pharmacology

Question 1

what 3 things are considered when considering a drug’s effects?

Answer 1

where the effect(s) are produced

the drug’s target

response produced after interaction with target

Question 2

how would the effects of cocaine be described when considering the 3 main points (location of effect, target, response produced)?

Answer 2

overall: euphoric ‘high’

where effect takes place
- dopaminergic neurons in nucleus accumbens in brain

target of drug
- dopamine reuptake protein on pre-synaptic terminal

response produced
- cocaine blocks dopamine reuptake protein, preventing quick removal of dopamine from synapse (therefore more available to bind to receptor and activate it)

Question 3

what is the key thing that allows a drug to produce an effect?

Answer 3

drug ‘binds’ to target

either enhances activation (“stimulation”) or prevents activation (block effect from being produced)

Question 4

what are the 4 classes of drug target proteins? give an example of a drug that targets each one.

Answer 4

receptors (e.g. nicotine)

enzymes (e.g. aspirin)

ion channels (e.g. local anaesthetic)

transport proteins (e.g. Prozac)

Question 5

how does aspirin act on enzymes (target protein) to bring about an effect?

Answer 5

aspirin binds to the enzyme cyclooxygenase

blocks production of prostaglandins

Question 6

how does local anaesthetic act on ion channels (target protein) to bring about an effect?

Answer 6

block sodium ion channels

prevents nerve conduction

Question 7

how does Prozac act on transport proteins (target protein) to bring about an effect?

Answer 7

block serotonin carrier proteins

prevents serotonin being removed from the synapse

Question 8

how does nicotine act on receptors (target proteins) to bring about an effect?

Answer 8

binds to and activates nicotinic acetylcholine receptor

Question 9

what characteristic must a drug display to be an effective therapeutic agent?

Answer 9

high degree of selectivity for particular drug target

Question 10

why is it difficult to produce drugs with complete selectivity? what effect does this have?

Answer 10

many drugs and chemicals are structurally quite similar - therefore they all have some degree of specificity for the receptors of the other chemicals

when producing a drug, there is a chance that the drug will interact with receptors that aren’t the intended one, producing side-effects

Question 11

how does drug dose relate to drug selectivity?

Answer 11

at lower dose, drug will interact with only one target to produce the intended effect

as dose increases, effects become less specific as drug begins to interact with other drug targets

Question 12

what is an example of how drug dose affects selectivity?

Answer 12

Pergolide (treatment of Parkinson’s)

low dose

• target: dopamine D2 receptor
• effect: anti-Parkinsonian

medium dose

• target: serotonin receptor
• effect: hallucinations

high dose

• target: adrenergic receptor
• effect: hypotension

Question 13

what are the 4 types of interaction between drugs and receptors?

Answer 13

electrostatic

hydrophobic

covalent bonds

stereospecific

Question 14

what types of bonds are involved in electrostatic interactions between drugs and receptors?

Answer 14

(most common interaction)

includes hydrogen bonds and van del Waal’s forces

Question 15

when are hydrophobic interactions between drugs and receptors important?

Answer 15

in use of lipid soluble drugs

Question 16

why are covalent bond interactions the least common type of interaction between drugs and receptors?

Answer 16

irreversible

Question 17

why is stereospecific interaction between drugs and receptors important?

Answer 17

many drugs exist as stereoisomers and interact stereospecifically with receptors

Question 18

what is pharmacology?

Answer 18

study of how a drug interacts with living organisms and how this influences physiological function

Question 19

what does the term ‘pharmacodynamics’ refer to?

Answer 19

what the drug does to the body

Question 20

what does the term ‘pharmacokinetics’ refer to?

Answer 20

what the body does to the drug

Question 21

how can the basic reaction between a drug and its receptor be represented?

Answer 21

equilibrium between drug and receptor, drug-receptor complex

for a specific concentration of the drug, a specific number of drug receptor complexes are formed

Question 22

what happens to the equilibrium between and drug and receptor and the drug-receptor complexes when the concentration increases?

Answer 22

more drug molecules available to bind to free receptors

equilibrium shifts to the right

Question 23

what happens to the equilibrium between and drug and receptor and the drug-receptor complexes when the concentration decreases?

Answer 23

more receptors become available due to lower drug concentration

shifts equilibrium to the left

Question 24

what are the 2 categories of drug in terms of interaction with receptors?

Answer 24

agonist

antagonists

Question 25

what is the difference between agonist and antagonists?

Answer 25

both bind to receptors, but only agonists bind and activate receptors

Question 26

what are the 2 key properties of agonists?

Answer 26

affinity

efficacy

Question 27

what does the affinity of a drug determine?

Answer 27

strength of binding of drug to receptor, the strength of each drug-receptor complex

therefore affinity is strongly linked to receptor occupancy

Question 28

how is affinity linked to receptor occupancy?

Answer 28

each individual drug receptor interaction is transient, with many interactions only lasting milliseconds - at any given moment a particular drug molecule might be bound to a receptor, or it may have unbound and may currently be free with the potential to bind another receptor

therefore if two drugs were added to the tissue (i.e. same number of receptors available), the drug with the higher affinity will form stronger drug receptor complexes

thus at any given moment, it is more likely that more of this drug will be bound to receptors

Question 29

what is efficacy?

Answer 29

ability of an individual drug molecule to produce an effect once bound to a receptor

Question 30

what are the 3 types of drug with reference to efficacy?

Answer 30

antagonists

partial agonists

full agonists

Question 31

how does an antagonist work with reference to efficacy?

Answer 31

drug has affinity for the receptor but no efficacy

effectively ‘blocking’ a receptor when bound to it

prevents an agonist from binding to the receptor and inducing activation

Question 32

how does a partial agonist work with reference to efficacy?

Answer 32

drug has affinity for the receptor and sub-maximal efficacy

when bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor

Question 33

how does a full agonist work with reference to efficacy?

Answer 33

drug has affinity for the receptor and maximal efficacy

produces the maximal response expected from receptor when bound to it

Question 34

what is potency?

Answer 34

concentration or dose of a drug required to produce a defined effect

Question 35

what is the standard measure of potency?

Answer 35

determine the concentration or dose of a drug required to produce a 50% tissue response

called EC50 (half maximal effective concentration) or ED50 (half maximal effective dose)

Question 36

what is the difference between EC50 and ED50?

Answer 36

concentration that produced a 50% response is EC50

in some cases it is difficult to assess what a 50% response is (e.g. what does a 50% improvement in breathlessness look like?)

therefore dose of drug that produced the desired effect in 50% or the individuals tested is used (ED50)

Question 37

how is potency related to dose?

Answer 37

the lower the dosage required to produce a particular effect, the more potent the drug is (often compared using ED50)

Question 38

what is the relationship between efficacy and potency?

Answer 38

potency is related to dose, efficacy is not

highly potent drugs produce a large response at relatively low concentrations

highly efficacious drugs can produce a maximal response - effect not particularly related to drug concentration

Question 39

what is the clinical relevance of the difference between potency and efficacy?

Answer 39

efficacy more important - drug should induce a maximal response

potency only gives dose needed to produce a response

if 2 drugs have equal efficacy, potency does not matter (maximal response with the less potent drug can be achieved by administering a slightly higher concentration)

Question 40

what are the 4 major pharmacokinetic factors?

Answer 40

absorption

distribution

metabolism

excretion

Question 41

how is absorption defined with regard to pharmacokinetics?

Answer 41

passage of a drug from site of administration into plasma

Question 42

what is bioavailability (with regard to absorption in pharmacokinetics)?

Answer 42

fraction of the initial dose that gains access to the systemic circulation

Question 43

what is the difference between absorption and bioavailability?

Answer 43

absorption deals with the process for drug transfer into the systemic circulation

bioavailability deals with the outcome of drug transfer into the systemic circulation (i.e. how much)

determined by site of administration-

e. g. IV administration of drug
- absorption (process for drug passage): injecting dose into circulation
- bioavailability: 100% (hypothetical)

Question 44

what are some common forms of drug administration?

Answer 44

IV

oral

inhalational

dermal (percutaneous)

intra-nasal

Question 45

what are the 2 ways that drugs move around the body?

Answer 45

bulk flow transfer (i.e. in the bloodstream)

diffusional transfer (i.e. molecule by molecule across short distances)

Question 46

why is bioavailability likely to be less than 100% when drugs are not administered through an IV?

Answer 46

if IV is used, bulk flow transfer will deliver drug to intended site of action

other routes - in order for the drug to reach the bloodstream it is first going to need to diffuse across at least one lipid membrane

Question 47

what are the 4 mechanisms by which chemicals diffuse across plasma membranes?

Answer 47

pinocytosis

diffusion across aqueous pores

diffuse across lipid membranes

carrier mediated transport

Question 48

what is pinocytosis and and what is its relevancy in drug transport?

Answer 48

small part of cell membrane envelopes chemical molecule and forms a vesicle

chemical released on other side of membrane

e.g. insulin access to brain

but rarely used to transport drugs

Question 49

why is diffusion across an aqueous pores not a major route for drug transport across membranes?

Answer 49

most pores are less than 0.5nm in diameter

very few drugs are this small

therefore there is little movement of drugs across this aqueous route

Question 50

how do most drugs move across membranes?

Answer 50

diffusion across lipid membrane down concentration gradient

carrier mediated transport (transmembrane protein binds drug molecules on one side of membrane, transfers them across to the other side - can be against concentration gradient using ATP)

Question 51

why are the majority of drugs more water soluble than lipid soluble?

Answer 51

large proportion of drug molecules are given orally

need to be water soluble to dissolve in the aqueous environment of GI tract and be available for absorption

Question 52

what feature of a drug affects its lipid solubility?

Answer 52

ionisation

drugs are either weak acids (e.g. aspirin) or bases (e.g. morphine) - donate/accept protons respectively when ionised

unionised form of drug retains more lipid solubility - more likely to diffuse across plasma membranes

Question 53

what 2 things affect the ionisation of a drug?

Answer 53

dissociation constant (pKa) for that drug

pH in that particular part of the body

Question 54

how does a drug’s dissociation constant (pKa) and the pH in a particular area of the body affect a drug’s ionisation when the drug is a weak acid?

Answer 54

if drug pKa and tissue pH are equal, drug will be equally dissociated between the two forms (i.e. 50% ionised and 50% unionised)

as pH decreases below pKa (more acidic tissue): unionised form starts to dominate (equilibrium shifts to the left)

as pH increases above pKa (more basic tissue): ionised form starts to dominate (equilibrium shifts to the right)

Question 55

how does a drug’s dissociation constant (pKa) and the pH in a particular area of the body affect a drug’s ionisation when the drug is a weak base?

