Pharmacokinetics and pharmacodynamics Flashcards

Question

what shows affinity?

Answer 1

shown by both antagonists and agonists

Answer 2

- only agonists show efficacy | - antagonists show zero efficacy

Answer 3

- affinity - efficacy - number of receptors at tissue - signal amplification

Answer 4

- the less number of receptors at a tissue will result in more drug being required to illicit the same effect and vice versa - in most cases it is possible to still get maximum response despite a reduction in receptor numbers meaning you only need a small number of receptors to get a full response - example of drug that will inactivate a receptor is: bromoacetyl alprenolol menthane (BAAM) which is an irreversible B-adrenoceptor antagonist - an equation called the Furchgott equation is used to calculate how many receptors are available - receptor reserve/Spare receptors: • many tissues have holds for a full agonist, this reserve can be large or small depending on the tissue • there is no receptor reserve for a partial agonist

Answer 5

used to calculate how many receptors are available in a tissue

Answer 6

- when a ligand binds to a receptor it sets off a signalling cascade - signal amplification determines how powerful the response will be - determined by the type of tissue the receptor is based in

Answer 7

- substance binds to a receptor to change the receptor's response to stimulus - bind to allosteric site - affinity modulation: change in EC50 - efficacy modulation: change in Emax - modulation can be positive-allosteric or negative-orthosteric

Answer 8

benzodiazepine

Answer 9

a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist; <0% efficacy

Answer 10

has no activity in the absence of an agonist or inverse agonist but can block the activity of either; 0% efficacy

Answer 11

- the diminishing effect of a drug resulting from repeated administration at a given dose - seen with continuous, repeated high concentration of drug over time

Answer 12

- uncoupled - receptor can’t interact with G-protein - receptor is internalised in vesicle of cell - receptor becomes degraded

Answer 13

- the ability of a protein's binding site to bind specific ligands - the fewer ligands a protein can bind, the greater its specificity - describes the strength of binding between a given protein and ligand

Answer 14

- how a ligand may bind more preferentially to one receptor than another - defined with respect to the binding of ligands to a substrate forming a complex

Answer 15

- isoprenaline is a non-selective B-adrenoceptor agonist so it activates both B1 (heart) & B2 (lungs) receptors - whereas salbutamol is a selective B2-adrenoceptor agonist, but at very high concentrations it loses its specificity so will activate both B1 and B2

Answer 16

phospholipase A2

Answer 17

converts membrane phospholipid to arachidonic acid

Answer 18

cyclooxygenase

Answer 19

converts arachidonic acid to prostaglandin H2

Answer 20

include aspirin and ibuprofen but there are about 50

Answer 21

• analgesic • anti-pyretic (reduces fever) • anti-inflammatory • they inhibit the enzyme cyclooxygenase (COX) which is responsible for the breakdown of arachidonic acid to prostaglandin H2 (PGH2) • NSAIDs work by preventing arachidonic acid from reaching the active site of the COX enzyme and thus from being broken down into prostaglandin H2 - this is achieved by competitive inhibition

Answer 22

``` PGH2 is acted on by specific synthases to generate prostanoids: • Prostaglandin D2 (PGD2) • Prostaglandin E2 (PGE2) • Prostaglandin I2 (PGI2) • Thromboxane A2 (TXA2) ```

Answer 23

* Prostaglandin D2 (PGD2) * Prostaglandin E2 (PGE2) * Prostaglandin I2 (PGI2) * Thromboxane A2 (TXA2)

Answer 24

* Prostaglandin D2 - mast cells * Prostaglandin I2 - vascular endothelial cells * Thromboxane A2 - platelets * Prostaglandin E2 - macrophages (most widely found and mediates largest number of effects in the body)

Answer 25

- prevents arachidonic acid from reaching the active site of the COX enzyme and thus from being broken down into prostaglandin H2 (competitive inhibition) - irreversibly blocks the active site resulting in irreversible inactivation of the COX enzyme

Answer 26

* COX-1: found normally and widely around the body (normal physiology) * COX-2: this is induced and found mainly in inflammation only

Answer 27

* aspirin is non-selective so acts on both COX-1 and COX-2 | * whereas celecoxib for example is COX-2 selective

Answer 28

captopril and enalapril

Answer 29

- anti-hypertensives - work by inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II meaning there is less angiotensin II so less bind to angiotensin receptors (AT1) resulting in reduced vasoconstriction and thus hypertension as well as less aldosterone release further reducing hypertension

Answer 30

* Captopril - mimic dipeptides; His and Leu * Enalapril - mimic tripeptides; Phe, His and Leu * both captopril and enalapril work by binding to ACE active site thereby meaning it is unable to convert angiotensin I to angiotensin II

Answer 31

penicillins, amoxicillin and cephalosporins

Answer 32

work by inhibiting cell wall biosynthesis of peptidoglycan bacterial cell walls by inhibiting the activity of certain enzymes

Answer 33

- most drugs are excreted by the kidneys but lipophilic drugs are not effectively removed as they are passively absorbed because they can diffuse through cell membranes easily - in these cases Cytochrome P450 is required to introduce a hydroxyl (OH) group into the drug to enable it to be excreted more easily by the kidneys - note: some drugs act to either inhibit or induce CYP450s to either make drugs remain in the system for longer or to be excreted quickly (e.g. quite toxic drugs)

Answer 34

omeprazole, lansoprazole, pantoprazole and rabeprazole

Answer 35

- they are all activated in acidic (i.e. stomach) environments - they act to inhibit acid secretion - when prostaglandin E2 (PGE2) released from chromaffin cells, it binds to EP3 receptors on parietal cells, this causes a reduction in the concentration of H+ and thus acidity of the stomach by reducing the activity of the H+/K+ ATPase pump - PGE2 inhibits parietal cells - when histamine released from histaminocytes, binds to H2 receptors on parietal cells, this causes the H+/K+ ATPase pump to increase activity resulting in a higher concentration of H+ being pumped into the gastric lumen thereby increasing acidity - histamine activates parietal cells - PPIs act to irreversibly inactivate the proton pump (H+/K+ ATPase) resulting in a marked reduction in acidity of the stomach, thereby helping with reflux etc.

Answer 36

- act to inhibit symporters - the increased excretion of water is useful for the treatment of hypertension and heart failure since the removal of water from the blood will reduce its volume and thus blood pressure

Answer 37

furosemide can inhibit the NKCC2 pump on the thick ascending part of the loop of Henle thereby reducing the amount of Na+,Cl- and K+ ions able to enter the medullary interstitium thereby reducing hyperosomolarity meaning that less water will diffuse out of the collecting ducts into the blood, resulting in more water loss in the urine and thus dehydration

Answer 38

act to inhibit the Na/Cl cotransporter on the distal tubule of the nephron; this results in increased water loss

Answer 39

dopamine, noradrenaline, serotonin and GABA

Answer 40

cause an increased concentration of neurotransmitter in the synapse by preventing their re-uptake

Answer 41

tri-cyclic anti-depressant that mostly inhibits the reuptake of noradrenaline (majority) and serotonin

Answer 42

inhibits reuptake of dopamine

Answer 43

inhibits the reuptake of GABA (the inhibitory transmitter in CNS) thus useful for the treatment of panic disorders

Answer 44

lidocaine and procaine

Answer 45

- these local anaesthetics work by interrupting axonal neurotransmission in the sensory nerves - they do this by blocking voltage dependent sodium channels thereby preventing the neurones from depolarising, meaning the threshold isn’t met and thus no action potential is developed to be propagated - this rests in pain relief since pain isn’t transmitted to the brain to be perceived - local anaesthetics can diffuse through mucus membranes easily thus sometimes can act on muscles too

Answer 46

any compound that is administered with an intended therapeutic effect

Answer 47

* uptake into the plasma * distribution from the plasma * elimination from the plasma

Answer 48

- rate of diffusion is directly proportional to the concentration gradient - it is a first order process - an increase in concentration will result in a higher rate of diffusion from plasma to tissue - rate of diffusion is directly proportional to temperature (most drugs won't work outside normal physiological temperature) - rate is influenced by chemical reactions between the drug and solute (i.e. plasma)

Answer 49

rate is directly proportional to the concentration of drug (rate ∝ [drug])

Answer 50

rate is directly proportional to the square of the concentration of the drug (rate ∝ [drug]^2)

Answer 51

rate is directly proportional to the cube of the | concentration of the drug (rate ∝ [drug]^3)

Answer 52

rate is unrelated to the concentration of the drug | rate ∝ [drug]0

Answer 53

first order

Answer 54

where the rate of reaction is governed by one of the components involved in the reaction whose quantity or magnitude is changing

Answer 55

• the plasma is the fluid fraction or aqueous solution that remains when cells are removed from the blood • proteins (including antibodies) are found in the plasma as a result of their polar amino acid side chains • the pH of the interstitium is reflected in the plasma • plasma has a slightly higher pH than interstitium due to diffusion gradient

Answer 56

pharmacokinetic theory considers the body as 3 main compartments divided by tissue lipid rich barriers

Answer 57

- plasma (5 litres) - interstitial (15 litres) - intracellular (45 litres)

Answer 58

- vessel rich viscera: muscle tissue | - vessel poor: fat stores/subcutaneous tissue

Answer 59

1. simple diffusion 2. facilitated diffusion 3. active transport 4. through extracellular spaces 5. non-ionic diffusion

Answer 60

• movement of solutes from a region of their high concentration to a region of their low concentration through a lipid barrier • first order process

Answer 61

