (10 mins) and long half-life (10-20 hours)

Answer 796

Voltage-gated K channel enhancer - Potassium channel opener specific for Kᵥ7 α-subunit - Only licensed for adjunctive treatment - Fast onset (30mins); ∼10 hour half-life

Answer 797

Voltage-gated calcium channel blocker - T-type Ca²⁺ channel antagonist - Mainly used for absence seizures - Long half-life (50 hours)

Answer 798

Voltage-gated calcium channel blocker - Thought to inhibit α2δ subunit - Indicated for partial seizures

Answer 799

- Binds to synaptic vesicle associated protein (SV2A) preventing glutamte release - Monotherapy for focal seizures - Fast onset (1 hour); half-life (10 hours)

Answer 800

- Inhibits GluK5 subunit of kainate receptor - Also affects VGSCs and GABA receptors - Indicated for most types of epilepsy - Fast onset (1 hour); long half-life (20 hours)

Answer 801

- Selective inhibitor of AMPA receptor - Only licensed in 2013 as an adjunct for partial seizures - Fast onset (1 hour); long half-life (24 hours)

Answer 802

1. GABA can be released tonically and also following neuronal stimulation 2. GABA activates inhibitory post-synaptic GABAᴬ receptors 3. GABAᴬ receptors are chloride (Cl⁻) channels → membrane hyperpolarisation 4. GABA is taken up by GAT 5. GABA is metabolised by GABA transaminate (GABA-T)

Answer 803

- Benzodiazepine (BZD) indicated for all forms of epilepsy | - Fast onset (2 hours); long half-life (30 hours)

Answer 804

- Indicated for most forms of epilepsy except absence seizures - Acts as a sedative in adults and may cause behavioural disturbances in children - Interacts with numerous drugs - Very fast-onset (20 mins); long half-life (60 hours)

Answer 805

- Selective inhibitor of GAT-1 (GABA transporter) - Adjunctive treatment for partial seizures - Fast onset (45 mins); short half-life (6 hours)

Answer 806

- Indicated for all forms of epilepsy - Inhibits GABA transaminase - Fast onset (1 hour); half-life (12 hours)

Answer 807

- Irreversible inhibits GABA transaminase enzyme | - Monotherapy for infantile spasms or as an adjunct for partial seizures

Answer 808

Valproate | Ethosuximide

Answer 809

Topiramate | Valproate

Answer 810

Carbamazepine

Pharmacology And Therapeutics Flashcards

(847 cards)