Clinical Pharmacology

Question 1

What are inhibitors of the p450 enzyme system?

Answer 1

Inhibitors of the P450 system include
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine,omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin

Question 2

What are inducers of the P450 enzyme system?

Answer 2

Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors where effects are seen rapidly

Inducers of the P450 system include
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)

Question 3

How does carbamazepine reduce the efficiency of the COC pill?

Answer 3

Carbamazepine is a P450 enzyme inducer. Ethinylestradiol is used in the combined oral contraceptive (COC) pill and is a substrate of the CYP3A4 P450 isoenzyme system. Inducers of the P450 enzymes increase the speed of the breakdown of ethinylestradiol and reduce the efficacy of the COC pill.

Question 4

what is Ethylene glycol and what are the stages of toxicity ?

Answer 4

Ethylene glycol is a type of alcohol used as a coolant or antifreeze

Features of toxicity are divided into 3 stages:
Stage 1: symptoms similar to alcohol intoxication: confusion, slurred speech, dizziness
Stage 2: metabolic acidosis with high anion gap and high osmolar gap. Also tachycardia, hypertension
Stage 3: acute kidney injury

Question 5

What is the management of Ethylene Glycol toxicity?

Answer 5

ethanol has been used for many years
works by competing with ethylene glycol for the enzyme alcohol dehydrogenase
this limits the formation of toxic metabolites (e.g. glycoaldehyde and glycolic acid) which are responsible for the haemodynamic/metabolic features of poisoning
fomepizole, an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanol
haemodialysis also has a role in refractory cases

Question 6

How does fomepizole work in Ethylene glycol toxicity?

Answer 6

fomepizole acts as a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase is the primary enzyme responsible for metabolising ethylene glycol into its toxic metabolites, including glycoaldehyde and glycolic acid. By competitively inhibiting this enzyme, fomepizole prevents the formation of these harmful substances and allows the body to excrete unmetabolised ethylene glycol via renal elimination.

Question 7

which antibiotics inhibit cell wall formation?

Answer 7

> peptidoglycan cross-linking: penicillins, cephalosporins, carbopenems

> peptidoglycan synthesis: glycopeptides (e.g. vancomycin)

Question 8

Which antibiotics inhibit protein synthesis?

Answer 8

> 50S subunit: macrolides, chloramphenicol, clindamycin, linezolid, streptogrammins
30S subunit: aminoglycosides, tetracyclines

Question 9

What antibiotics inhibit DNA synthesis?

Answer 9

quinolones (e.g. ciprofloxacin)

Question 10

What antibiotic damage DNA?

Answer 10

Metronidazole

Question 11

What antibiotics inhibit folic acid formation ?

Answer 11

sulpohonamides
trimethoprim

Question 12

What antibiotics inhibit RNA synthesis?

Answer 12

Rifampicin

Question 13

what is the mechanism of action of teicoplanin?

Answer 13

Teicoplanin is similar to vancomycin (e.g. a glycopeptide antibiotic), but has a significantly longer duration of action, allowing once daily administration after the loading dose

Question 14

what is the criteria for liver transplantation in paracetamol liver failure?

Answer 14

Arterial pH < 7.3, 24 hours after ingestion

or all of the following:
prothrombin time > 100 seconds
creatinine > 300 µmol/l
grade III or IV encephalopathy

Question 15

How is paracetamol overdose managed?

Answer 15

The minority of patients who present within 1 hour may benefit from activated charcoal to reduce absorption of the drug.

Acetylcysteine should be given if:
the plasma paracetamol concentration is on or above a single treatment line joining points of 100 mg/L at 4 hours and 15 mg/L at 15 hours, regardless of risk factors of hepatotoxicity
there is a staggered overdose* or there is doubt over the time of paracetamol ingestion, regardless of the plasma paracetamol concentration; or
patients who present 8-24 hours after ingestion of an acute overdose of more than 150 mg/kg of paracetamol even if the plasma-paracetamol concentration is not yet available
patients who present > 24 hours if they are clearly jaundiced or have hepatic tenderness, their ALT is above the upper limit of normal
acetylcysteine should be continued if the paracetamol concentration or ALT remains elevated whilst seeking specialist advice

Question 16

Why is acetycysteine given over 1 hour now instead of 15 minutes?

Answer 16

Acetylcysteine is now infused over 1 hour (rather than the previous 15 minutes) to reduce the number of adverse effects.

Question 17

What is the common reaction to Acetylcysteine?

Answer 17

Acetylcysteine commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release). Anaphylactoid reactions to IV acetylcysteine are generally treated by stopping the infusion, then restarting at a slower rate.