``` • movement of solutes from a region of their high concentration to a region of their low concentration through protein channels • no energy required ```

Answer 62

``` • movement of solutes from a region of their low concentration to a region of their high concentration using protein carriers • require energy • goes against the concentration gradient • first order reaction initially but when saturated it becomes zero order ```

Answer 63

* movement of solutes through pores in cell membrane | * protein typically cannot enter through these pores

Answer 64

``` • the movement of ionic molecules (which find it difficult to diffuse across a lipid membrane) across a lipid membrane (such as that found in a cell) into the cell • ionised molecules are water soluble • un-ionised molecules are freely diffusable and lipid soluble • the mechanism of action of non-ionic diffusion is that an ionic molecule becomes less ionic and thus more non- ionic to enable it to cross the lipid membrane and enter the cell ```

Answer 65

• ionised molecules are water soluble • un-ionised molecules are freely diffusable and lipid soluble

Answer 66

• the degree of ionisation of weak acids and weak bases is influenced by pH • non-ionic diffusion is enhanced if adjacent compartments have a pH difference

Answer 67

weak acid: more ionised | weak base: less ionised

Answer 68

weak acid: less ionised | weak base: more ionised

Answer 69

amount of drug taken up as a proportion of the amount administered

Answer 70

has the greatest variability due to different factors involved; surface area of gut, diarrhoea (bioavailability is greatly decreased) and pH of gut (alkaline at duodenum)

Answer 71

simple diffusion of the lipid | soluble freely diffusible non ionised fraction

Answer 72

- has the greatest variability due to different factors involved; surface area of gut, diarrhoea (bioavailability is greatly decreased) and pH of gut (alkaline at duodenum) - unpredictable - movement across the gut membrane is simple diffusion of the lipid soluble freely diffusible non ionised fraction - most tablets are either weak acids or weak bases - water soluble tablets will not pass across the membranes of cells unless there is carrier mediated transport

Answer 73

close to 1

Answer 74

should be 1

Answer 75

- such as a skin patch | - has a lower bioavailability than I.V.

Answer 76

- oral - intramuscular - IV - transcutaneous - intrathecal (into CSF) - sublingual - inhalation - topical - rectal

Answer 77

* aspirin is acidic * in the stomach the acidic tablet dissolves but it then becomes less ionised due to the fact that a weak acid (such as aspirin) becomes less ionised in lower pH * movement of the un-ionised aspirin across the gut is rapid * in the plasma, aspirin is more ionised due to the higher pH * gastric pH affects the amount of aspirin uptake

Answer 78

due to higher pH

Answer 79

* in the plasma aspirin is more ionised due to the higher pH | * gastric pH affects the amount of aspirin uptake

Answer 80

* in the stomach the acidic tablet dissolves but it then becomes less ionised due to the fact that a weak acid (such as aspirin) becomes less ionised in lower pH * movement of the un-ionised aspirin across the gut is rapid

Answer 81

- antacids act to increase pH e.g. treatment of ulcer - omeprazole (PPI) and ranitidine (H2 blocker) acts to reduce acid secretion in stomach and thus increase pH - ingesting alkali foods results in an increased pH - a raised pH results in the reduced uptake of aspirin from the stomach and thus a reduction in bioavailability

Answer 82

a raised pH results in the reduced uptake of aspirin from the stomach and thus a reduction in bioavailability

Answer 83

a drug is distributed in the plasma according to its chemical properties and molecular size

Answer 84

dissolved gases and small ionic molecules

Answer 85

hydrophobic areas of plasma proteins

Answer 86

- proteins/large molecules are only active in the plasma compartment (5L) - water soluble molecules are active in plasma and interstitial compartment (5L + 15L) - lipid soluble molecules are only active in the intracellular fluid (45L)

Answer 87

plasma compartment (5L)

Answer 88

plasma and interstitial compartments (5L + 15L)

Answer 89

intracellular fluid (45L)

Answer 90

derived value from steady state (where drug intake is in equilibrium with its elimination) plasma level studies

Answer 91

* volume of distribution = total amount of drug in body ÷ concentration of drug in plasma * it is the volume (litres) that the drug would occupy if it was distributed through all the compartments as if they were all plasma

Answer 92

* the volume of distribution can appear to be larger than it actually is, this is because when calculating volume of distribution, concentration and volume is taken from the plasma (blood) * however, when a drug is injected it can be taken up by organ systems (such as the liver, lungs and kidney etc.) this will mean its concentration in the blood will decrease * thus when you calculate the volume of distribution after the drug has been partly taken up then the value you get can be much larger than it physically is * drugs that are highly lipid soluble, enter the CNS and have a high volume of distribution

Answer 93

drugs that are highly lipid soluble, enter the CNS and have a high volume of distribution

Answer 94

* plasma expanders * immunoglobulin * warfarin

Answer 95

* aspirin/ other NSAIDs * antibiotics * muscle relaxants

Answer 96

* steroids * local anaesthetics * opioids * CNS drugs * paracetamol * amiodarone (has a volume of distribution of 450L i.e. very easily taken up by tissue)

Answer 97

* assumes plasma is in equilibrium * shows plasma concentration against time during the distribution of drug phase * line of best fit to 1,2 or 3 compartment models of distribution

Answer 98

C = C0 e^-kt

Answer 99

C = C0 e^-kαt + C0 e^-kβt

Answer 100

C = C0 e^-kαt + C0 e^-kβt + C0 e^-kλt

Answer 101

for every compartment you add to the model you add another “C0 e-kt”

Answer 102

most lipid soluble drugs have 3 compartment models - this suggests that the movement between the compartments is plasma > viscera > adipose tissue

Answer 103

plasma compartment

Answer 104

* renal and/or hepatic elimination are the route for the vast majority of drugs * in renal failure, a patient will not be able to eliminate for up to a week

Answer 105

first order process

Answer 106

* the volume of plasma that can be completely cleared of drug per unit time (mls minute^-1 (ml/min)) * the rate at which plasma drug is eliminated per unit plasma concentration (mls minute^-1 (ml/min))

Answer 107

- the removal of drug from the plasma by either liver or kidney is clearance - both definitions are measures of efficiency - can influence the rate of elimination depending on plasma concentration of drug

Answer 108

* the rate at which plasma drug is eliminated = mg per minute * per unit plasma concentration = mg per ml * total = mg per minute ➗ mg per ml * cancel out the “mg” * results in = mls minute^-1 (ml/min) * thus the units of clearance are mls minute-1 (ml/min)

Answer 109

• all of the factors affecting renal blood flow affect clearance most notably blood pressure • water soluble molecules which pass through the glomerular endothelial gap are eliminated by glomerular filtration • larger water soluble molecules can be eliminated by active tubular secretion

Answer 110

- the calculation assumes; rate of elimination = rate of appearance in urine - plasma concentration measured during the clearance process is assumed to be constant - clearance = rate of appearance in urine ➗ plasma concentration - creatinine is used as a marker substance in kidney

Answer 111

creatinine

Answer 112

renal blood flow is 18% of cardiac output = 1L/min

Answer 113

renal plasma flow is 60% of blood flow = 600mls/min

Answer 114

glomerular filtration is 12% of renal blood flow = 130mls/min

Answer 115

- many drugs are eliminated by the kidney either by glomerular filtration e.g digoxin and gentamicin or via active secretion e.g. penicillin, frusemide and thiazides - many highly lipid soluble drugs metabolised to water soluble glucuronic acid conjugates are eliminated by active secretion e.g. morphine 3 & 6 glucuronides - only free plasma is cleared - highly protein bound drugs have little exposure to renal clearance - most drugs eliminated by the kidney are water soluble and small molecules