Answer 55

if drug pKa and tissue pH are equal, drug will be equally dissociated between the two forms (i.e. 50% ionised and 50% unionised)

as pH decreases below pKa (more acidic tissue): ionised form starts to dominate (equilibrium shifts to the right)

as pH increases above pKa (more basic tissue): unionised form starts to dominate (equilibrium shifts to the left)

Question 56

what is ion trapping?

Answer 56

weak bases poorly absorbed from stomach due to low pH causing high drug ionisation - ions are “trapped” in the stomach

weak acids can be absorbed from the stomach (low pH allows them to stay unionised) but when they become ionised due to higher physiological pH ions may become “trapped” in the blood

Question 57

how is ion trapping overcome?

Answer 57

transport proteins

weak bases become “trapped” in the stomach - however, when the small intestine is reached, many transport proteins will allow absorption from GI tract

weak acids become “trapped” in blood - however, most tissues have transport proteins that could move the ionised drug out of the bloodstream into the tissue

Question 58

what are the 4 places where the most important carrier systems for drug action are found?

Answer 58

renal tubule

biliary tract

blood brain barrier

gastrointestinal tract

Question 59

what are carrier systems in the renal tubule, biliary tract, blood brain barrier and GI tract responsible for?

Answer 59

(overcoming ion trapping)

drug access to the bloodstream (absorption from GI tract)

drug access to certain tissues (absorption across blood brain barrier)

excretion of drugs from the body (excretion from the kidney of the GI tract)

Question 60

what is distribution?

Answer 60

when a drug is absorbed it is then distributed to various tissues where they eventually take effect

Question 61

what are the 4 factors that influence tissue distribution?

Answer 61

regional blood flow

plasma protein binding

capillary permeability

tissue localisation

Question 62

how does regional blood flow affect tissue distribution?

Answer 62

different tissues receive different amounts of cardiac output

therefore more drug will be distributed to those tissues that receive most blood flow

distribution can change depending on circumstances:

• during exercise there is more blood flow to muscles
• after a large meal the stomach and intestines will receive more blood flow

Question 63

how does plasma protein binding affect tissue distribution?

Answer 63

drugs often bind to plasma proteins (e.g. albumin) when they reach systemic circulation

only free drug is available to diffuse out of the blood and access tissues - bound drugs cannot leave the blood until they dissociate from the protein

free drug + protein binding site ↔ drug-protein binding site

Question 64

what 3 factors affect the amount of drug that binds to plasma protein?

Answer 64

free drug concentration

affinity for the protein binding sites

plasma protein concentration

Question 65

why are plasma proteins never saturated with drugs?

Answer 65

e. g. albumin
- albumin blood concentration: 0.6mmol/l
- each molecule has 2 binding sites
- therefore binding capacity: 1.2mmol/l

drug plasma concentration required for clinical effect is generally less than 1.2mmol/l

therefore plasma proteins are never saturated with drugs

Question 66

what factor affects differences in the extent of plasma protein binding?

Answer 66

mostly due to particular affinity for protein binding sites for a particular drug

e.g. acidic drugs bind particularly well to albumin, therefore tend to be more heavily plasma protein bound

Question 67

what are the 4 different types of capillary structure?

Answer 67

continuous

blood brain barrier

fenestrated

discontinuous

Question 68

how does a continuous capillary structure affect capillary permeability and therefore drug distribution?

Answer 68

most capillaries in the body have the continuous structure

if drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue

Question 69

what does a continuous capillary structure look like?

Answer 69

endothelial cells aligned in single file with small gap junctions between the cells

Question 70

what does the blood brain barrier’s capillary structure look like?

Answer 70

continuous structure, but with tight junctions between endothelial cells

Question 71

what are the 4 different types of capillary structure?

Answer 71

continuous

blood brain barrier

fenestrated

discontinuous

Question 72

how does a continuous capillary structure affect capillary permeability and therefore drug distribution?

Answer 72

most capillaries in the body have the continuous structure

if drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue

Question 73

what does a continuous capillary structure look like?

Answer 73

endothelial cells aligned in single file with small gap junctions between the cells

Question 74

what does the blood brain barrier’s capillary structure look like?

Answer 74

continuous structure, but with tight junctions between endothelial cells

Question 75

why is the brain the most difficult tissue in the body for drugs to gain access to?

Answer 75

blood brain barrier’s capillary structure

Question 76

how are less lipid soluble drugs transported into the tissue?

Answer 76

if very small, can pass through gap junctions

otherwise, via carrier proteins

Question 77

what is an example of a tissue with a discontinuous capillary structure?

Answer 77

liver

Question 78

how does a fenestrated capillary structure allow the kidney to carry out its function?

Answer 78

kidney is a key tissue involved in excretion of chemicals (including many drugs)

fenestrations allow for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs

Question 79

what does a discontinuous capillary structure look like?

Answer 79

big gaps between capillary endothelial cells

Question 80

what does a fenestrated capillary structure look like?

Answer 80

fenestrations - circular windows within endothelial cells that allow for passage of small molecular weight substances (including some drugs)

Question 81

what is an example of a tissue with a fenestrated capillary structure?

Answer 81

kidney glomerulus

Question 82

how does a discontinuous capillary structure allow the liver to carry out its function?

Answer 82

kidney is a key tissue involved in excretion of chemicals (including many drugs)

fenestrations allow for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs

Question 83

how does tissue localisation affect drug distribution?

Answer 83

both lipid and water soluble drugs diffuse out of the blood into the brain down a concentration gradient, establishing an equilibrium between the blood and brain

however, equilibrium position is different in lipid and water soluble drugs -

lipid soluble: equilibrium more heavily weighted towards retention in the brain as brain has higher fat content

water soluble: equilibrium more heavily weighted towards retention in the plasma as blood has the higher water content

therefore a larger proportion of the lipid soluble drug will be ‘localised’ in the brain as compared with the water soluble drug

Question 84

what are the 3 main mechanisms of action of phase 1 of drug metabolism?

Answer 84

oxidation (produces electrophiles)

reduction (produces nucleophiles)

hydrolysis (produces nucleophiles)

Question 85

what happens during oxidation in phase 1 of drug metabolism?

Answer 85

(most common mechanism)

all oxidation reactions start with a hydroxylation step using the cytochrome P450 system to incorporate oxygen into non-activated hydrocarbons

Question 86

what enzymes within the liver are responsible for drug metabolism?

Answer 86

mostly cytochrome P450

Question 87

what are the the 2 kinds of drug metabolism that act together to decrease lipid solubility?

Answer 87

phase 1 – introduce a reactive group to the drug

phase 2 – add a conjugate to the reactive group

Question 88

what are the 3 main mechanisms of action of phase 1 of drug metabolism?

Answer 88

oxidation

reduction

hydrolysis

Question 89

what happens in oxidation in phase 1 of drug metabolism?

Answer 89

(most common mechanism)

all oxidation reactions start with a hydroxylation step using the cytochrome P450 system to incorporate oxygen into non-activated hydrocarbons

Question 90

what is the end result of phase 1 of drug metabolism?

Answer 90

incorporation of certain functional groups (-OH, -COOH, -SH, NH2) or unmasking existing groups in the parent drug

produces metabolites with functional groups that serve as a point of attack for conjugating systems of phase 2

Question 91

what are pro-drugs?

Answer 91

phase 1 of drug metabolism often produces pharmacologically active metabolites

sometimes the parent drug has no activity of its own - will only produce an effect once it has been metabolized to the respective metabolite (i.e. pro-drugs)

Question 92

what enzymes are used in phase 2 of drug metabolism?

Answer 92

transferases

transfer the substituent group onto the phase 1 metabolite

Question 93

what occurs in phase 2 of drug metabolism?

Answer 93

attachment of a substituent group to functional groups

produces metabolites that are more water soluble and are usually inactive to facilitate excretion in the urine or bile

Question 94

what are the common phase 2 conjugates that complement the usual phase 1 metabolites?

Answer 94

for electrophiles:
- glutathione conjugation

for nucleophiles:

• glucoronidation
• acetylation
• sulfation

Question 95

what is first pass (pre-systemic) hepatic metabolism?

Answer 95

orally administered drugs are mostly absorbed from the small intestine and enter the hepatic portal blood supply - therefore pass through the liver before reaching systemic circulation

drug is heavily metabolised so not much active drug will reach systemic circulation

Question 96

what are the 3 major routes for drug excretion via the kidney?

Answer 96

glomerular filtration

active tubular secretion (or reabsorption)

passive diffusion across tubular epithelium

Question 97

what is the problem with the usual solution for first pass (pre-systemic) hepatic metabolism

Answer 97

extent of first pass metabolism varies amongst individuals, therefore the amount of drug reaching the systemic circulation also varies

therefore drug effects and side effects are difficult to predict

Question 98

what are the 2 most important routes of excretion?

Answer 98

via kidney (in urine)

via liver (in bile)

Question 99

what are some other routes of excretion (excluding the kidney and liver)?

Answer 99

via lungs

in breast milk

Question 100

what are the 3 major routes for drug excretion via the kidney?

Answer 100

glomerular filtration

active tubular secretion (or reabsorption)

passive diffusion across tubular epithelium

Question 101

why does excretion of different drugs vary so much?

Answer 101

extent to which drug use each of the 3 major routes for drug excretion in the kidney varies between drugs

also impacted by the rate of metabolism

Question 102

why does urine pH affect the process of excretion by passive diffusion in the kidney?

Answer 102

urine pH varies from 4.5 to 8

acidic drugs are better reabsorbed at lower pH

basic drugs are better reabsorbed at higher pH

Question 103

why is active tubular secretion the most important method of excretion via kidney?

Answer 103

only 20% of renal plasma is filtered at the glomerulus, the rest passes onto the blood supply to proximal tubule - more drug delivered to proximal tubule than glomerulus

Question 104

what is the process of excretion by active tubular secretion in the kidney?

Answer 104

depends on transporters

2 active transport carrier systems within the proximal tubule capillary endothelial cells (one for acidic drugs, one for basic drugs)

both systems can transport drugs against a concentration gradient

Question 105

why does drug metabolism affect the process of excretion by passive diffusion in the kidney?

Answer 105

phase 2 metabolites tend to be more water soluble than the parent drug

therefore less well reabsorbed

Question 106

why does urine pH affect the process of excretion by passive diffusion in the kidney?

Answer 106

urine pH varies from 4.5 to 8

acidic drugs are better reabsorbed at lower pH

basic drugs are better reabsorbed at higher pH

Question 107

what is the process of excretion by passive diffusion in the kidney?

Answer 107

leads to reabsorption from kidney tubule

as glomerular filtrate moves through the kidney most of the water filtered is reabsorbed

if drugs are more lipid soluble they will also be reabsorbed, diffusing across the tubule back into the blood

Question 108

how are drugs excreted via the bile?