Question 18

Why should you not give hypotonic intravenous fluids to children?

Answer 18

In paediatric patients, there are at higher risk of hyponatraemic encephalopathy. This is most noted in those who receive hypotonic intravenous fluids such as 0.45% sodium chloride.

Question 19

what drugs commonly cause urticaria?

Answer 19

aspirin
penicillin
NSAIDs
Opiates

Question 20

what is the mechanism of action of unfractionated heparin?

Answer 20

Unfractionated heparin activates antithrombin III, forms a complex that inhibits thrombin, factors Xa, Ixa, Xia and XIIa

Question 21

What’s the action of LMWH?

Answer 21

increases the action of antithrombin III on factor Xa

Question 22

What is HIT?

Answer 22

Heparin-induced thrombocytopaenia (HIT)
> immune mediated - antibodies form against complexes of platelet factor 4 (PF4) and heparin
> these antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors
> usually does not develop until after 5-10 days of treatment
> despite being associated with low platelets HIT is actually a prothrombotic condition
> features include a greater than 50% reduction in platelets, thrombosis and skin allergy
> address need for ongoing anticoagulation:
direct thrombin inhibitor e.g. argatroban
danaparoid

Question 23

How can heparin overdose be reversed?

Answer 23

Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH.

Question 24

What is IVIG used for?

Answer 24

primary and secondary immunodeficiency
idiopathic thrombocytopenic purpura
myasthenia gravis
Guillain-Barre syndrome
Kawasaki disease
toxic epidermal necrolysis
pneumonitis induced by CMV following transplantation
low serum IgG levels following haematopoietic stem cell transplant for malignancy
dermatomyositis
chronic inflammatory demyelinating polyradiculopathy

Question 25

What antibiotic is contraindicated in G6PD deficiency?

Answer 25

Ciprofloxacin is contraindicated in G6PD deficiency.
It can lead to potentially fatal haemolytic anaemia

Question 26

What is the target of rituximab?
What is it effective in treating?

Answer 26

Rituximab - monoclonal antibody against CD20 antigen on B lymphocytes.
It binds to the CD20 molecules on the surface of these cells leading to cell death either through complement-dependant cytoxicity or antibody-dependant cellular toxicity.
his makes rituximab effective in treating diseases characterised by excessive, malignant, or dysfunctional B cells such as non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.

It is also used in the treatment of rheumatoid arthritis

Question 27

How are monoclonal antibodies manufactured?

Answer 27

somatic cell hybridisation
this involves the fusion of myeloma cells with spleen cells from a mouse that has be immunised with the desired antigen. The resulting fused cells are termed a hybridoma and act as a factory for producing monoclonal antibodies

Question 28

what is one limitation of monoclonal antibodies?

Answer 28

The main limitation to this is that mouse antibodies are immunogenic leading to the formation of human anti-mouse antibodies. This problem is overcome by a process known as humanising. One method involves combining the variable region from the mouse body with the constant region from a human antibody.

Question 29

What is the action of Infliximab and what is it used in ?

Answer 29

infliximab (anti-TNF): used in rheumatoid arthritis and Crohn’s

Question 30

What is the action of cetuximab and what is it used in?

Answer 30

cetuximab (epidermal growth factor receptor antagonist): used in metastatic colorectal cancer and head and neck cancer

Question 31

what is the action of trastuzumab and what is it used in?

Answer 31

trastuzumab (HER2/neu receptor antagonist): used in metastatic breast cancer

Question 32

what is the action of alemtuzumab and what is used in?

Answer 32

alemtuzumab (anti-CD52): used in chronic lymphocytic leukaemia

Question 33

what is the action of abciximab and what is it used in?

Answer 33

abciximab (glycoprotein IIb/IIIa receptor antagonist): prevention of ischaemic events in patients undergoing percutaneous coronary interventions

Question 34

what is the action of OKT3 and what is it used in?

Answer 34

OKT3 (anti-CD3): used to prevent organ rejection

Question 35

Which patients are at risk of developing hepatoxocity following paracetamol overdose?

Answer 35

patients taking liver enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine, chronic alcohol excess, St John’s Wort)
malnourished patients (e.g. anorexia nervosa) or patients who have not eaten for a few days

Question 36

what may actually be protective against developing hepatotoxicity?

Answer 36

Interestingly, acute alcohol intake, as opposed to chronic alcohol excess, is not associated with an increased risk of developing hepatotoxicity and may actually be protective.

Question 37

how does metformin cause b12 deficiency?

Answer 37

by altering small bowel motility, leading to bacterial overgrowth and deconjugation of bile salts, which in turn impairs B12 absorption.

Question 38

what is the mechanism of action of metformin?