Answer 116

water soluble and small molecules

Answer 117

reduced pre-renal perfusion

Answer 118

diabetes and hypertension

Answer 119

reduced clearance and prolonged elimination of a large number of drugs

Answer 120

* for patients with renal impairment, choose drugs that are eliminated by the liver instead * hypoalbuniaemia means lipid soluble drugs in the plasma have highly freely diffusable fractions and greater effects * elevated plasma creatinine and urea compete for lipid binding sites on protein and displace more lipid soluble free drug * patients with renal impairment have unpredictable reactions to drugs due to oedema in compartments

Answer 121

- choose alternatives not eliminated by the kidney - avoid nephrotoxic drugs - make corrections based on plasma creatinine which estimated the percentage reduction in clearance and then alter dose - measure plasma concentrations if there is a toxicity risk

Answer 122

* has no equivalent to glomerular filtration * all hepatic clearance involves active transport * there is active secretion (if water soluble) from the liver into the bile duct

Answer 123

hepatic blood flow is 24% of cardiac output (3/4 from portal vein and 1/4 from hepatic artery)

Answer 124

the proportion of drug removed by one passage through the liver

Answer 125

can be so high that clearance is only limited by hepatic blood flow - perfusion limited

Answer 126

the process is slow and not efficient with a low amount | removed - diffusion limited

Answer 127

- liver enzymes can alter the HER - if the liver is exposed to a low HER drug then it will produce more enzymes to enable it to increase clearance - high HER drugs have little effect on the number of new enzymes produced

Answer 128

drugs with a high HER are described as having a high first pass metabolism and thus have limited uptake from oral administration since they will first go to the liver before it can reach its target but by that time most of it will have been eliminated - ineffective

Answer 129

* some large water soluble molecules are secreted unchanged in bile * most large lipid soluble drugs are metabolised to increase their water solubility so that they may be excreted more easily by the kidney * pro-drugs are activated in the liver, whereby the pro-drug is cleaved into the active drug via metabolism e.g hydrocortisone is broken down into the active drug cortisol

Answer 130

95% of phase I reactions are in liver smooth endoplasmic | reticulum

Answer 131

aim is to make the drug more hydrophilic so that it can be excreted by the kidneys - it does this by adding a hydroxyl group to the drug

Answer 132

- they introduce or expose hydroxyl (-OH) groups or other reactive sites that can be used for conjugation reactions (the Phase II reactions) - introduces reactive group to drug - attack point for conjugation - hydrophilic molecules usually do not reach the metabolising enzymes since they are excreted easily - oxidation - reduction: add hydrogen (saturate unsaturated bonds) - hydrolysis: split amide (peptide bond (between a carboxyl (COOH) and amino (NH) group) O=C-NH) and ester (the H from a COOH (carboxylic acid) is replaced by some sort of hydrocarbon) bonds

Answer 133

* hydroxylation (add -OH) * dealkylation (remove -CH side chains) * deamination (remove -NH) * hydrogen removal

Answer 134

add hydrogen (saturate unsaturated bonds)