Answer 108

hepatocytes transport some drugs from plasma to bile
- mostly via transporters (similar to those in the kidney)

very effective at removing phase 2 glucuronide metabolites

drugs transported to bile are excreted into intestines, eliminated in faeces

Question 109

how can enterohepatic recycling prolong drug effect?

Answer 109

glucuronide metabolite is transported into bile

metabolite is excreted into the small intestine and is hydrolysed by gut bacteria - releases glucuronide conjugate

loss of glucuronide conjugate increases molecule’s lipid solubility

increased lipid solubility allows greater reabsorption from small intestine back into the hepatic portal blood system for return to liver

molecule returns to the liver - a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body

Question 110

what is the primary mechanism of action of metformin?

Answer 110

primary effect:
metformin activates AMPK in hepatocyte mitochondria

inhibits ATP production

blocks gluconeogenesis and subsequent glucose output

secondary effect:
blocks adenylate cyclase which promotes fat oxidation

both help to restore insulin sensitivity

Question 111

what is the drug target of metformin?

Answer 111

5′-AMP-activated protein kinase (AMPK) (enzyme)

Question 112

what is the primary site of action of metformin?

Answer 112

hepatocyte mitochondria

Question 113

what are the side effects of metformin?

Answer 113

GI side effects (20-30% of patients)

• abdominal pain
• decreased appetite
• diarrhoea
• vomiting

particularly evident when very high doses are given - slow increase in dose may improve tolerability

high doses may produce high lactic acid levels

(low risk) low blood glucose

Question 114

why may metformin accumulate the in the liver and the GI tract to produce therapeutic and side effects respectively?

Answer 114

highly polar structure, requires organic cation transporter-1 (OCT-1) to access tissues

Question 115

when is metformin most effective?

Answer 115

in the presence of endogenous insulin

i.e. with some residual functioning pancreatic islet cells

Question 116

what is an example of a DPP-4 inhibitor?

Answer 116

sitagliptin

Question 117

what is the primary mechanism of action of DPP-4 inhibitors?

Answer 117

primary effect:
inhibiting DPP-4 action
(enzyme is present in vascular endothelium and can metabolise incretins in plasma)

Question 118

what are the functions of incretins (e.g. GLP-1)?

Answer 118

secreted by enteroendocrine cells

help stimulate the production of insulin when it is needed (e.g. after eating)

reduce the production of glucagon by the liver when it is not needed (e.g. during digestion)

slow down digestion and decrease appetite

Question 119

what is the drug target of DPP-4 inhibitors?

Answer 119

DPP-4 (enzyme)

Question 120

what is the primary site of action of DPP-4 inhibitors?

Answer 120

vascular endothelium

Question 121

what are the side effects of DPP-4 inhibitors?

Answer 121

upper respiratory tract infections (5% of patients)

flu-like symptoms (e.g. headache, runny nose, sore throat)

serious allergic reactions (skin rash, increased upper respiratory tract infections)/ avoid in patients with pancreatitis (less common)



Question 122

what is a benefit of DPP-4 inhibitors as opposed to other anti-diabetic drugs?

Answer 122

do not cause weight gain

Question 123

what is required for DPP-4 inhibitor effectiveness?

Answer 123

some residual pancreatic beta-cell activity

since they act mainly by augmenting insulin secretion

Question 124

what is an example of a sulphonylurea?

Answer 124

gliclazide

Question 125

what is the primary mechanism of action of sulphonylureas?

Answer 125

inhibit ATP-sensitive potassium (KATP) channel on the pancreatic beta cell (controls beta cell membrane potential)

inhibition causes depolarisation

depolarisation stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

Question 126

what is the drug target of sulphonylureas?

Answer 126

ATP-sensitive potassium channel (ion channel)

Question 127

what is the primary site of action of sulphonylureas?

Answer 127

pancreatic beta cell



Question 128

what are the side effects of sulphonylureas?

Answer 128

weight gain (likely)

hypoglycaemia (2nd most common)

Question 129

what is required for sulphonylurea effectiveness?

Answer 129

some residual pancreatic beta-cell activity

since they act mainly by augmenting insulin secretion

Question 130

how is the weight gain caused by sulphonylureas mitigated?

Answer 130

concurrent administration with metformin

Question 131

when especially should the risk of hypoglycaemia associated with sulphonylureas be discussed with the patient?

Answer 131

when concomitant glucose-lowering drugs are prescribed

Question 132

what is an example of a sodium-glucose co-transporter (SGLT2) inhibitor?

Answer 132

dapaglifozin

Question 133

what is the primary mechanism of action of SGLT2 inhibitors?

Answer 133

reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule

reduces glucose reabsorption, increases urinary glucose excretion

Question 134

what is the drug target of SGLT2 inhibitors?

Answer 134

SGLT2 (transport protein)

Question 135

what is the primary site of action of SGLT2 inhibitors?

Answer 135

proximal convoluted tubule

Question 136

what are the side effects of SGLT2 inhibitors?

Answer 136

uro-genital infections due to increased glucose load (5% of patients)

slight decrease in bone formation

can worsen diabetic ketoacidosis (stop immediately)



Question 137

what are some added benefits of SGLT2 inhibitors?

Answer 137

weight loss

reduction in BP

Question 138

what is required for SGLT2 inhibitors effectiveness?

Answer 138

depends on normal renal function

less effective in patients with renal impairment

Question 139

what drugs can be used in the treatment of diabetes?

Answer 139

metformin

DPP-4 inhibitors

SGLT2 inhibitors

sulphonylureas

Question 140

what drugs can be used in the treatment of epilepsy?

Answer 140

lamotrigine

sodium valproate

diazepam

levetirecetam

Question 141

what is the primary mechanism of action of lamotrigine?

Answer 141

blocks voltage gated Na+ channels, preventing Na+ influx

prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity

Question 142

what is the drug target of lamotrigine?

Answer 142

voltage gated Na+ channels

Question 143

what are the main (common) side effects of lamotrigine?

Answer 143

rash

drowsiness

Question 144

what are the main (more uncommon but serious) side effects of lamotrigine?

Answer 144

Steven-Johnson’s syndrome

suicidal thoughts

Question 145

how is lamotrigine used in treatment of allergic reactions?

Answer 145

lamotrigine introduced gradually - important in reducing frequency and severity of allergic skin reactions

Question 146

what is the primary mechanism of action of sodium valproate?

Answer 146

inhibits GABA transaminase (prevents GABA breakdown)

directly increases GABA concentrations pre-synaptically in the synapse

indirectly prolongs GABA in the synapse (extraneuronal metabolism of GABA is slowed, slows GABA removal from synapse)

increased GABA availability

Question 147

what is the drug target of sodium valproate?

Answer 147

GABA transaminase (inhibitory presynaptic terminal)

Question 148

what are the main (common) side effects of sodium valproate?

Answer 148

stomach pain

diarrhoea

drowsiness

weight gain

hair loss

Question 149

what are the main (serious) side effects of sodium valproate?

Answer 149

hepatotoxicity

teratogenicity

pancreatitis

Question 150

how does sodium valproate interact with other drugs?

Answer 150

broad CYP (cytochrome P450) enzyme inhibitor

increases serum concentration of many co-administered drugs

Question 151

what is the primary mechanism of action of diazepam?

Answer 151

increases Cl- influx in response to GABA binding at GABA A receptor

increased Cl- influx associated with hyperpolarisation of excitatory neurones

Question 152

what is the drug target of diazepam?

Answer 152

benzodiazepine site on the GABA A receptor

Question 153

what are the main (common) side effects of diazepam?

Answer 153

drowsiness

respiratory depression (if IV or at high dose)

Question 154

what are the main (more uncommon but serious) side effects of diazepam?

Answer 154

haemolytic anaemia

jaundice

Question 155

why is diazepam not used for long term suppression of seizures?

Answer 155

development of tolerance

Question 156

why is diazepam

a Schedule 4 controlled drug?

Answer 156

addiction prone individuals more likely to become dependent on diazepam

Question 157

what is the primary mechanism of action of levetiracetam?

Answer 157

inhibition of synaptic vesicle protein SV2A in excitatory presynaptic terminal, prevents vesicle exocytosis

reduction in glutamate secretion reduces glutamate excitotoxicity

Question 158

why is levetiracetam favourable in terms of lack of drug–drug interactions?

Answer 158

metabolism of levetiracetam has no effect on cytochrome P450 enzyme system

Question 159

what drugs are used in treatment of depression?

Answer 159

sertraline

citalopram

fluoxetine

venlafaxine

mirtazapine

Question 160

what is the primary mechanism of action of sertraline?

Answer 160

serotonin reuptake inhibition causes accumulation

serotonin in CNS aids regulation of mood, personality, and wakefulness

Question 161

what is the drug target of sertraline?

Answer 161

serotonin transporter

Question 162

what are the main side effects of sertraline?

Answer 162

GI effects (nausea, diarrhoea)

sexual dysfunction

anxiety

insomnia

Question 163

how does sertraline interact with CYP2D6 at high doses (150mg)?

Answer 163

partial inhibition

Question 164

how does sertraline interact with dopamine transporters?

Answer 164

mild inhibition

Question 165

how is sertraline discontinued?

Answer 165

gradually decreased

Question 166

what is the primary mechanism of action of citalopram?

Answer 166

serotonin reuptake inhibition causes accumulation

serotonin in CNS aids regulation of mood, personality, and wakefulness

Question 167

what is the drug target of citalopram?

Answer 167

serotonin transporter

Question 168

what are the main side effects of citalopram?

Answer 168

GI effects (nausea, diarrhoea)

sexual dysfunction

anxiety

insomnia

Question 169

how does citalopram interact with muscarinic and histamine (H1) receptors?

Answer 169

mild antagonism

Question 170

how is citalopram discontinued?

Answer 170

gradually decreased

Question 171

how is citalopram metabolised?

Answer 171

CYP2C19

Question 172

what is the primary mechanism of action of fluoxetine?

Answer 172

serotonin reuptake inhibition causes accumulation

serotonin in CNS aids regulation of mood, personality, and wakefulness

Question 173

what is the drug target of fluoxetine?

Answer 173

serotonin transporter

Question 174

what are the main side effects of fluoxetine?

Answer 174

GI effects (nausea, diarrhoea)

sexual dysfunction

anxiety

insomnia

Question 175

which receptors does fluoxetine antagonise?

Answer 175

mild antagonism of 5HT2A and 5HT2C receptors

Question 176

which receptors does fluoxetine inhibit?

Answer 176

complete inhibition of CYP2D6

significant inhibition of CYP2C19

Question 177

what does inhibition of CYP2C19 and CYP2D6 by fluoxetine contraindicate?

Answer 177

caution with warfarin

Question 178

what is the primary mechanism of action of venlafaxine?

Answer 178

potent inhibitor of serotonin reuptake than norepinephrine reuptake

(noradrenaline in CNS implicated in emotional regulation and cognition)

Question 179

what are the drug targets of venlafaxine?