Answer 38

acts by activation of the AMP-activated protein kinase (AMPK)
increases insulin sensitivity
decreases hepatic gluconeogenesis
may also reduce gastrointestinal absorption of carbohydrates

Question 39

what are the adverse effects of metformin?

Answer 39

gastrointestinal upsets are common (nausea, anorexia, diarrhoea), intolerable in 20%
reduced vitamin B12 absorption - rarely a clinical problem
lactic acidosis with severe liver disease or renal failure
it is now increasingly recognised that lactic acidosis secondary to metformin is rare, although it remains important in the context of exams

Question 40

what are the contraindications to metformin?

Answer 40

CKD - it should be reviewed if creatinine is > 130ummol/l or eGFR < 45 and stopped if the creatinine is > 150 µmol/l (or eGFR < 30 ml/min)

metformin may cause lactic acidosis if taken during a period where there is tissue hypoxia. Examples include a recent myocardial infarction, sepsis, acute kidney injury and severe dehydration

iodine-containing x-ray contrast media: examples include peripheral arterial angiography, coronary angiography, intravenous pyelography (IVP); there is an increasing risk of provoking renal impairment due to contrast nephropathy; metformin should be discontinued on the day of the procedure and for 48 hours thereafter

alcohol abuse is a relative contraindication

Question 41

What are the clinical features of ecstasy poisoning?

Answer 41

neurological: agitation, anxiety, confusion, ataxia
cardiovascular: tachycardia, hypertension
hyponatraemia
this may result from either syndrome of inappropriate ADH secretion or excessive water consumption whilst taking MDMA
hyperthermia
rhabdomyolysis

Hyperthermia

Question 42

How does Ecstasy cause hyperthermia?

Answer 42

occurs due to increased serotonin release in the hypothalamus, which regulates body temperature. Additionally, the use of ecstasy in club settings where users are dancing and overheating can exacerbate this effect.

Question 43

How is ecstasy poisoning managed?

Answer 43

supportive
dantrolene may be used for hyperthermia if simple measures fail

Question 44

What is the pathophysiology of carbon monoxide poisoning?

Answer 44

Carbon monoxide has a high affinity for haemoglobin and myoglobin resulting in a left-shift of the oxygen dissociation curve and tissue hypoxia.
Pathophysiology
carbon monoxide binds readily to haemoglobin, forming carboxyhaemoglobin → reduced oxygen-carrying capacity
in carbon monoxide poisoning the oxygen saturation of haemoglobin decreases leading to an early plateau in the oxygen dissociation curve

Question 45

What are the features of carbon monoxide poisoning?

Answer 45

headache: 90% of cases
nausea and vomiting: 50%
vertigo: 50%
confusion: 30%
subjective weakness: 20%
severe toxicity: ‘pink’ skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death

Question 46

How do you investigate for carbon monoxide poisoning?

Answer 46

pulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin

therefore a venous or arterial blood gas should be taken

typical carboxyhaemoglobin levels
< 3% non-smokers
< 10% smokers
10 - 30% symptomatic: headache, vomiting
> 30% severe toxicity

an ECG is a useful supplementary investgation to look for cardiac ischaemia

Question 47

How do you manage carbon monoxide poisoning?

Answer 47

100% high-flow oxygen via a non-rebreather mask
from a physiological perspective, this decreases the half-life of carboxyhemoglobin (COHb)
should be administered as soon as possible, with treatment continuing for a minimum of six hours
target oxygen saturations are 100%
treatment is generally continued until all symptoms have resolved, rather than monitoring CO levels

hyperbaric oxygen
due to the small number of cases the evidence base is limited, but there is some evidence that long-term outcomes may be better than standard oxygen therapy for more severe cases
therefore, discussion with a specialist should be considered for more severe cases (e.g. levels > 25%)
in 2008, the Department of Health publication ‘Recognising Carbon Monoxide Poisoning’ also listed loss of consciousness at any point, neurological signs other than headache, myocardial ischaemia or arrhythmia and pregnancy as indications for hyperbaric oxygen

Question 48

What is the mechanism of action of Aspirin?

Answer 48

Aspirin works by blocking the action of both cyclooxygenase-1 and 2. Cyclooxygenase is responsible for prostaglandin, prostacyclin and thromboxane synthesis. The blocking of thromboxane A2 formation in platelets reduces the ability of platelets to aggregate

Question 49

Why can rifampicin decrease the INR in patients taking warfarin

Answer 49

Rifampicin is a potent inducer of the cytochrome P450 enzyme system, which is responsible for the metabolism of warfarin. This induction leads to an increased clearance of warfarin and thus, a decreased INR.