Answer 135

``` split amide (peptide bond (between a carboxyl (COOH) and amino (NH) group) O=C-NH) and ester (the H from a COOH (carboxylic acid) is replaced by some sort of hydrocarbon) bonds ```

Answer 136

* introduces reactive group to drug * includes adding or exposing; -OH,-SH,-NH2,-COOH * the product of the reaction is usually more reactive * there is a small increase in hydrophilicity

Answer 137

- mainly occur in the liver | - mainly catalysed by cytochrome P450 enzymes

Answer 138

- type of microsomal enzyme i.e. found on liver smooth endoplasmic reticulum - involved in Phase I reactions

Answer 139

- uses heme group (Fe2+) to oxidise substances - products of P450 enzymes are more water soluble - requires energy and molecular oxygen

Answer 140

some drugs act to inhibit cytochrome P450 such as amiodarone and cimetidine resulting in drugs lasting longer/not being eliminated as fast

Answer 141

- also known as glucuronidation, used if drug is very hydrophobic - essentially adding a glucuronic acid group (glucuronide) to the drug to make it more hydrophilic - process forms covalent bonds

Answer 142

- enzyme: glucuronosyltransferase (Uridine 5’-diphospho- glucuronosyltransferase) (UGT) - microsomal enzyme, used in phase II reactions, catalyses reaction - uridine diphospho-glucuronic acid (UDPGA) - essentially a co- enzyme/donor compound required to conjugate glucuronic acid

Answer 143

UDPGA + drug -> uridine diphosphate + drug-glucoronide | - catalysed by UGT

Answer 144

- phase I water soluble metabolites and phase 2 glucuronides enter the bile and then enter the gut via the cystic duct - some phase I metabolites and phase 2 glucuronides also enter the blood and are actively excreted into the urine - during cholestasis (stoppage of bile flow), increased amounts are excreted by the kidneys - conversely biliary secretion may increase if renal function is reduced

Answer 145

* large bowel flora tend to metabolise the glucuronic acid group on the phase 2 glucuronide * this results in the liberation of the drug from the glucuronic acid * the drug is then able to re-diffuse from the gut into the blood and then have a prolonged effect before going back to the liver to be re-conjugated and excreted again * thus the enterohepatic circulation can prolong the action of some drugs

Answer 146

- isolated liver failure with no effects on other organs is unusual - there is minimal effect on drug metabolism until at least 70% of functioning liver is lost

Answer 147

the prolonged duration of the action of a drug comes with the risk of drug accumulation and thus toxicity

Answer 148

- the prolonged duration of the action of a drug comes with the risk of drug accumulation and thus toxicity - hypoalbuminaemia means an increased free plasma levels of freely diffusable lipid soluble drugs - pharmacodynamic (how drug affects body) alterations are often secondary to disease - the nitrogen containing substances that are cleared by the liver contribute to toxicity

Answer 149

- Prednisone - Isosorbide dinitrate - Codeine - Diamorphine - L-dopa - Cortisone - Morphine

Answer 150

- Insulin - Heparin - Antibiotics - Frusemide - Anti-arrhythmics - Sedation anaesthsia

Answer 151

- enables steady state plasma (where drug intake is in equilibrium with its elimination) levels to be maintained for as long as possible - enables highly accurate drug delivery - useful for drugs that are ineffective administered by other routes or those who cannot absorb oral medication - is the quickest administration route - guarantees 100% bioavailability (the gold standard)

Answer 152

- much less accurate drug delivery since bioavailability can be highly variable resulting in uncertainty or effectiveness of treatment - however it does have excellent patient compliance with one tablet a day

Answer 153

- requires constant monitoring of patency of IV access, replenishing of drug delivery and observation of response to therapy - has the potential for serious calculation errors - limited by the number of places a cannula can be inserted

Answer 154

patency of IV access, replenishing of drug delivery and observation of response to therapy

Answer 155

- IV regimes lack standardisation of prescription - units are mg hour-1 (mg/hour) - drug dosage is based on body weight - problematic with extreme body weights - monitoring necessary to look at therapeutic response

Answer 156

* high volume of distribution means that there will be a small fraction in the plasma so it will take a long time to reach a steady state * with high volume of distribution drugs, adjusting infusions rate takes ages to change the plasma concentration * thus a ‘loading’ bolus dose is often recommended to speed up saturation of all the components * steady state means that infusion dosage = rate of elimination from plasma * increasing infusion rate aims to raise plasma level and maintain equilibrium * if elimination becomes saturated then this will lead to the accumulation of the drug and thus toxicity

Answer 157

* high volume of distribution means that there will be a small fraction in the plasma so it will take a long time to reach a steady state * with high volume of distribution drugs, adjusting infusions rate takes ages to change the plasma concentration * thus a ‘loading’ bolus dose is often recommended to speed up saturation of all the components

Answer 158

steady state means that infusion dosage = rate of elimination from plasma

Answer 159

increasing infusion rate aims to raise plasma level and maintain equilibrium

Answer 160

if elimination becomes saturated then this will lead to the accumulation of the drug and thus toxicity

Answer 161

- one with a small volume of distribution so it is easy to reach steady state and so that the plasma concentration is responsive to dose rate - one which is broken down by tissue/plasma enzymes irrespective of liver and renal function - one with an obvious and predictable dose to response relationship - one with a low risk of toxicity and that is easy to determine the concentration of it in the plasma

Answer 162

* insulin is infused with 10% dextrose for managing a diabetic who is nil by mouth * there is a danger of hypoglycaemia if the insulin is not given alongside dextrose since plasma glucose can change rapidly

Answer 163

* type of antibiotic * requires plasma level monitoring of peak (sample hour after drug given) and trough (sample hour before next dose) level after three doses

Answer 164

• anti arrhythmic drug • has problem of returning arrhythmia when the infusion is turned off • is a high volume of distribution drug and thus often steady state is not achieved after 48hrs of IV infusion

Answer 165

* for emergency anticoagulation if at high risk of thrombosis * chemical reaction works in minutes

Answer 166

* alpha-1 agonist * used as a vasoconstrictor * given for the treatment of septic shock

Answer 167

- GnRH (pituitary) when given in continuos infusion results in a contraceptive effect - pulsatile GnRH however is a physiological fertility treatment - desensitisation occurs with many agonist drug infusions, perhaps pulsatile delivery could avoid this

Answer 168

intermittent/pulsatile IV gentamicin results in a higher peak level than steady state infusion and thus has higher bactericidal activity

Answer 169

patient controlled morphine analgesia only requires a 1/3 of the normal IV dose if given as intermittent IM injections, this is very beneficial since there is less respiratory depression than with IV infusion

Answer 170

* somatic (NMJ) = voluntary = acetylcholine (ACh) | * autonomic = involuntary = ACh and Noradrenaline (NAd)

Answer 171

* parasympathetic - ACh | * sympathetic - NAd

Answer 172

* nicotinic (nAChR) - ion channel receptors | * muscarinic (mAChR) - G-protein coupled receptor

Answer 173

muscarinic ACh receptors (M1, M2, M3 - most common)

Answer 174

ACh mediates the release of adrenaline (Ad) and | noradrenaline (NAd)

Answer 175

nicotinic receptors (nAChR) mediate the response of ACh in the somatic system at the neuromuscular junction

Answer 176

nicotinic ACh receptors (nAChR)

Answer 177

- choline acetyl transferase enzyme is required to make ACh from acetyl CoA and choline (substrate) in the neurone - ACh is then packaged into a vesicle ready to be released when the neurone is stimulated - after ACh has been used it is broken down in the synaptic cleft by acetylcholinesterase AChE into choline and acetate - choline is taken up into the neurone where it can be used to make more ACh

Answer 178

choline acetyl transferase enzyme makes ACh from acetyl CoA and choline (substrate) in the neurone

Answer 179

after ACh is used, it's broken down in the synaptic cleft by acetylcholinesterase into choline and acetate

Answer 180

* lethal toxin | * inhibits ACh release into the neuromuscular junction resulting in paralysis

Answer 181

* uses protease to degrade vesicle proteins | * thereby preventing vesicle fusion and thus the release of ACh into the synaptic cleft

Answer 182

cosmetic and spasticity

Answer 183

- competitive nAChR antagonist - nAChR found at the neuromuscular junction - arrow poison known as tubocurarine - acts as a neuromuscular blockade by binding to the 2 nicotinic binding sites on the nAChR thereby preventing the binding of ACh

Answer 184

- results in a muscle relaxant effect | - can result in being conscious but aware of pain and paralysed

Answer 185

can reverse the block using sugammadex which is a selective relaxant binding agent that encapsulates the blocker thereby preventing it from binding

Answer 186

- suxamethonium is essentially 2 ACh stuck together - acts to desensitise the receptor resulting in paralysis of skeletal muscle - action is fast and short duration (less than 10 mins)

Answer 187

remains in the NMJ for a while since it is a poor substrate for acetylcholinesterase; can only be broken down by plasma cholinesterase, not synaptic acetylcholinesterase

Answer 188

neostigmine

Answer 189

- blocks cholinesterase reversibly - resulting in an increase of ACh at the synaptic cleft since it isn't broken down - thus ACh remains for longer and thus signal stimulated for longer

Answer 190

reversible cholinesterase inhibitor

Answer 191

useful in treatment of myasthenia gravis whereby the immune system produces antibodies against nAChR, resulting in less receptors and thus a weak skeletal muscle response - thus having ACh remain longer will result in stronger responses

Answer 192

organophosphates: - insecticides (diazinon) - nerve gas (sarin)

Answer 193

irreversibly inhibit acetylcholinesterase, meaning ACh remains indefinitely, leading to huge accumulation

Answer 194

insecticides (diazinon) and nerve gas (sarin)

Answer 195

twitching, severe weakness and paralysis

Answer 196

salivation, defectation, urination, bradycardia and hypotension

Answer 197

confusion, loss of reflexes, convulsions and coma

Answer 198

* normal physiological conditions | * rest and digest

Answer 199

* stress | * fight or flight

Answer 200

- eye agonists - lungs - bladder - GI tract

Answer 201

* pilocarpine (stimulates saliva (dry mouth)) is a partial agonist of the muscarinic 3 receptor (M3) * constrictor muscle and ciliary muscle contract, resulting in miosis (excessive constriction of pupil) * leads to improved filtration of aqueous fluid * lowers intraocular pressure (to treat glaucoma) which is associated with optic nerve damage

Answer 202

• the intrinsic tone of the airways is governed by the parasympathetic system • mediated by cholinergic (ACh) muscarinic M3 receptors • excessive parasympathetic activation can result in bronchoconstriction mediated via the M3 receptor • seen in COPD and asthma • antagonists either short-acting (ipratropium) or long-acting (tiotropium) act as bronchodilators

Answer 203

pilocarpine

Answer 204

muscarinic 3 receptor

Answer 205

- leads to contraction of the constrictor muscle and the ciliary muscle, resulting in miosis (excessive constriction) - leads to improved filtration of aqueous fluid - lowers intraocular pressure in glaucoma, which would lead to optic nerve damage

Answer 206

parasympathetic system via cholinergic (ACh) muscarinic M3 receptors

Answer 207

excessive parasympathetic activation of the M3 receptors in the lungs can lead to bronchoconstriction

Answer 208

ipratropium | - acts as a bronchodilator

Answer 209

tiotropium | - acts as a bronchodilator

Answer 210

short-acting antagonist of the M3 receptors in the lungs | - is a bronchodilator

Answer 211

long-acting antagonist of the M3 receptors in the lungs | - is a bronchodilator

Answer 212

causes contraction of the bladder

Answer 213

a bladder agonist results in more contraction e.g. bethanechol - useful in urinary retention

Answer 214

a bladder antagonist is used to relax the bladder e.g. | oxybutinin - useful in urinary frequency

Answer 215

acts to increase GI motility

Answer 216

GI antagonist such as mebeverine and scopolamine are useful at decreasing GI motility - especially useful in Irritable Bowel Syndrome (IBS)

Answer 217

* Diarrhoea * Urination * Miosis (excessive pupil constriction) * Bradycardia * Emesis (vomiting) * Lacrimation (tears) * Salivation/sweating * Remember by DUMBELS!

Answer 218

- competitive antagonist at the nAChR at autonomic ganglia - blocks both parasympathetic and sympathetic divisions of the autonomic nervous system - has no effect on the neuromuscular junction

Answer 219

* secretions reduced * constipation * urinary retention * blurred vision

Answer 220

marked hypotension

Answer 221

the first antihypertensive drug

Answer 222

* ACh stimulates the vomiting centre in the brain | * scopolamine (anti-muscarinic) used for motion sickness treatment

Answer 223

* dopamine is low in Parkinsons sufferers * ACh stimulates the reuptake of dopamine * benzatropine blocks the reuptake and thus increases the amount of dopamine at cleft

Answer 224

• there is a lack of cholinergic neurones and thus a reduction in ACh • donepezil acts to inhibit acetylcholinesterase and is specific to the CNS resulting in increased ACh in the CNS

Answer 225

NAd is a neurotransmitter and Ad is a hormone

Answer 226

``` acetylcholine • rest and digest • constricts pupils • stimulates tears • stimulates salivation • lowers heart rate • reduces respiration • constricts blood vessels • stimulates digestion • contracts bladder • erection ```