Answer 179

serotonin transporter

noradrenaline transporter

Question 180

what are the main side effects of venlafaxine?

Answer 180

GI effects (nausea, diarrhoea)

sexual dysfunction

anxiety

insomnia

(at higher doses) hypertension

Question 181

how is venlafaxine discontinued?

Answer 181

gradually decreased

Question 182

what is the primary mechanism of action of mirtazapine?

Answer 182

antagonises central presynaptic alpha-2-adrenergic receptors - causes increased serotonin and norepinephrine release

antagonises central 5HT2 receptors - leaves 5HT1 receptors unopposed, causing anti-depressant effects

Question 183

what are the drug targets of mirtazapine?

Answer 183

alpha-2 receptor

5-HT2 receptor

(high affinity for H1 receptor causes sedation, low affinity for 5-HT3 receptor has anti-emetic effect)

Question 184

what are the main side effects of mirtazapine?

Answer 184

weight gain

sedation

(low probability of sexual dysfunction)

Question 185

how does mirtazapine affect REM sleep behaviour disorder?

Answer 185

causes exacerbation, suppresses REM sleep

beneficial impact on sleep continuity and duration

(sedation due to histamine H1 receptor blocking)

Question 186

what drugs can be used in the treatment of hypertension?

Answer 186

angiotensin converting enzyme (ACE) inhibitors

calcium channel blockers

thiazide or thiazide-like diuretics

angiotensin receptor blockers

Question 187

what are some examples of angiotensin converting enzyme (ACE) inhibitors?

Answer 187

ramipril (pro-drug)

lisinopril

perindopril

Question 188

what is the primary mechanism of action of angiotensin converting enzyme (ACE) inhibitors?

Answer 188

inhibit angiotensin converting enzyme

prevent conversion of angiotensin I to angiotensin II

Question 189

what is the drug target of angiotensin converting enzyme (ACE) inhibitors?

Answer 189

angiotensin converting enzyme (ACE)

Question 190

what are the main side effects of angiotensin converting enzyme (ACE) inhibitors?

Answer 190

cough

hypotension

hyperkalaemia (care with K+ supplements or K+-sparing diuretics)

foetal injury (avoid in pregnant women)

renal failure (in patients with renal artery stenosis)

urticaria/angioedema

Question 191

what must be monitored regularly when taking angiotensin converting enzyme (ACE) inhibitors?

Answer 191

eGFR

serum potassium

Question 192

what kind of drugs are most angiotensin converting enzyme (ACE) inhibitors (not lisinopril)?

Answer 192

pro-drugs

require hepatic activation to generate active metabolites required for therapeutic effects

Question 193

what are some examples of calcium channel blockers?

Answer 193

amlodipine

felodipine

Question 194

what is the primary mechanism of action of calcium channel blockers?

Answer 194

block L-type calcium channels (predominantly on vascular smooth muscle)

causes decreased in calcium influx, with downstream inhibition of myosin light chain kinase and prevention of cross-bridge formation (i.e. muscular contraction)

resultant vasodilation reduces peripheral resistance

reduced cardiac contraction and cardiac output

Question 195

what is the drug target of calcium channel blockers?

Answer 195

L-type calcium channel

Question 196

what are the main side effects of calcium channel blockers?

Answer 196

ankle oedema

constipation

palpitations

flushing/headaches

Question 197

what kind of calcium channel blockers demonstrate a higher degree of vascular selectivity?

Answer 197

dihydropyridine type

Question 198

what are some examples of thiazide or thiazide-like diuretics?

Answer 198

bendro-flumethiazide (thiazide)

indapamide (thiazide-like diuretic)

Question 199

what is the primary mechanism of action of thiazide or thiazide-like diuretics?

Answer 199

block Na+, Cl- co-transporter in early apical DCT

Na+ and Cl- reabsorption is inhibited

osmolarity of tubular fluid increases, decreasing the osmotic gradient for water reabsorption in the collecting duct

(decreased blood volume, decreased venous return, decreased cardiac output)

Question 200

what is the drug target of thiazide or thiazide-like diuretics?

Answer 200

sodium/chloride cotransporter

Question 201

what are the main side effects of thiazide or thiazide-like diuretics?

Answer 201

hypokalaemia

hyponatremia

metabolic alkalosis (increased hydrogen ion excretion)

hypercalcemia

hyperglycaemia (hyperpolarised pancreatic beta cells)

hyperuricemia

Question 202

how long do the diuretic effects of thiazide and thiazide-like diuretics last?

Answer 202

lose diuretic effects within 1-2 weeks of treatment

Question 203

thiazide and thiazide-like diuretics lose their diuretic effect within 1-2 weeks - what allows continuing anti-hypertensive action?

Answer 203

vasodilating properties (more pronounced for thiazide-like diuretics)

Question 204

what are some examples of angiotensin receptor blockers?

Answer 204

losartan

irbesartan

candesartan

Question 205

what is the primary mechanism of action of angiotensin receptor blockers?

Answer 205

these agents act as insurmountable (i.e. non-competitive) antagonists at AT1 receptor (found on kidneys and on the vasculature)

Question 206

what is the drug target of angiotensin receptor blockers?

Answer 206

angiotensin receptor

Question 207

what are the main side effects of angiotensin receptor blockers?

Answer 207

hypotension

hyperkalaemia (care with K+ supplements or K+-sparing diuretics)

foetal injury (avoid in pregnant women)

renal failure (in patients with renal artery stenosis)

Question 208

how does the efficacy of angiotensin receptor blockers compare with angiotensin converting enzyme (ACE) inhibitors?

Answer 208

angiotensin receptor blockers are not as effective anti-hypertensive agents as ACE inhibitors

ACE inhibitors are cheaper

Question 209

what kind of drugs are losartan and candesartan (angiotensin receptor blockers)?

Answer 209

pro-drugs

require hepatic activation to generate active metabolites required for therapeutic effects

Question 210

what drugs can be used in the treatment of asthma?

Answer 210

salbutamol

fluticasone

mometasone

budesonide

montelukast

Question 211

what is the primary mechanism of action of salbutamol?

Answer 211

β2 receptor agonist on airway smooth muscle cells

activation reduces Ca2+ entry - prevents smooth muscle contraction, prevents constriction

(adrenaline binds to β2 adrenergic receptor to cause bronchodilation)

Question 212

what is the drug target of salbutamol?

Answer 212

beta 2 (β2) adrenergic receptor

Question 213

what are the main side effects of salbutamol?

Answer 213

palpitations/agitation

tachycardia/arrhythmias

hypokalaemia (at higher doses)

Question 214

what is salbutamol an example of?

Answer 214

short acting beta agonist (SABA)

Question 215

what is the half life of salbutamol?

Answer 215

2.5 - 5 hrs

Question 216

how does salbutamol produce cardiac side effects?

Answer 216

beta 2 selectivity is not absolute

beta 1 is also activated (causing cardiac side effects)

Question 217

how does salbutamol produce hypokalaemia as a side effect?

Answer 217

via effects on sodium/potassium ATPase

Question 218

how can hypokalaemia as a result of salbutamol administration be exacerbated?

Answer 218

co-administration with corticosteroids

Question 219

what are the primary mechanisms of action of fluticasone?

Answer 219

(multiple actions on many different cell types)

directly decreases number of inflammatory cells (eosinophils, monocytes, mast cells, macrophages, dendritic cells etc.) and number of cytokines they produce

affects IL-5 to prevent growth, differentiation, and activation of eosinophils

Question 220

what is the drug target of fluticasone?

Answer 220

glucocorticoid receptor

Question 221

what are the main local side effects of fluticasone?

Answer 221

sore throat

hoarse voice

opportunistic oral infections

Question 222

what are the main systemic side effects of fluticasone?

Answer 222

growth retardation in children

hyperglycaemia

decreased bone mineral density

immunosuppression

effects on mood

(etc.)

Question 223

how does fluticasone’s affinity for the glucocorticoid receptor compare to that of cortisol?

Answer 223

greater affinity

Question 224

why is any systemic delivery of fluticasone via the inhaled route predominantly through the pulmonary vasculature?

Answer 224

oral bioavailability <1%

Question 225

what are the primary mechanisms of action of mometasone?

Answer 225

(multiple actions on many different cell types)

directly decreases number of inflammatory cells (eosinophils, monocytes, mast cells, macrophages, dendritic cells etc.) and number of cytokines they produce

Question 226

what are the main local side effects of mometasone?

Answer 226

sore throat

hoarse voice

opportunistic oral infections

Question 227

what are the main systemic side effects of mometasone?

Answer 227

growth retardation in children

hyperglycaemia

decreased bone mineral density

immunosuppression

effects on mood

(etc.)

Question 228

how does mometasone’s affinity for the glucocorticoid receptor compare to that of cortisol?

Answer 228

greater affinity

Question 229

why is any systemic delivery of mometasone via the inhaled route predominantly through the pulmonary vasculature?

Answer 229

oral bioavailability <1%

Question 230

what are the primary mechanisms of action of budesonide?

Answer 230

(multiple actions on many different cell types)

directly decreases number of inflammatory cells (eosinophils, monocytes, mast cells, macrophages, dendritic cells etc.) and number of cytokines they produce

Question 231

what is the drug target of mometasone?

Answer 231

glucocorticoid receptor

Question 232

what is the drug target of budesonide?

Answer 232

glucocorticoid receptor

Question 233

what are the main local side effects of budesonide?

Answer 233

sore throat

hoarse voice

opportunistic oral infections

Question 234

what are the main systemic side effects of budesonide?

Answer 234

growth retardation in children

hyperglycaemia

decreased bone mineral density

immunosuppression

effects on mood

(etc.)

Question 235

how does the potency of budesonide compare to that of fluticasone and mometasone?

Answer 235

less potent

Question 236

why does inhaled budesonide result in some systemic absorption through the GI tract?

Answer 236

oral bioavailability >10%

Question 237

what is the primary mechanism of action of montelukast?

Answer 237

antagonises CysLT1 leukotriene receptor on eosinophils, mast cells and airway smooth muscle cells

decreases eosinophil migration, bronchoconstriction, inflammation induced oedema

Question 238

what is the drug target of montelukast?

Answer 238

CysLT1 leukotriene receptor

Question 239

what are the main mild side effects of montelukast?

Answer 239

diarrhoea

fever

headaches

nausea or vomiting

Question 240

what are the main serious side effects of montelukast?

Answer 240

mood changes

anaphylaxis

Question 241

when should montelukast be administered for prophylaxis of exercise-induced bronchoconstriction?

Answer 241

at least 2 hours before initiating exercise

Question 242

what drugs are used in treatment of GORD/peptic ulcer disease?