Answer 227

``` noradrenaline • fight or flight • dilates pupil • inhibits tears • inhibits salivation • activates sweat glands • increases heart rate • increases respiration • inhibits digestion • release of adrenaline • relaxes bladder • ejaculation in males ```

Answer 228

noradrenaline (20%) and adrenaline (80%)

Answer 229

- monoamine neurotransmitter, an organic compound that has a catechol and a side chain amine - noradrenaline, adrenaline, DOPA and dopamine

Answer 230

tyrosine -> DOPA -> dopamine -> noradrenaline -> adrenaline

Answer 231

tyrosine hydroxylase

Answer 232

DOPA decarboxylase

Answer 233

dopamine beta-hydroxylase

Answer 234

phenylethanolamine N-methyltransferase

Answer 235

monoamine oxidase and catechol-O-methyl transferase inactivate noradrenaline release by metabolising it thus reducing its stimulant effect - metabolise other catecholamines too

Answer 236

- alpha-1 and alpha-2 - beta-1, beta-2 and beta-3 - all are GPCRs

Answer 237

- coupled with Gq protein and phospholipase C - phosphatidylinositol is converted into DAG and IP3 - DAG activates protein kinase C - IP3 triggers release of Ca2+ -> contraction

Answer 238

- coupled with Gi protein | - Gi protein inhibits adenylyl cyclase, which would usually produce cAMP which would activate protein kinase A

Answer 239

- vasoconstriction - pupil dilation - bladder contraction

Answer 240

presynaptic inhibition of noradrenaline (negative feedback) i.e. when blood sugar is low then alpha-2 in pancreas will be stimulated to reduce noradrenaline release thereby reducing insulin levels being released from the pancreas

Answer 241

- Gs protein and adenylyl cyclase - converts ATP to cAMP - cAMP activates protein kinase A

Answer 242

- increased force of heart contraction (positive inotropic effect) - increased heart rate - increased electrical conduction in heart - increased renin release from the kidney - increased blood pressure

Answer 243

- bronchodilation - vasodilation - reduced GI motility

Answer 244

- increased lipolysis | - relaxation of bladder

Answer 245

- non-selective agonist | - non-selective since it works at any alpha or beta adrenoceptor

Answer 246

• anaphylaxis - reduced blood pressure and increased bronchoconstriction • cardiac arrest • acute hypotension

Answer 247

* blood vessels (Alpha-1) * heart (Beta-1) * bronchial smooth muscle (Beta-2)

Answer 248

* vasoconstriction (Alpha-1) * positive inotropic effect (Beta-1) * bronchodilation (Beta-2)

Answer 249

- blood vessels and bladder | - phenylephrine and oxymetazoline

Answer 250

* results in vasoconstriction | * useful as a nasal decongestant since vasoconstriction results in less fluid leakage from vessels

Answer 251

- pre-synaptic neurone | - clonidine

Answer 252

it inhibits noradrenaline release therefore is useful as an anti-hypertensive

Answer 253

- heart | - dobutamine

Answer 254

has a positive inotropic effect in the heart thus increases force of heart contraction

Answer 255

- lungs | - salbutamol

Answer 256

bronchodilation

Answer 257

- bladder | - mirabegron

Answer 258

relaxation of the bladder

Answer 259

adrenaline (works on all alpha and beta receptors)

Answer 260

- amphetamines and cocaine | - MAO and COMT inhibition

Answer 261

* work by inhibiting the noradrenaline transporter on the pre-synaptic neurone thereby resulting in a build up of catecholamines, especially noradrenaline but dopamine too, in the synapse * results in CNS overstimulation

Answer 262

* this results in the build up of noradrenaline as well as other catecholamines such as dopamine * useful in the treatment of Parkinson’s and depression

Answer 263

doxazosin and tamsulosin

Answer 264

- alpha-1 adrenergic antagonist | - vasodilator; reduces blood pressure; is a anti-hypertensive

Answer 265

- alpha-1 adrenergic antagonist - relaxes bladder neck and aids in urination - useful in men with enlarged prostates who find it difficult to urinate

Answer 266

- alpha-2 adrenergic antagonist - blocks alpha-2 receptor - noradrenaline inhibition does not occur, leading to an increase in noradrenaline and other catecholamines e.g. dopamine

Answer 267

- results in a reduction in cardiac output as well as a reduction in renin thus a reduction in blood pressure - useful in treating hypertension, angina and arrhythmia

Answer 268

propanolol; works on all beta receptors

Answer 269

atenolol, metoprolol, bisoprolol, betaxolol

Answer 270

non-selective beta and alpha-1 antagonist which affects the heart and causes vasodilation

Answer 271

- partial agonists: intrinsic sympathomimetic activity | - membrane stabilising activity

Answer 272

beta-blockers that are able to stimulate beta-adrenergic receptors (agonist effect) as well as acting like antagonists too - e.g. penbutolol and acebutolol

Answer 273

• can inhibit the propagation of action potentials across a membrane • useful in the treatment of arrhythmias • propranolol and betaxolol

Answer 274

vasoconstriction and bladder contraction

Answer 275

presynaptic inhibition

Answer 276

increased cardiac effects

Answer 277

bronchodilation

Answer 278

bladder relaxation and increased lipolysis

Answer 279

- “to treat like with like” - quite possible there is a placebo effect - one advantage is that there are unlikely to be any drug interactions with homeopathic treatments

Answer 280

- medicine from plants - can be medically effective - but the industry is unregulated e.g. heavy metals found in asian herbal products - also these medicines can interfere and interact with normal medication

Answer 281

* digitalis from foxglove plant - for heart failure treatment * morphine from poppy - analgesic * atropine from deadly nightshade - scarlet fever treatment * vincristine from periwinkle - cancer treatment

Answer 282

digitalis from foxglove plant

Answer 283

morphine from poppy

Answer 284

atropine for deadly nightshade

Answer 285

vincristine from periwinkle

Answer 286

chance and rational drug design

Answer 287

penicillin and sildenafil

Answer 288

propanolol and ritonavir

Answer 289

- using fermentation | - led to discovery of other antibiotics e.g. streptomycin

Answer 290

* lovastatin (statin) * cyclosporine (immunosuppressant) * ivermectin (broad spectrum antibiotic)

Answer 291

asymmetry; an object is chiral if it's distinguishable from its mirror image; it cannot be superimposed onto it - D (S form) or L (R form) - may influence drug action - some drugs have chiral centres (asymmetric carbon) e.g. salbutamol

Answer 292

L-amino acids (R form)

Answer 293

* rational drug design * developer undertook physiochemical considerations such as solubility, electrostatic and bulk * was developed as a antagonist to counter the agonist noradrenaline * is a Beta-antagonist used in treatment of hypertension

Answer 294

* was developed under rational drug design * developed as a antagonist to counter the agonist histamine * is a H2-antagonist used in the treatment of peptic ulcers

Answer 295

- extracted from beef/pork pancreas first - then eventually engineered insulin analogues was developed - second generation insulin analogues

Answer 296

- Lispro - Aspart - Glulisine

Answer 297

- Degludec - Detemir - Glargine

Answer 298

- insulin (recombinant human protein) - erythropoetin - growth hormone - interleukin 2 - gamma interferon - interleukin 1 receptor antagonist

Answer 299

mAb (monoclonal antibody) technology

Answer 300

• mouse is immunised against the antigen of interest • B cells are isolated to check they are producing antibodies against the antigen • if desired antibody is being produced then the mouse spleen is removed • B cells in the spleen are removed and then cultured along with myeloma tumour cells (these cells can divide indefinitely but cannot produce antibodies) • solution is added to fuse the B cells with the tumour cells to produce hybridomas (fused cells) that can divide indefinitely and produce antibodies • the hybridomas are then cloned and undergo clonal expansion • then the monoclonal antibodies produced are extracted and then used for clinical purposes

Answer 301

* these were mouse derived and thus tended to illicit immune responses against themselves since the human immune system recognised the antibodies as foreign * also these antibodies had a poor half-life

Answer 302

- chimeric antibodies | - humanised antibodies

Answer 303

- have a mix of human and mouse antibody | - but since mouse antibody is still present still can illicit immune response

Answer 304

- have 3 hypervariable regions (cutting edge of antigen recognition) and are less likely to illicit immune response - reason why mAbs and humanised mABs recognise the same target e.g. TNF is due to similarities in hypervariable regions

Answer 305

- infliximab - adalimumab - trastuzumab - omalizumab

Answer 306

type: chimeric target: TNF use: RA, Crohn's

Answer 307

type: humanised target: TNF use: RA

Answer 308

type: humanised target: HER2 (EGFR) use: breast cancer

Answer 309

type: humanised target: IgE use: asthma

Answer 310

adalimumab, trastuzumab, omalizumab

Answer 311

infliximab

Answer 312

- delivery of nucleic acid polymer to cell - DNA is delivered using a viral vector - therapeutic gene administered to treat effects of mutated gene - suppresses mutated gene gene expression

Answer 313

* biochemical modification of natural products * tropical rain forest and the sea are important sources of natural products * note: chemical modifications of natural products may be very difficult

Answer 314

- Penicillin - Cyclosporine - Quinine - Morphine

Answer 315

- large enzyme complexes generate natural products | - then manipulate biosynthetic machinery to generate structural analogues

Answer 316

- combinatoral chemistry and biosynthesis - huge library of compounds - high throughput screening -> hits -> leads

Answer 317

can screen around 50,000 compounds a day, roughly 2.5 million a year

Answer 318

- looks a biological activity of compounds - computers collate and retrieve data and analyse whether any compound has clinical efficacy - rapid way to identify ‘hits’

Answer 319

* bioavailability * pharmacokinetics * toxicology these still need to be tested for using traditional methods

Answer 320

the path from a lead to a drug is very long, expensive and has a high attrition rate

Answer 321

unpleasant sensory and emotional experience associated with actual or potential tissue damage

Answer 322

* sensory * emotional * actual/potential tissue damage

Answer 323

* warning of tissue damage * immobilisation for healing * protection of the species: establishment of memory

Answer 324

* increased heart rate * increased blood pressure * increased respiratory rate

Answer 325

- acute pain - cancer pain - chronic non cancer pain - nociceptive - neuropathic

Answer 326

post-op pain and non-surgical causes (most common)

Answer 327

palliative pain

Answer 328

visceral and MSK pain

Answer 329

inflammatory chemicals reach nerves to stimulate pain

Answer 330

where the nerve is directly injured - pain originates in nervous system

Answer 331

* generally lasts less than a week | * results from the activation of sensory nerve fibres called nociceptors

Answer 332

- the nerve endings of the peripheral nervous system - myelinated A delta fibres - unmyelinated C afferent fibres - located is most body tissues except the brain

Answer 333

complex mix of activation of different afferent fibres types

Answer 334

1. noxious stimulus 2. nociceptors 3. spinal cord (ascending pathway) 4. spinal cord modulation 5. thalamus 6. cortical areas, somatosensory cortex and prefrontal cortex 7. pain experience and memory

Answer 335

- mechanical - thermal - chemical

Answer 336

- the breakdown of membrane lipids leads to the formation of arachidonic acid under the action of the enzyme phospholipase A2 - arachidonic acid is then converted to prostaglandins under the action of the enzyme cyclooxygenase (COX) - prostaglandins are irritants to nerve fibres and stimulate pain

Answer 337

* prostaglandins * act directly on the nociceptors (peripheral terminals of A delta and c fibres) and lower their threshold to thermal stimuli * results in a sensation of burning at room temperature

Answer 338

C fibres and A delta fibres

Answer 339

- unmyelinated | - characterised by diffuse dull intense pain

Answer 340

- small and myelinated | - conduct localised sharp sensation

Answer 341

A beta fibres

Answer 342

A delta fibres and C fibres

Answer 343

- there is a balance of activity between large (A beta fibres) and small (A delta fibres and C fibres) fibres - interneurons of the substansia gelatinosa regulate this input in Lamina V (dorsal horn of spinal cord) - if A beta fibres are not stimulated by nociceptive stimulus then the pain signal goes through to the brain and is perceived - if A beta fibres are stimulated then the pain signal is halted and does not reach the brain and is thus not perceived - this means that low intensity stimulation of the skin or peripheral nerves or vibration in order to stimulate the A beta fibres will generate analgesia

Answer 344

interneurons of the substantia gelatinosa regulate the input in Lamina V (dorsal horn of the spinal cord)

Answer 345

if A beta fibres are not stimulated by nociceptive stimulus then the pain signal goes through to the brain and is perceived

Answer 346

if A beta fibres are stimulated then the pain signal is halted and does not reach the brain and is thus not perceived

Answer 347

low intensity stimulation of the skin or peripheral nerves or vibration which stimulates the A beta fibres will generate analgesia

Answer 348

* rubbing site of injury * application of heat * TENS - trans cutaneous nerve stimulation of A beta fibres * spinal cord stimulation

Answer 349

higher centre inputs

Answer 350

various neurotransmitters

Answer 351

- play key role in endogenous pain system - they inhibit the firing of the dorsal horn neutron that responds to noxious stimulus (gate control theory) - changing the levels of neurotransmitters at the level of synapses meaning less pain is transmitted

Answer 352

- contains a high concentration of opiod receptors and endogenous opioids - under situations of extreme stress this pathway can be activated, resulting in the modulation of afferent noxious transmission - it projects to the dorsal horn - once the dorsal horn is activated, opioid receptors are activated resulting in a reduction in pre-synaptic neuronal sensitivity (thereby reducing Substance P release) which in turn results in reduced pain sensation - meaning less impulses travel up the first, second and third order neurones to the somatosensory cortex, meaning less pain is felt

Answer 353

once the dorsal horn is activated, opioid receptors are activated resulting in a reduction in pre-synaptic neuronal sensitivity (thereby reducing Substance P release) which in turn results in reduced pain sensation

Answer 354

release increases pain

Answer 355

- once the dorsal horn is activated, opioid receptors are activated resulting in a reduction in pre-synaptic neuronal sensitivity (thereby reducing Substance P release) which in turn results in reduced pain sensation - meaning less impulses travel up the first, second and third order neurones to the somatosensory cortex, meaning less pain is felt

Answer 356

* Enkephalin * Dynorphine * Beta endorphine: effect similar to morphine

Answer 357

opioids such as morphine, methadone, codeine and oxycodone mimic this effect by binding to the opioid receptors in the periaqueductal grey thereby conferring profound analgesia

Answer 358

* reducing excitatory neurotransmitters (glutamate) and excitation of the nerve (with respect to pain transmission) * enhancing inhibitory neurotransmitters

Answer 359

- basis for using anti epileptics | - local anaesthetics are Na+ channel blockers

Answer 360

- GABA is the main inhibitory neurotransmitter | - noradrenaline and serotonin are also inhibitory; used as basis for anti depressants

Answer 361

- GABA is the main inhibitory neurotransmitter | - noradrenaline and serotonin are also inhibitory; used as basis for anti depressants

Answer 362

in presence of pain

Answer 363

- acupuncture - bearable pain - placebo - psychological modulation of pain

Answer 364

• prostaglandins act directly on the nociceptors and reduce their threshold meaning normal stimuli can activate them resulting in a sensation of pain (peripheral sensitisation) • opioids • local anaesthetics

Answer 365

block the conduction of the nerve by blocking Na+ channels thereby preventing the depolarisation of the nerve and the propagation of an action potential

Answer 366

ongoing persistent pain greater than 3-6 months

Answer 367

- beyond the usual course of an acute disease | - after healing/cure has taken place

Answer 368

* ongoing persistent pain greater than 3-6 months * recurs at intervals for months or years * due to persisting stimulation in areas of ongoing tissue damage * serve no useful biological function, but has profound effects on the patient and their family

Answer 369

- physical: immobility - emotional: distress - social: little social interaction leading to isolation - economical: job issues - day to day activity is severely affected

Answer 370

- improve pain perception - improve function/mobility - improve sleep - improve emotional and psychological consequences of pain - improve quality of life

Answer 371

a response to a drug which is noxious and unintended

Answer 372

* occur in 10-20% of hospital patients * cost the NHS £1 billion a year * recognised as being associated with drug

Answer 373