Answer 242

NSAIDS

PPIs

histamine (H2) receptor antagonists

paracetamol (aka acetaminophen)

Question 243

what are some examples of NSAIDS?

Answer 243

ibuprofen

naproxen

diclofenac

Question 244

what is the primary mechanism of action of NSAIDS?

Answer 244

inhibit cyclo-oxygenase enzyme (COX) - rate limiting step for production of all prostanoids (prostaglandins, thromboxanes) from parent arachidonic acid

prostanoids act through many prostanoid receptors, produces highly complex array of actions

Question 245

how do the effects of NSAIDS vary depending on the type of COX inhibition?

Answer 245

anti-inflammatory (and most analgesic and antipyretic actions) related to COX-2 inhibition

unwanted effects mostly a result of COX-1 inhibition

Question 246

what is the drug target of NSAIDS?

Answer 246

cyclo-oxygenase (COX) enzyme

Question 247

what are the common side effects of NSAIDS?

Answer 247

gastric irritation

ulceration

bleeding

Question 248

what are the more extreme side effects of NSAIDS?

Answer 248

perforation

reduced creatinine clearance, possible nephritis

bronchoconstriction in susceptible individuals (contraindicated in asthma)

skin rashes & other allergies, dizziness, tinnitus.

Question 249

what are the side effects of NSAIDS following prolonged used/in patients with pre-existing cardiovascular risk?

Answer 249

adverse cardiovascular effects (hypertension, stroke, MI)

Question 250

what is prolonged analgesic abuse over a period of years associated with?

Answer 250

chronic renal failure

Question 251

what rare condition in children has aspirin been linked with?

Answer 251

post-viral encephalitis (Reye’s syndrome)

Question 252

how can NSAIDS be used?

Answer 252

analgesics - mild to moderate pain relief (e.g. musculoskeletal pain, headache, dysmenorrhoea)

antipyretics - reduce fever

anti-inflammatory drugs - chronic control of inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis)

anti-aggregatory agent (aspirin only) - inhibit platelet aggregation in patients at risk of stroke or MI

Question 253

what are some examples of PPIs?

Answer 253

omeprazole

lansoprazole

Question 254

what is the primary mechanism of action of PPIs?

Answer 254

irreversible inhibitors of H+/K+ ATPase in gastric parietal cells

weak bases, so accumulate in acid environment of parietal cell canaliculi (concentrates and prolongs duration of action)

(omeprazole plasma half-life approx. 1 h but single daily dose affects acid secretion for 2-3 days)

PPIs inhibit basal and stimulated gastric acid secretion by >90%

Question 255

what is the drug target of PPIs?

Answer 255

H+/K+ ATPase (‘proton pump’)

Question 256

what are the main side effects of PPIs?

Answer 256

headache

diarrhoea

bloating

abdominal pain

rashes

Question 257

symptoms of which condition may be masked by use of PPIs?

Answer 257

gastric cancer

Question 258

omeprazole inhibits cytochrome P2C19 - what other drugs are affected by this?

Answer 258

reduced function in antiplatelet medication e.g. clopidogrel, when platelet function is monitored

Question 259

how are PPIs administered?

Answer 259

generally given orally

degrade rapidly at low pH so administered as capsules containing enteric-coated granules

Question 260

how do PPIs affect H+ ion transport in parietal cells?

Answer 260

PPIs are pro-drugs - converted into 2 reactive species at low pH

react with sulphydryl groups in H+/K+ ATPase responsible for transporting H+ ions out of the parietal cells

Question 261

what are some examples of histamine (H2) antagonists?

Answer 261

ranitidine

cimetidine

Question 262

what is the primary mechanism of action of histamine (H2) antagonists?

Answer 262

structural analogues of histamine are competitive antagonists of H2 histamine receptors

inhibit stimulatory action of histamine released from enterochromaffin-like (ECL) cells on gastric parietal cells surface

inhibit gastric acid secretion
(histamine receptors increase acid production via cAMP dependent activation of H+/K+ ATPase - less acid production means less corrosive environment, less irritation of stomach wall due to damaged mucosal barrier)

Question 263

what is the drug target of histamine (H2) antagonists?

Answer 263

histamine H2 receptors

Question 264

what are the main side effects of histamine (H2) antagonists?

Answer 264

diarrhoea

dizziness

muscle pains

transient rashes

Question 265

why is cimetidine (histamine H2 antagonist) contraindicated with some drugs?

Answer 265

inhibits cytochrome P450

may retard the metabolism and potentiate the effects of a range of drugs

Question 266

what are some drug categories contraindicated by cimetidine?

Answer 266

various - includes oral anticoagulants and TCAs

Question 267

why does ranitidine only have 50% bioavailability?

Answer 267

undergoes first pass metabolism

Question 268

why is twice daily dosing of ranitidine effective?

Answer 268

ranitidine plasma half-life 2-3 h - well tolerated

Question 269

when do histamine (H2) antagonists not necessarily need to be on prescription?

Answer 269

low dose over-the-counter formulations available from pharmacies for short term use without prescription

Question 270

what is the primary mechanism of action of paracetamol in GORD?

Answer 270

mechanism of action unclear

(current hypothesis)
both central and peripheral actions possibly involving interactions with a COX-3 isoform (inhibition of prostaglandin synthesis), cannabinoid receptors or the endogenous opioids

interactions at 5HT or adenosine receptors also proposed

Question 271

where are the effects of paracetamol mostly restricted to?

Answer 271

nervous tissue

Question 272

what is the drug target of paracetamol?

Answer 272

not yet well defined - COX-3 isoform?

Question 273

what are some side effects of paracetamol?

Answer 273

few side effects at therapeutic doses

no gastric irritation but in overdose serious hepatotoxicity may occur

occasional allergic skin reactions

Question 274

why is paracetamol not an NSAID?

Answer 274

little anti-inflammatory activity

Question 275

what are the broad therapeutic effects of paracetamol?

Answer 275

good analgesic for mild-to-moderate pain

some antipyretic activity

Question 276

what is step 1 of the 7 step process of prescribing?

Answer 276

identify the patient’s problem

Question 277

what is step 2 of the 7 step process of prescribing?

Answer 277

specify the therapeutic objective

Question 278

what is step 3 of the 7 step process of prescribing?

Answer 278

select a drug on the basis of comparative efficacy, safety, cost and suitability

Question 279

what is step 4 of the 7 step process of prescribing?

Answer 279

discuss choice of medication with patient (and carer) and make a shared decision about treatment

Question 280

what is step 5 of the 7 step process of prescribing?

Answer 280

write a correct prescription

Question 281

what is step 6 of the 7 step process of prescribing?

Answer 281

counsel the patient on appropriate use of the medicine

Question 282

what is step 7 of the 7 step process of prescribing?

Answer 282

make appropriate arrangements for follow up

Question 283

BMI: 31

1st BP: 144/92 mmHg
2nd BP: 148/91 mmHg

HbA1c: 65mmol/mol

LDL: 5.18 mmol/L (200 mg/dL)

HDL: 0.8 mmol/L (30mg/dL)

triglycerides: 6.53 mmol/L (252 mg/dL)

glycosuria, no ketones

no polydipsia, polyuria or weight loss

what is the patient’s problem?

Answer 283

fasting glucose > 7
HbA1c > 48mmol/L (6.5%)
- diabetes

blood pressure high
- hypertensive

HDL < 50mg/dl
LDL > 100mg/dl, triglycerides > 150mg/dl
- dyslipidaemia

BMI 30-34.9
- obesity

overall, metabolic syndrome?

Question 284

fasting glucose > 7
HbA1c > 48mmol/L (6.5%)
- diabetes

blood pressure high
- hypertensive

HDL < 50mg/dl
LDL > 100mg/dl, triglycerides > 150mg/dl
- dyslipidaemia

BMI 30-34.9
- obesity

overall, metabolic syndrome?

what are the therapeutic objectives for this patient?

Answer 284

lose weight – reduced adiposity should help reduce insulin resistance linked to diabetes

reduce blood pressure – reduce CVD risk

improve lipid profile – reduce CVD risk

reduce blood glucose – reduce complications (microvascular and (atherosclerotic) macrovascular) associated with prolonged elevated blood glucose

Question 285

what should be done when HbA1c rises to 48 mmol/mol (6.5%) on lifestyle intervention? (adult with T2DM, can take metformin)

Answer 285

offer standard release metformin (500 mg per day, oral)

support person to aim for 48 mmol/mol

Question 286

what is the first intensification (when HbA1c rises to 58 mmol/mol (7.5%)) for adults with T2DM that can take metformin?

Answer 286

consider dual therapy with:

• DPP-4 inhibitors e.g. sitagliptin (100 mg per day, oral)
• SGLT2 inhibitors e.g. dapaglifozin (5 mg per day, oral)
• sulphonylureas e.g. gliclazide (40-80 mg per day)
• pioglitazone (15-45 mg per day)

support person to aim for 53 mmol/mol (7.0%)

Question 287

what is the second intensification (when HbA1c rises to 58 mmol/mol (7.5%)) for adults with T2DM that can take metformin?

Answer 287

consider triple therapy with:

• metformin, a DPP-4i and an SU
• metformin, pioglitazone and an SU - metformin, pioglitazone or an SU, and an SGLT-2i

or insulin-based treatment

support person to aim for 53 mmol/mol (7.0%)

Question 288

what are the benefits of metformin treatment?

Answer 288

decreases glucose production by liver

increases insulin sensitivity of body tissues

anorexiant effect (appetite suppression, thereby reducing caloric intake)

Question 289

expression of the organic cation transporter 1 (OCT-1) is highest in: liver hepatocytes (highest expression), small intestinal enterocytes and the renal proximal tubules.

why is this relevant to the pharmacokinetics of orally-administered metformin?

Answer 289

relation to absorption
- shows that metformin has a mechanism to leave small intestines and access the hepatic portal vein

relation to distribution

• shows that metformin has a mechanism to access the liver
• shows that metformin can access the kidney tubules

Question 290

what is a side effect of pioglitazone?

Answer 290

increased incidence of heart failure

Question 291

why may renal impairment cause problems for diabetic patients on metformin?

Answer 291

90% of standard dose (‘unchanged’,
active) of oral metformin excreted
via kidney

Question 292

how should metformin administration be adjusted with an eGFR of >60?

Answer 292

no adjustment needed

Question 293

how should metformin administration be adjusted with an eGFR of 45-60?

Answer 293

monitor eGFR in 3-6 months

Question 294

how should metformin administration be adjusted with an eGFR of 30-45?

Answer 294

do not initiate metformin

if already taking metformin, consider 50% dose decrease

Question 295

how should metformin administration be adjusted with an eGFR of <30?

Answer 295

contraindicated

Question 296

how is depression screened for in primary care?

Answer 296

patient health questionnaire 9 (PHQ 9)

Question 297

how is a PHQ-9 score related to depression severity?