``` Type A - augmented: • commonest • an extension of the clinical effect • predictable • dose related • self-limiting ```

Answer 374

- diuretic causing dehydration - anticoagulant causing bleeding - drug for hypertension causing hypotension

Answer 375

* those with renal or hepatic impairment are at a higher risk of ADR due to elimination difficulties i.e. have high blood plasma levels of the drug for longer * also the elderly (above 65) are at higher risk since as you get older there is decreased glomerular filtration and hepatic impairment etc.

Answer 376

``` type B - bizarre • unexpected • unrelated to dosage and not expected from known pharmacological action • unpredictable • mostly immunological mechanisms • hypersensitivity • genetically linked ```

Answer 377

heparin causing hair loss

Answer 378

* those with predisposing factors such as; history of allergy, asthmatics and some family history are at greater risk * can be seen in drugs that inhibit certain metabolic pathways

Answer 379

type C - chronic: • occurs after long term therapy • may not be immediately obvious with new medicines

Answer 380

steroids predispose to hypoglycaemia - may result in diabetes

Answer 381

type D - delayed: • also occurs after a long period of time after treatment (many years) • common to see patient having treatment, then after 20-30 years they suffer an ADR

Answer 382

type E - end of use: • relatively long term use (days/weeks) • withdrawal reactions • serious complication of stopping related to clinical effect

Answer 383

* A - Augmented * B - Bizarre * C - Chronic * D - Delayed * E - End of Use

Answer 384

- is there a history of allergy? - Type B (Bizarre) - is it predictable from the mechanism of action? does it seem dose-related? - Type A (Augmented) - has the patient been using the medication for a long time? - Type C (Chronic) - is the patient withdrawing from a medicine? - Type E (End of Use) - has the patient uses a drug in the past that could be causing a problem now? - Type D (Delayed)

Answer 385

history of allergy

Answer 386

reaction is predictable from mechanism of action and it seems dose-related

Answer 387

patient has been using medication for a long time

Answer 388

if patient is withdrawing from a medicine

Answer 389

if patient used a drug in the past that could be causing a problem now

Answer 390

- age - elderly - gender - more common in females - pregnancy - negative effect on baby etc. - disease - liver or renal in particular - drug interactions - diet or alcohol intake changes - genetics - hypersensitivity

Answer 391

* type 1: IgE-mediated drug hypersensitivity; anaphylaxis * type 2: IgG-mediated cytotoxicity - some drugs can cause renal failure through this type * type 3: immune-complex deposition; reacts with antibiotics * type 4: T-cell mediated; usually substance containing metals

Answer 392

- prior exposure to antigen (drug) - virgin B lymphocyte activation to IgE producing plasma cells - IgE becomes attached to mast cells, expressed as cell surface receptors

Answer 393

* monocyte in skin, sub mucosal, around blood vessels * dormant indefinitely * many are found in bronchial mucosa * see a lot of mast cell activity beneath the skin, around lungs and blood vessels

Answer 394

cross linking of IgE receptors releasing: - histamine - thromboxanes, prostaglandins - Tumour Necrosis Factor (TNF) - all of above are acute inflammatory mediators

Answer 395

- histamine - thromboxanes, prostaglandins - Tumour Necrosis Factor (TNF) - all of above are acute inflammatory mediators

Answer 396

* not caused by any IgE antibodies * due to direct mast cell degranulation * previously called anaphylactoid reactions * some drugs are recognised to cause this * no prior exposure * clinically identical to immune anaphylaxis

Answer 397

* exposure to drug, immediate rapid onset * rash with characteristic blotches * swelling of lips, face, oedema, central cyanosis (go blue/purple) * wheeze * hypotension (Anaphylactic shock) * cardiac arrest

Answer 398

- cardiorespiratory arrest | - no skin changes

Answer 399

- commence basic life support: A (airway), B (breathing), C (circulation) - specific/drug treatment - effect of adrenaline

Answer 400

- stop drug if infusion - adrenaline 1mg (10mls of 1:10,000 (IV)) 1ml IV increments - note: if cardiac arrest then may need to give cardiac massage in order to get drugs circulating - IV anti-histamine (Chlorphenamine 10mg) - IV Hydrocortisone (100 to 200mg) - note: unlikely to cause harm in excess so can’t really give too much

Answer 401

vasoconstriction, bronchodilation and increased cardiac output

Answer 402

* protein or polysaccharide base macro molecules e.g. penicillin * mono-clonal antibodies (proteins) can cause reactions

Answer 403

* more common in females compared to males | * immunosuppression

Answer 404

certain HLA groups (gene that encodes major histocompatibility complex (MHC))

Answer 405

- drug allergy is a highly specific term clinically; local rash, local swelling - specific - GI upset (from NSAIDs) is not allergy - type A (Augmented) is not allergy, but some people can be more sensitive e.g. more likely to develop hypotension with anti-hypertensives

Answer 406

- elicit a full medication history and previous reactions - check useful sources to find if ADR is described e.g BNF, eMC, Medicine Information Centres and MHRA (medical health regulation agency) - identify markers

Answer 407

serum concentration - plasma monitoring

Answer 408

- tryptase - released from only mast cells; best test to confirm allergy based ADR - urine methylhistamine; breakdown product of histamine

Answer 409

* continue the drug and manage the ADR by other means * reduce the dose of the drug * stop the drug

Answer 410

* dose-related * may respond to dose-reduction or temporary withdrawal * severe reactions may require active treatment

Answer 411

* not usually dose-related * should usually withdraw the medicine immediately * give supportive treatment if the reaction is severe e.g. anaphylaxis

Answer 412

- MHRA Yellow-card scheme is the main method of surveillance of ADRs - can complete it; online, by post or by telephone

Answer 413

* all suspected ADRs for new medicines * all ADRs in children * all serious reactions, even if well-documented to include

Answer 414

- fatal - life threatening - disabling - incapacitation or resulting in prolonged hospitalisation

Answer 415

where the actions of 2 drugs combine

Answer 416

* clavulanic acid and amoxil to make augmentin | * paracetamol and codeine to increase analgesic effect

Answer 417

where one drug blocks the action of the other

Answer 418

- polypharmacy - on many different drugs - old age - genetics - e.g. slow/fast metabolism - hepatic disease - renal disease

Answer 419

- narrow therapeutic index - steep dose/response curve - saturable metabolism - e.g. paracetamol and alcohol are metabolised at a set rate

Answer 420

- motility - acidity - solubility - non-absorbed complex formation - direct action on enterocytes

Answer 421

- erythromycin increases gut motility | - oral contraceptive pill and antibiotics have the commonest interaction causing motility changes

Answer 422

often with antacids and proton pump inhibitors - these change the pH of the stomach so if taking with other medication it can alter absorption of the drug

Answer 423

eating avocado (high in fat) and taking a fat soluble drug e.g. anti-coagulant then will dissolve the drug meaning there will be little or no drug absorption

Answer 424

large complexes in intestinal lumen - cholestyramine and thyroxin, warfarin or digoxin

Answer 425

grapefruit juice inhibits P-glycoprotein resulting in the | increased uptake of certain drugs

Answer 426

- affects drug concentration in plasma thus reduces distribution thus less available to have effect - occurs with sulphonamide antibiotics and warfarin

Answer 427

- drug A (inhibits CYP450) blocks metabolism of drug B, leaving more free drug B in the plasma - increase effects - note: in pro-drugs if metabolism is blocked then will be a decreased effect

Answer 428

- drug C induces CYP450 isoenzyme, leading to increased metabolism of drug D resulting in decreased therapeutic effects - note: in pro-drugs if metabolism is increased then there will be increased therapeutic effects

Answer 429

affects CYP3A4 resulting in increased bioavailability thus this can make a drug more effective

Answer 430

renal and biliary

Answer 431

- renal excretion is pH dependent - weak bases - cleared faster if urine is acidic - weak acids - cleared faster if urine is alkali - can alter pH of urine to alter excretion

Answer 432

* aspirin - try to alkalinise urine to help increase excretion with aspirin overdose * ibuprofen * paracetamol * warfarin

Answer 433

* amphetamine * atropine * propranolol * salbutamol

Answer 434

- receptor based - signal transduction - physiological systems

Answer 435

- bind to receptor | - for example, alcohol and benzodiazepine at GABA A receptor

Answer 436

- partially bind/activation at receptor | - for example buprenorphine for opioid addiction

Answer 437

- block receptor - can be competitive and non-competitive - for example beta-blockers and asthma (competitive) - never give beta-blockers to asthmatics since they will be on beta-agonists to help with bronchodilation, if using beta-blockers then will cause bronchoconstriction and increased risk of asthma attack

Answer 438

* rarer but examples exist * commencing beta-blockers in a diabetic resulting in action at beta3 receptors in adipose tissues which normally detect and alter blood glucose, but action at B2 receptors can suppress hypoglycaemic awareness so they will not detect fall in glucose as well

Answer 439

* different drugs that effect different receptors, but in the same physiological system * Ca2+ channel antagonists and beta-blockers * ACE inhibitors and NSAIDs have a degree of nephrotoxicity

Answer 440

- digoxin works on cardiac fibres and its effect is increased if there are low levels of potassium in blood plasma - furosemide is a diuretic that lowers arterial pressure but favours the loss of potassium - this could lead to hypokalaemia, which could increase the toxicity of digoxin

Answer 441

- prescribe rationally - BNF - medicines information service

Answer 442

amiodarone

Answer 443

terfenadine, diphenhydramine

Answer 444

felodipine, nifedipine, nimodipine, nicardipine

Answer 445

simvastatin

Answer 446

atorvastatin

Answer 447

cyclosporin, tacrolimus

Answer 448

- amiodarone - terenadine, diphenhydramine - simvastatin

Answer 449

- felodipine, nifedipine, nimodipine, nicardipine - atorvastatin - cyclosporin, tacrolimus

Answer 450

rhabdomyolysis (muscle pain/breakdown)

Answer 451

itraconazole, erythromycin, clarithromycin, diltiazem, verapamil, amiodarone

Answer 452

20-200x increase in plasma concentrations

Answer 453

erythromycin, clarithromycin, tramadol, amiodarone

Answer 454

monitor INR at day 3, then weekly, up to 4 weeks post commencement

Answer 455

serotonin syndrome

Answer 456

tricyclic antidepressants, tramodol

Answer 457

renal failure

Answer 458

NSAID or COX2 inhibitor, plus ACEi, plus dehydration or furosemide

Answer 459

- avocado reduces effectiveness of warfarin; could increase risk of blood clots - grapefruit juice increases effectiveness of calcium channel blockers and anti-rejection medication - garlic increases anti-platelet activity so can increase risk of bleeding - soya increases effectiveness of NSAIDs and warfarin so can increase risk of bleeding - ginger reduces effectiveness of anticoagulants so increases risk of bleeding

Answer 460

- diagnosis - drug treatment - indications and contraindications - peculiar properties of either the diagnosis or drugs: • does it require plasma monitoring? • is there a risk of drug interaction? - patient name - dose - route - frequency - duration - total number of tablets - drug name - date and signature

Answer 461

- home: current medications, self prescribing? - hospital admission: continue home meds, investigation, diagnosis - inpatient: new treatment? - discharge from hospital: pre-admission drugs, new prescription

Answer 462

* home: drug history and pharmacy printout * hospital admission: inpatient prescription chart * inpatient: multi-disciplinary prescribing * discharge from hospital: take home medication or not and discharge summary to GP

Answer 463

* the number of different times the same information is translated or transposed * information on admission * duplication; paper, different teams * clerical/legibility/ administration errors * emergency situations

Answer 464

- are avoidable; is classed as neglect - carelessness since staff generally have the appropriate knowledge but do not use it at the time - ward pharmacists check prescriptions carefully but only do daily checks - not continuous - specify whether IV or intrathecal (spinal cord); can be confused easily leading to spinal cord damage

Answer 465

beware that drugs with co-something-amol actually contain paracetamol, so inform patients of this because they might supplement this with more paracetamol leading to a potential paracetamol overdose - need to be careful

Answer 466

tazocin and augmentin

Answer 467

- withdrawal reactions if stopping most long term drugs; analgesics, anti hypertensives and anti depressants - the vast majority of drugs should be continued unless there is a specific reason related to the presenting complaint

Answer 468

- nil by mouth policy for fluids is 2 hours, due to fear of aspiration under anaesthesia - a sip of water with tablets is OK; can safely have a small drop of water for the taking of medications prior to surgery

Answer 469

* ACE inhibitors, losartan (angiotensin receptor blocker) * warfarin should be bridged to heparin (easier to manage dosage since injected) * diabetes drugs - a detailed guidance proforma for this exists

Answer 470

opioid receptor agonist • the oral bioavailability of morphine is about 50% due to liver metabolism • in 10% of the population codeine won’t work and in 10% it works too well

Answer 471

- naturally occurring opioids from the opium poppy (contains both morphine and codeine) - simple chemical modifications - synthetic opioids - synthetic partial agonists - antagonists

Answer 472

* morphine | * codeine (weak)

Answer 473

* diamorphine (heroin) * oxycodone * dihydrocodeine (more predictable than codeine)

Answer 474

* pethidine * fentanyl (very potent) * alfentanil (very potent) * remifentanil (very potent)

Answer 475

buprenorphine - if overdose there is no respiratory depression

Answer 476

naloxone - give to reverse overdose

Answer 477

- oral (simplest route) - 10mg orally is equivalent to 5mg parenterally (subcutaneous, intramuscular and IV) - single dose of morphine lasts 3-4 hours - subcutaneous - IV

Answer 478

• 50% of oral morphine is metabolised by first pass metabolism in the liver • give half the dose if giving parenterally (sub-cutaneous, intramuscular and intravenous (IV))

Answer 479

• fastest mode of administration, once given it will go around the whole body in one minute • will take 5 minutes for morphine to reach brain

Answer 480

- dose can be self-administered by patient every 5 minutes with lockout - safe since the patient will sleep before the onset of respiratory depression - danger if somebody else presses the button for delivery e.g. grandchildren

Answer 481

more potent and faster acting (crosses BBB quickly)

Answer 482

- opioid drugs simply use the existing pain modulation system - natural endorphins (endogenous morphine) and enkephalins - G protein coupled receptors act via second messengers - they inhibit the release of pain transmitters at spinal cord and midbrain and modulate pain perception in higher centres - euphoria - to change the emotional perception of pain - opioids block descending pain transmission - they were never designed for sustained activation; designed only to be used for 30 minutes or so - sustained activation leads to tolerance and addiction

Answer 483

- greek letter μ for morphine (MOP) - soon after delta (DOP) and kappa (KOP) receptors were identified - more recently the nociceptin opioid-like (NOP) receptor was identified

Answer 484

aim of opioid development is to develop opioid analgesic without the side effects of respiratory depression or addiction

Answer 485

mental depression instead of euphoria

Answer 486

* midbrain * spine * GI tract - can get constipated with opioid use * breathing centre - it communicates using opioid receptors, opioid use can cause respiratory depression

Answer 487

whether a drug is ‘strong’ or ‘weak’ - relates to how well the drug binds to the receptor - the binding affinity

Answer 488

- diamorphine - 5mg (twice as potent as morphine) - morphine - 10mg - pethidine - 100mg (10 times weaker than morphine)

Answer 489

• is it possible to get a maximal response with the drug or not? • or if all the receptor sites are occupied, do you get a ceiling response? • the concept of full or partial agonists (e.g. buprenorphine)

Answer 490

• down-regulation of the receptors with prolonged use • need higher doses to achieve the same effect • can develop with continued morphine use due to the desensitisation of μ receptors

Answer 491

``` • morphine given with naloxone (antagonist) will reduce the efficacy of morphine since naloxone is a competitive receptor antagonist • given to correct morphine overdose ```

Answer 492

* psychological - craving of euphoria | * can be physical

Answer 493

begins within 24 hours, lasts about 72 hours - can give methadone to provide a slower and thus safer reduction in opioid

Answer 494

- opioid receptors exist outside the pain system e.g. digestive tract and respiratory control centre - respiratory depression - sedation - nausea and vomiting - constipation - itching - immune suppression - endocrine effects - different patients have quite a range of sensitivity to opioids - start with small dose and titrate up as necessary

Answer 495

* A (airway), B (breathing), C (circulation) * administer naloxone - IV is fastest route - 400 micrograms per ml * titrate to effect - don't give all at once - once a drug has been injected you cannot get it back! - dilute 1ml in 10ml saline * naloxone has a short half-life so give a depot of naloxone, some IV and some subcutaneous - so if the naloxone wears off then the depot will maintain levels

Answer 496

- opioids for non-cancer pain start to lose effectiveness fairly quickly (within weeks) - addiction to the drug leads to manipulative behaviour - easy to start but can be very difficult to get patient off them

Answer 497

- codeine is a prodrug; it needs to be metabolised by cytochrome CYP2D6 to work - CYP2D6 activity is decreased in 10-15% of the caucasian population, so codeine will not be as effective - CYP2D6 activity is absent in 10% of the caucasian population meaning codeine will have no effect - CYP2D6 is overactive in 5% of the caucasian population - these individuals may be at increased risk of respiratory depression with codeine; this is the reason why codeine is banned from children and breast feeding mothers in case they are in the 5%

Answer 498

- morphine is metabolised to morphine-6-glucuronide which is more potent than morphine - morphine-6-glucuronide is renally excreted and will build up and cause respiratory depression in renal failure

Answer 499

pethidine is metabolised to norpethidine which is epileptogenic and will build up and cause fits in renal failure

Pharmacokinetics and pharmacodynamics Flashcards

(531 cards)