Answer 297

0-4 - none/minimal

5-9 - mild

10-14 - moderate

15-19 - moderately severe

20-27 - severe

Question 298

hypertension - losartan (angiotensin 2 receptor blocker) but BP still high (141/91 mmHg)

erythromycin for chronic prostatitis

uneasy

low mood

low self esteem

difficulty getting to sleep

inability to think clearly

strained personal relationship

job performance affected?

PHQ-9 score - 14

what is the patient’s problem?

Answer 298

indicative of moderate depression

major depressive disorder includes minor, moderate and severe depression

Question 299

hypertension - losartan (angiotensin 2 receptor blocker) but BP still high (141/91 mmHg)

erythromycin for chronic prostatitis

uneasy

low mood

low self esteem

difficulty getting to sleep

inability to think clearly

strained personal relationship

job performance affected?

PHQ-9 score - 14

likely moderate depression

what are the therapeutic objectives?

Answer 299

alleviate depressive symptoms:

• improve mood
• help with sleep difficulties
• improve self-esteem
• improve ability to think clearly

reduce the likely functional impairment the depressive symptoms have on daily life:

• improve personal relationships
• improve job performance

Question 300

the 3 most common SSRIs are sertraline, citalopram and fluoxetine - which is contraindicated with erythromycin?

Answer 300

citalopram

Question 301

why is citalopram contraindicated with erythromycin?

Answer 301

both erythromycin and citalopram prolong QT interval - most manufacturers advise avoiding 2+ drugs that do this

severe interaction

Question 302

what may be seen on an ECG if polymorphic ventricular tachycardia is occurring in the context of QT prolongation (e.g. interaction of citalopram and erythromycin)?

Answer 302

torsades de pointes

Question 303

what are some factors that predispose to QT prolongation?

Answer 303

increasing age

female sex

disease

metabolic disturbance (notably hypokalaemia)

Question 304

what is the optimal SSRI dose (normalised to fluoxetine) to cause 50% or greater reduction in depression rating after 8 weeks of treatment?

Answer 304

30 mg

Question 305

what is the link between dropouts due to adverse effects and 50% or greater reduction in depression rating after 8 weeks of treatment?

Answer 305

as SSRI dose increases, dropouts due to adverse effects increases

reduction in depression rating begins at 1.0 at 0 mg, peaks at 30 mg, returns to 1.0 by 80 mg

20-30 mg is optimal dose to manage adverse effects

Question 306

why does the plateau in therapeutic effect occur in anti-depressant action (based on action at serotonin transporter)?

Answer 306

limited receptor numbers

Question 307

why is caution required when switching from one antidepressant to another?

Answer 307

risk of drug interactions

risk of serotonin syndrome

withdrawal symptoms

relapse

Question 308

what is required before starting a new drug?

Answer 308

washout

high starting doses

Question 309

why may venlafaxine be preferred to mirtazapine in a patient with hypertension?

Answer 309

noradrenaline mediates the sympathetic nervous system effects on the heart

> 150 mg per day - adrenergic effects

> 300 mg per day - increased BP, increased HR

Question 310

rheumatoid arthritis for 9 years – awaiting total right knee arthroplasty

BP

• initial: 149/93mmHg
• subsequent: 147/92mmHg and 145/91mmHg

generally well

smokes (< 10 per day)

height: 167 cm
weight: 85kg

what is the patient’s problem? (check Q-risk score)

Answer 310

Q-risk = 14.9%

stage 1 hypertension

Question 311

Q-risk = 14.9%

stage 1 hypertension

what are the therapeutic objectives for this patient?

Answer 311

set reasonable blood pressure reduction goals (previous case reduce below 140/90 mmHg)

reduce cardiovascular risk associated with increased morbidity and mortality (modifiable risk factors = obesity and smoking)

no new medication that interferes with upcoming procedures/other treatment

Question 312

what is the Q-risk score?

Answer 312

shows risk of heart attack or stroke within 10 years

e.g. score of 12% - in a population of 100 all of whom have the same risk factors, 12 are likely to die of heart attack/stroke within 10 years

Question 313

what is the procedure if ambulatory or home blood pressure monitoring (ABPM or HBPM) shows a BP under 135/85 mmHg?

Answer 313

monitor at least every 5 years

Question 314

what is the procedure if ambulatory or home blood pressure monitoring (ABPM or HBPM) shows a BP between 135/85 - 149/94 mmHg? (stage 1 hypertension)

Answer 314

start drug treatment if there is:

target organ damage

CVD

renal disease

diabetes

10 year CVD risk >10%

Question 315

what is the procedure if ambulatory or home blood pressure monitoring (ABPM or HBPM) shows a BP over 150/95 mmHg? (stage 2 hypertension)

Answer 315

start drug treatment

Question 316

when is ambulatory or home blood pressure monitoring (ABPM or HBPM) offered?

Answer 316

clinic BP 140/90 mmHg or over

Question 317

what is clearance?

Answer 317

measure of body’s ability to eliminate a drug

clearance by means of various organs of elimination is additive

elimination of drug may occur as a result of processes that occur in the liver, kidney, and other organs

Question 318

what is elimination half life?

Answer 318

length of time required for drug concentration to decreasetohalf of itsstarting dose in the body

Question 319

what is time to peak plasma levels?

Answer 319

time required for a drug to reach peak concentration in plasma

the faster the absorption rate, the lower the time to peak plasma concentration

Question 320

why may amlodipine be better than felodipine considering BP tends to increase most rapidly in the morning after waking up?

Answer 320

felodipine has higher plasma clearance, shorter elimination half life and shorter time to peak plasma levels

therefore causes dose dependent decrease in systolic and diastolic BP along with reflex tachycardia

amlodipine has slow onset and longer half life - slow onset mitigates reflex tachycardia

Question 321

what is the mechanism of action of ACE inhibitors in the treatment of hypertension?

Answer 321

inhibits angiotensin converting enzyme (ACE) on pulmonary and renal endothelium

prevents conversion of angiotensin I to angiotensin II

causes vasodilation, less salt and water retention, less aldosterone secretion

Question 322

why may ACE inhibitors have a negative effect on eGFR?

Answer 322

angiotensin II causes efferent vasoconstriction (increased pressure for filtration) - helps maintain GFR when renal perfusion is low (renal artery stenosis, volume depletion, older people with congestive heart failure)

Question 323

why may ACE inhibitors have a negative effect on serum potassium?

Answer 323

hyperkalaemia

usually aldosterone increases Na+ reabsorption and water in distal convoluted tubule at the expense of K+ (increasing plasma volume and blood pressure) A

increasing the gene expression and availability of:

• Na+ ion permease enzyme - more Na+ crosses from the lumen to the inside of the renal tubular cell
• Na+/K+ATPase on the peritubular side of the renal tubular cell - transfer increased cytosolic Na+ into peritubular fluid (so lower intracellular electronegativity)
• citrate synthase - more activity within the mitochondria for more ATP (for Na+/K+ATPase)

less aldosterone from the adrenal cortex means overall reduction Na+ and water reabsorption, allows K+ retention

Question 324

thiazide-like diuretics are excreted unchanged in urine - why is this a vital part of their therapeutic action?

Answer 324

diuretic needs to move from the blood

it is transported on basolateral side, uses a transporter on apical side

only then can it access the sodium chloride transporter on the apical side of distal tubule

Question 325

why do thiazides increase potassium excretion?

Answer 325

increase delivery from early distal tubule

Question 326

why does the diuretic effect of thiazides only work for 1-2 weeks?

Answer 326

kidney becomes tolerant to the diuretics due to rebound activation of renin angiotensin system

consequent increasing sodium reabsorption counteracts diuretic effect

Question 327

why do the antihypertensive effects of thiazides continue while the diuretic effect of thiazides only works for 1-2 weeks?

Answer 327

further vasodilating action (not as well understood)

Question 328

how often should BP and medication be checked once stabilised?

Answer 328

6-12 months

Question 329

how often should serum potassium and creatinine be checked once BP is stabilised?

Answer 329

yearly

Question 330

3 yr old

great difficulty in breathing

whistle like wheeze when exhaling, occasional coughing

slight temperature (38.2°C)

history and physical examination reveal nothing

has had mild breathlessness before, usually when she has an infection of some type

what is the patient’s problem?

Answer 330

first presentation of asthma

no allergic trigger, and most likely precipitated by the viral infection

hard to objectively diagnose asthma in children < 5 years old

no evidence that this is atopic at the moment, based on history

Question 331

first presentation of asthma

no allergic trigger, and most likely precipitated by the viral infection

what are the therapeutic objectives for this patient?

Answer 331

short term = relief
- relieve symptoms of breathlessness and expiratory wheeze during the acute asthma attack

long term = prevention

• dampen/prevent late phase of the asthma attack
• reduce the risk of further asthma attacks.
• attempt to improve lung function

Question 332

what is the difference between the early phase and late phase of asthma?

Answer 332

early phase - bronchospasm
- immediate decrease in forced expiratory volume

some recovery in between

late phase - inflammation (up to 6 hours after early phase)
- further decrease in forced expiratory volume

Question 333

what is the first line treatment for asthma in under 5s?

Answer 333

SABA (salbutamol)

Question 334

what are the differences between oral and inhalation routes when taking salbutamol?

Answer 334

inhaled has local effects

oral has systemic effects (undergoes first pass metabolism etc.)

Question 335

how does acetylcholine cause bronchoconstriction?

Answer 335

post ganglionic PSNS nerve releases acetylcholine

binds to M2 and M3 muscarinic receptor on bronchial smooth muscle

causes bronchoconstriction

Question 336

why is a nebulizer the best method for delivering salbutamol in emergency situations?

Answer 336

many drug solutions

can deliver combinations

minimal patient co operation required

can deliver to all ages

concentration and dose can be modified

normal breathing pattern

Question 337

what are the 5 places where are inhaled drugs lost?

Answer 337

1 - exhalation

2 - lack of absorption from lungs

3 - mucociliary clearance (trapped by cilia or mucous)

4 - swallowed (down oesophagus rather than trachea)

5 - some absorbed across mucous membrane in oral cavity and pharynx

Question 338

due to drug loss and consequent difference between expected and actual dose, why is a spacer clinically useful (especially in children)?

Answer 338

inhalation indicator makes it easier to coordinate breathing in and pressing your puffer

increased space allows better delivery to lungs

Question 339

why are eosinophils dangerous in asthma?

Answer 339

asthma can be exacerbated by viral infection

common viral infections (e.g. rhinovirus) release mediators that specifically activate eosinophils

eosinophils can induce epithelial damage (e.g. due to release of major basic protein)

increased susceptibility to viral infections (and therefore increased likelihood of asthma exacerbation)

Question 340

why is the oral bioavailability (proportion of drugs reaching plasma via GI tract) of some inhaled drugs (e.g. fluticasone) low despite a significant proportion being swallowed?

Answer 340

first pass inactivation

Question 341

what is the mechanism of action of montelukast?

Answer 341

targets CysLT1 receptor (Cysteinyl leukotriene receptor 1)

located on eosinophils/mast cells/airway smooth muscle

decreases smooth muscle constriction, eosinophil migration and oedema

Question 342

why is the mechanism of action of montelukast useful in NSAID induced asthma?

Answer 342

NSAIDs generally work by blocking the production of prostaglandins (both leukotrienes and prostaglandins derive from arachidonic acid)

if the leukotriene pathway is blocked, more prostaglandin will be formed to combat NSAID effect

Question 343

71-year-old man

osteoarthritis

• prescribed diclofenac gel (1%)
• regular paracetamol (500-1000mg orally every 6 hours when required) to help with the pain

bilateral knee pain diclofenac and paracetamol have reduced his pain, but he still has moderate pain when walking or carrying out strenuous activities such as gardening

pain is restricting his mobility and he has not been able to carry out the exercises that he has been advised to do

GP prescribes naproxen (250-500mg orally twice daily when required) as an additional analgesic

after taking the naproxen pain associated with his osteoarthritis is much improved

however, he has been suffering with intermittent upper abdominal pain for the last 2 weeks - described as a dull, gnawing ache, sometimes wakes him at night

what is the patient’s problem?

Answer 343

pain from osteoarthritis that limits daily activities

upper abdominal pain since starting naproxen

Question 344

pain from osteoarthritis that limits daily activities

upper abdominal pain since starting naproxen

what are the therapeutic objectives for this patient?

Answer 344

treat pain from osteoarthritis to ensure it is not interfering with daily living (or at least minimising the effect on activities)

treat new stomach pain, ideally without impacting on treatment of osteoarthritis pain

(these objectives are trade-offs)

Question 345

how does naproxen have an analgesic effect on joint pain?

Answer 345

target – COX enzymes (naproxen is non-selective i.e. inhibits COX1 & COX2)

location – peripheral nociceptive nerve endings (analgesia)

effect – COX produces prostaglandins that do not directly cause pain themselves, but sensitise peripheral nociceptors mediators (bradykinin and histamine) which causes pain (NSAIDs inhibit COX)

indirect effect on pain – PGs mediate inflammation therefore NSAIDs will reduce inflammation

Question 346

how can opiates reduce pain?

Answer 346

increased activity in descending inhibitory pathways

decreased excitation of transmission neuron

desensitise peripheral nociceptors

Question 347

how does naproxen have an adverse effect within the stomach?

Answer 347

target – COX I enzyme

location – gastric mucosal cells

effect – inhibited prostaglandin production means inhibition of prostaglandin mediated protection of gastric mucosa

Question 348

how do prostaglandins in gastric mucosal cells protect from acid?

Answer 348

increase bicarbonate release

increase mucous production

increase blood flow

Question 349

why would a patient be on oral naproxen and topical diclofenac? (topical drugs can cause systemic side effects)

Answer 349

GP mistake

communication failure

Question 350

what changes should be made to a prescription of naproxen and topical diclofenac?

Answer 350

3 options:
stop the gel

switch to ibuprofen

stop NSAIDs completely

Question 351

after an oesophago-gastro-duodenoscopy that leads to a diagnosis of peptic ulcer disase with no active bleeding and H. pylori negative, what treatment should be given?

Answer 351

stop NSAIDs where possible

offer full dose PPI therapy for 4-8 weeks
e.g. omeprazole 20 mg once daily

Question 352

why do PPIs help with peptic ulcer disease associated with NSAIDs?

Answer 352

NSAIDs leave stomach wall exposed to the effect of acid, which is causing pain

PPIs reduce the acid production

Question 353

what is the disconnect when comparing guidance for PPI treatment and what happens in practice?

Answer 353

treatment algorithm states that patients should be given 20mg omeprazole once a day for 4-8 weeks

data suggests that most patients prescribed PPIs are treated for at least 3 months (above the recommended treatment duration of 4-8 weeks) at twice the standard treatment dose i.e. 40mg versus 20mg.

nearly 50% are still on 40mg after 12 months

(data does include PPI use for indigestion or dyspepsia)

Question 354

when suffering with osteoporosis as well as peptic ulcer disease, why is a histamine H2 receptor antagonist prescribed (as opposed to PPIs)?

Answer 354

PPIs increase fracture risk (worsens chances if patient has osteoporosis)

(mechanism of action is unclear- main theory)
absorption of calcium salts is pH dependent

change in pH induced by PPIs causes reduction in absorption and decrease in calcium available for bone

Question 355

21 year old

single episode of collapse with jerking

lost consciousness, started convulsing before coming around

stressed and not much sleep

occasionally makes a quick jerk of her arms as she wakes up

similar episode 18 months ago

urea, electrolytes, calcium, glucose: normal

general and neurological exams: normal

EEG shows interictal epileptiform discharge (IED)

what is the patient’s problem?

Answer 355

generalised tonic-clonic seizures

EEG shows interictal epileptiform discharge (IED) - increased risk of seizure recurrence

Question 356

generalised tonic-clonic seizures

EEG shows interictal epileptiform discharge (IED) - increased risk of seizure recurrence

what are the therapeutic objectives for this patient?

Answer 356

eliminate seizures or reduce their frequency to the maximum degree possible

avoid the adverse effects associated with long-term treatment

aid patients in maintaining or restoring their usual psychosocial and vocational activities, and in maintaining a normal lifestyle

Question 357

how does epilepsy affect driving?

Answer 357

must document advice to contact DVLA that they cannot drive

Question 358

what are the different types of seizure and how are they differentiated?

Answer 358

absence

focal

generalised tonic-clonic

myoclonic

Question 359

what are the features of an absence seizure?

Answer 359

lose awareness of your surroundings for a short time

• stare blankly into space
• look like they’re “daydreaming”
• flutter their eyes
• make slight jerking movements of their body or limbs

Question 360

what are the features of a simple partial focal seizure?

Answer 360

strange feeling that’s hard to describe

“rising” feeling in your tummy – like the sensation in your stomach when on a fairground ride

a feeling that events have happened before (déjà vu)

unusual smells or tastes

tingling in your arms and legs

an intense feeling of fear or joy

stiffness or twitching in part of your body, such as an arm or hand

remain awake and aware

Question 361

how long does a typical absence seizure last?

Answer 361

up to 15 secs, will not remember

Question 362

what can simple partial seizures indicate?

Answer 362

sometimes referred to as warnings or auras - can be a sign that another type of seizure is about to happen

Question 363

what are the features of a complex partial focal seizure?

Answer 363

lose sense of awareness, make random body movements, such as:

• smacking your lips
• rubbing your hands
• making random noises
• moving your arms around
• picking at clothes or fiddling with objects
• chewing or swallowing

unresponsive to anyone, no memory of it

Question 364

what are the features of a tonic-clonic seizure?

Answer 364

2 stages

tonic stage – lose consciousness, body goes stiff, may fall to the floor

clonic stage – limbs jerk about, may lose control of bladder or bowel, may bite tongue or the inside of cheek, might have difficulty breathing

Question 365

how long does a typical tonic-clonic seizure last?

Answer 365

normally stops after a few minutes, some last longer

may have a headache, difficulty remembering what happened

may feel tired or confused afterwards

Question 366

what are the features of a myoclonic seizure?

Answer 366

some or all of your body suddenly twitches or jerks, like you’ve had an electric shock (often happen soon after waking up)

Question 367

how long does a typical myoclonic seizure last?

Answer 367

usually only a fraction of a second but many can occur in a short space of time

Question 368

what is the difference between a tonic and atonic seizure?

Answer 368

tonic - all your muscles suddenly become stiff (like the first stage of a tonic-clonic seizure), may lose balance and fall over

atonic - all muscles to suddenly relax, so you may fall to the ground - tend to be very brief, usually able to get up straight away

Question 369

what is the first line of treatment for a generalised tonic-clonic seizure in men and women with no child bearing potential?

Answer 369

sodium valproate

Question 370

what is the first line of treatment for a generalised tonic-clonic seizure in men and women with child bearing potential?

Answer 370

lamotrigine or carbamazepine

Question 371

what is the first line of treatment for an absence seizure in men and women with no child bearing potential?

Answer 371

ethosuximide or sodium valproate

Question 372

what is the first line of treatment for an absence seizure in men and women with child bearing potential?

Answer 372

ethosuximide

Question 373

what is the first line of treatment for a focal seizure in men and women with no child bearing potential?

Answer 373

lamotrigine or carbamazepine

Question 374

what is the first line of treatment for a focal seizure in men and women with child bearing potential?

Answer 374

carbamazepine or levetiracetam

Question 375

what is the first line of treatment for a myoclonic seizure in men and women with no child bearing potential?

Answer 375

sodium valproate

Question 376

what is the first line of treatment for a myoclonic seizure in men and women with child bearing potential?

Answer 376

levetiracetam or topiramate

Question 377

what is the first line of treatment for a tonic or atonic seizure in men and women with no child bearing potential?

Answer 377

sodium valproate

Question 378

what is the first line of treatment for a tonic or atonic seizure in men and women with child bearing potential?

Answer 378

sodium valproate (pregnancy prevention programme)

Question 379

why is there a difference in epilepsy treatment depending on childbearing potential?

Answer 379

sodium valproate: first line in absence, tonic-clonic, tonic/atonic, myoclonic

can cause:
- neural tube defects
- decreased IQ
- autism
after in utero exposure

Question 380

how does lamotrigine interact with the combined oral contraceptive pill?

Answer 380

drug-drug interaction

COC appears to have an impact on lamotrigine blood levels – coadministration leads to a reduced level of lamotrigine in the blood

Question 381

what are the effects of drug interactions between lamotrigine and the combined oral contraceptive pill?

Answer 381

reduced seizure control but no contraceptive failure

Question 382

how may the combined oral contraceptive decrease lamotrigine concentrations in the blood?

Answer 382

reduce lamotrigine absorption - less gets into the blood in the first place

enhance lamotrigine metabolism - more cleared from the blood

enhance lamotrigine excretion - enhance clearance from the blood

Question 383

how does lamotrigine affect blood ethinyl estradiol levels?

Answer 383

appears to have no effect

Question 384

what prescription change should be made to lamotrigine if taken with the combined oral contraceptive?

Answer 384

increase lamotrigine dose

Question 385

when on the combined oral contraceptive with lamotrigine, why may more seizures occur during the second and third week? why may someone feel drowsy in the fourth week?

Answer 385

oestrogen = “seizure promoting”
increased seizure frequency during oestrogen peak

COC taken over four weeks:

• first three weeks: active drug
• fourth week: nothing or ‘dummy’

fourth week - no COC affecting
liver enzymes (usually induces UDPGA):
- liver enzymes normalise
- lamotrigine levels increase

Question 386

how can side effects in the fourth week of a combined oral contraceptive cycle when taken with lamotrigine be addressed?

Answer 386

decrease lamotrigine in fourth week

Question 387

what are some side effects in the fourth week of a combined oral contraceptive cycle when taken with lamotrigine?

Answer 387

dizziness

drowsiness

diarrhoea

loss of balance

abnormal eye movement

trouble speaking

Question 388

between lorazepam, diazepam and midazolam, which is best to administer out of hospital?

Answer 388

midazolam

others require IV access

Question 389

how may pregnancy affect seizure frequency?

Answer 389

may increase

Question 390

why may pregnancy affect seizure frequency (if on lamotrigine)?

Answer 390

lamotrigine dose may be reduced due to fears of harming the unborn child

pregnancy may lead to changes in liver metabolism - lamotrigine levels may decrease (so increased seizure risk)

Question 391

how can increased seizure frequency be avoided in pregnancy (if on lamotrigine)?

Answer 391

check serum lamotrigine at the beginning of pregnancy and during the second and third trimester

dose could then be adjusted as described

Question 392

how can increased seizure frequency during week 2-3 of the combined oral contraceptive cycle be addressed if lamotrigine is well tolerated?

Answer 392

change oral contraceptive to long-term progesterone implant (e.g. Implanon/Nexplanon)

progesterone = “seizure inhibiting”

Question 393

what are the 2 ways in which variation in adverse effects of drugs can be considered?

Answer 393

differences in concentrations of drug reaching the tissues (i.e. factors affecting absorption, distribution, metabolism and excretion of the drug)

differences in response of the target tissues to the same degree of stimulation (i.e. factors such as variation in receptor sensitivity, number and distribution)

Question 394

responses to a drug vary between individuals - how can the reasons for this be subdivided?

Answer 394

absolute differences in dose administered

relative overdose or underdose

Question 395

how can an absolute difference in dose administered take place?

Answer 395

(deliberate or accidental)

error in prescription or dispensing

patient non-compliance

drug formulation

Question 396

what are the 5 factors that may cause a relative overdose or underdose of a drug to produce variable effects?

Answer 396

environmental exposure to chemicals, including other drugs

food intake

fluid intake

age

disease

Question 397

how can environmental exposure to chemicals, including other drugs, cause relative overdose or underdose of a drug to produce variable effects?

Answer 397

enzyme induction

enzyme inhibition

Question 398

how can food intake cause relative overdose or underdose of a drug to produce variable effects?

Answer 398

drugs may interact chemically with components of food; this may alter their absorption (e.g. bisphosphonates chelated by Ca, Mg, Fe so not absorbed with food)

foods delay gastric emptying and alter gastric pH

Question 399

how can fluid intake cause relative overdose or underdose of a drug to produce variable effects?

Answer 399

most drugs are better absorbed if taken with water e.g. may dissolve better

fluids may stimulate gastric emptying

Question 400

how may newborn infants’ bodies cause relative overdose or underdose of a drug to produce variable effects?

Answer 400

more body water than adults

poorer renal function, with immature tubular secretion

an immature blood brain barrier

lower capacity for drug metabolism

Question 401

how can changes in drug absorption in elderly people cause relative overdose or underdose of a drug to produce variable effects?

Answer 401

decreased absorptive surface of small intestine

altered gastric and gut motility

increased rate of gastric emptying

Question 402

how can changes in drug distribution in elderly people cause relative overdose or underdose of a drug to produce variable effects?

Answer 402

reduced lean body mass and body water, relative increase in fat

lipid soluble drugs have increased volume of distribution and decreased blood levels

water soluble drugs have decreased volume of distribution and increased blood levels

reduced plasma albumin, so fewer plasma protein binding sites

Question 403

how can changes in drug metabolism in elderly people cause relative overdose or underdose of a drug to produce variable effects?

Answer 403

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

Question 404

how can changes in drug excretion in elderly people cause relative overdose or underdose of a drug to produce variable effects? (most important in drug handling in elderly patients)

Answer 404

reduced renal mass

reduced renal perfusion

reduced glomerular filtration rate

reduced tubular excretion

(steady decline is normal - situation worsened in renal disease)

Question 405

how can changes in organ sensitivity in elderly people cause relative overdose or underdose of a drug to produce variable effects?

Answer 405

elderly tend to be more sensitive to CNS active drugs

Question 406

what are the 5 aspects of ageing that affect relative overdose or underdose to produce variable effects?

Answer 406

drug absorption

drug distribution

drug metabolism

drug excretion

organ sensitivity

Question 407

what are the 6 aspects of disease that affect relative overdose or underdose to produce variable effects?

Answer 407

general nutritional status

GI disorders

congestive heart failure

kidney failure

liver failure

other acute or chronic disease states

Question 408

how can changes in general nutritional status (disease) cause relative overdose or underdose of a drug to produce variable effects?

Answer 408

unbalanced diets may lead to deficiency states and enzyme abnormalities

starvation – decreased plasma protein binding and metabolism

obesity – increased lipid fraction

Question 409

how can GI disorders (disease) cause relative overdose or underdose of a drug to produce variable effects?

Answer 409

e.g. achlorhydria, coeliac disease, Crohn’s disease

altered drug absorption

Question 410

how can congestive heart failure (disease) cause relative overdose or underdose of a drug to produce variable effects, especially in the elderly?

Answer 410

reduced splanchnic blood flow

intestinal mucosal oedema

reduced hepatic clearance

Question 411

how can kidney failure (disease) cause relative overdose or underdose of a drug to produce variable effects, especially in the elderly?

Answer 411

decreased drug excretion leading to toxicity

water overload leading to changes in drug concentrations in different body fluid compartments

Question 412

how can liver failure (disease) cause relative overdose or underdose of a drug to produce variable effects?

Answer 412

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

Question 413

how can other acute or chronic disease states (disease) cause relative overdose or underdose of a drug to produce variable effects?

Answer 413

varies

Question 414

72-year-old

atrial fibrillation which could not be converted back to sinus rhythm

suffered a small stroke, warfarin prescribed (‘thins’ blood) to prevent a recurrence

warfarin dose stabilized (checked by clotting time), but later develops a chest infection and is given clarithromycin for one week

effectively treats the infection, but now has a severe nosebleed, bruises very easily

how has this adverse drug reaction been caused (by what mechanism)?

Answer 414

increased external bleeding (nose bleed)

increased internal bleeding (bruising)

warfarin metabolised by cytochrome P450 pathway

Cyt P450 inhibited by clarithromycin, so increased plasma levels of warfarin

Question 415

72-year-old

atrial fibrillation which could not be converted back to sinus rhythm

suffered a small stroke, warfarin prescribed (‘thins’ blood) to prevent a recurrence

warfarin dose stabilized (checked by clotting time), but later develops a chest infection and is given clarithromycin for one week

effectively treats the infection, but now has a severe nosebleed, bruises very easily

what drugs might produce a similar effect to clarithromycin?

Answer 415

other antibiotics of same class (i.e. macrolides): e.g. erythromycin

some antibiotics of other classes: e.g. quinolones like ciprofloxacin

some systemic antifungal drugs: e.g. fluconazole

proton pump inhibitors (PPIs) - for peptic ulcers: e.g. omeprazole

some anti-HIV drugs, especially protease inhibitors

Question 416

what is INR?

Answer 416

International Normalized Ratio (INR) - standardized measure of blood clotting time

Question 417

how is INR calculated?

Answer 417

ratio of a patient’s prothrombin time (‘test’) to a control (‘normal’) sample, raised to the power of the ISI (International Sensitivity Index) value for the tissue factor used (usually 0.94 - 1.4)

(test PT / normal PT) ᶦˢᶦ

Question 418

what does a raised INR signify?

Answer 418

increased bleeding (decreased clotting)

bleeding risk increased

Question 419

what does a lowered INR signify?

Answer 419

less bleeding (increased clotting)

thrombosis risk increased

Question 420

what are the reference ranges for INR?

Answer 420

normal: 0.9-1.2

normal in atrial fibrillation: 2.0-3.0
(thrombosis risk increases <2.0)

> 4.0 serious bleeding risk increases

Question 421

why may self-medication with St. John’s Wort have an effect on warfarin requirement?

Answer 421

contains hypericin (inducer of cytochrome P450) (hyperforin also has this effect)

increases metabolism of warfarin, decreasing its concentration and making it less effective (less anticoagulant effect)

Question 422

what drugs may have similar adverse effects to St. John’s Wort when administered with warfarin?

Answer 422

fewer enzyme inducers than inhibitors but drugs that induce Cyt P450 include:

rifampicin: antibiotic used in TB therapy (onset/duration of induction can depend on half-life)

carbamazepine and phenytoin, as well as older and largely obsolete antiepileptic drugs phenobarbitone and primidone

griseofulvin (antifungal drug)

Question 423

what blood test should be done before increasing digoxin dose?

Answer 423

serum potassium

Question 424

why does serum potassium have to be checked before increasing digoxin dose?

Answer 424

digoxin binds to the Na+/K+ exchange ATPase on cardiac myocytes and nodal tissue

competes with K+ for its binding site

hypokalaemia means more digoxin binding (less competition by K+) - therefore, enhanced therapeutic and adverse effects of digoxin (heart ‘block’)

Question 425

how does hypokalaemia affect the effects of digoxin?

Answer 425

means more digoxin binding (less competition by K+)

therefore, enhanced therapeutic and adverse effects of digoxin (heart ‘block’)

Question 426

how does hyperkalaemia affect the effects of digoxin?

Answer 426

indication of possible kidney disease - possible reduced kidney function and therefore reduced digoxin clearance

more digoxin in system, enhanced therapeutic and adverse effects of digoxin

Question 427

how can you ensure that a dose of digoxin is correct?

Answer 427

measure plasma levels of digoxin directly – recognised target range for these

Question 428

why may confusion be caused in older patients taking temazepam (benzodiazepine)?

Answer 428

(pharmacokinetic) metabolism by liver of some drugs is reduced in older patients – so more temazepam
(pharmacodynamic) older patients may have increased sensitivity to drugs, even if metabolism is normal (may relate to changes in receptor number or function or other)

Question 429

why may INR increase as a consequence of malnutrition if a person is on warfarin?

Answer 429

metabolism of many drugs affected by malnutrition

warfarin: similar to a drug which inhibits cyt pathway (e.g. clarithromycin) – therefore, more warfarin

malnutrition also decreases plasma protein levels (warfarin is heavily plasma protein bound)

• decreases oxidative metabolism (warfarin is metabolised by oxidation)
• decreases GFR

(increased likelihood of adverse drug reaction)