Adverse Drug Reactions & Poisoning

Question 1

What does the clinical effectiveness of a first order drug after its been stopped depend on?

Answer 1

Therapeutic window

Minimal effective [drug]plasma

Question 2

How is paracetamol metabolised?

Answer 2

60% conjugated with glucuronide
30% conjugated with sulfate
10% oxidised by CYP450 to NAPQI (toxic)

NAPQI conjugated with glutathione to inactive metabolites

Question 3

What causes the toxic effects in paracetamol overdose?

Answer 3

Metabolism via gluronide & sulfate is saturated

Conjugation of NAPQI with glutathione is saturated

Build up of NAPQI causing liver damage (via free radicals)

Question 4

What is the treatment for paracetamol overdose?

Answer 4

1hr = ?activated charcoal (reduced absorption, disgusting)

4-8hrs and less than 12g or 150mg/kg = consult [paracetamol]

8hrs+ (or time and amount unknown) = start treatment immediately

Replace glutathione to reduce NAPQI concentration by giving N-acetylcysteine

note: can discontinue treatment after consulting [paracetamol] graph
note: more at risk of liver damage if mixed overdose/concurrent alcohol

Question 5

How would you calculate the loading dose required for a dose of phenytoin (92% salt given) for a 100kg man when the volume of distribution is 0.7l/kg and the [drug]target at steady state is 20mg/l?

(Loading dose = Vd x [drug]target at steady state)

Answer 5

Vd = 0.7l/kg [drug]target at steady state = 20mg/l

Vd = 0.7l/kg x 100kg = 70l

Loading dose = 70l x 20mg/l = 1400mg

1.4g/0.92 = 1.5g loading dose required

Question 6

How does the volume of distribution and clearance differ in children and the elderly?

Answer 6

Children:

• higher apparent volume of distribution
• higher clearance

Elderly:
- clearance reduced —> longer half life —> longer elimination time

Question 7

Give an approximation for the effect of reduced GFR on the clearance of a drug exclusively eliminated by the kidneys.

Answer 7

When GFR is halved, the half life roughly doubles

e. g. assuming t1/2 = 4hrs at GFR = 90ml/min/1.73m2
note: in CKD this can be compensated for better than AKI

Question 8

What are some common areas of actions and modes of action of drugs?

Answer 8

• cell surface receptors
• nuclear receptors
• enzyme inhibitors
• ion channel blockers
• transport inhibitors
• inhibitors of signal transduction proteins

Question 9

Define potency. How can it be calculated for agonists?

Answer 9

POTENCY = dose required to produce the desired biological response OR different doses of two drugs required to exact the same effect

Agonists: compare to agonist with 100% efficacy in vitro and add antagonist until EC50 is reached

Question 10

What is the effect on the dose response curve when increasing the [agonist] when competitive antagonists are present?

Answer 10

Dose response curve shifts to the right

i.e. EC50 changes but the maximal effect is the same

Question 11

What is the therapeutic index of a drug?

Answer 11

Range of doses that can effectively treat a condition whilst still remaining safe

EC50(adverse effect)/EC50(desired effect)

Question 12

How do changes in drug absorption effect drug ADME?

Answer 12

• changes in gut motility e.g. opiates, atropine both reduce gut motility
• interference with absorption e.g. Fe2+ and chelating agents, food and alcohol (reduced absorption —> reduced effect of drug)

Question 13

How do changes in drug distribution affect drug ADME?

Answer 13

• drugs with low volume of distribution more likely to interact with drugs that also have a low volume of distribution (and vice versa) due to competition at binding sites

Question 14

Where do drugs with low and high volumes of distribution distribute?

Answer 14

Low Vd:

• blood
• intracellular spaces

High Vd:

• muscle
• fat
• extracellular spaces

Question 15

How do changes in drug excretion affect drug ADME?

Answer 15

• reduced protein binding —> increased free [drug] —> increased excretion
• inhibition of tubular secretion —> increased [drug]plasma ———–> reduced excretion

Question 16

How do changes in drug metabolism affect drug ADME?

Answer 16

• inhibition of CYP450 (quick onset; related to half life and clearance of affected drug, plasma conc. at time of interaction)
• enzyme induction e.g. increased transcription/translation or slower degradation (usually phase 1 processes; rate depends on drug and enzyme in question)

Question 17

Give some examples of substances which induce CYP450 enzymes. What effect does this have on drugs metabolised by CYP450?

Answer 17

• phenytoin
• carbamazepine
• barbituates
• rifampicin
• alcohol (chronic)
• sulphonylureas
• St. John’s Wort

Increased activity of CYP450 —> drugs metabolised by CYP450 more rapidly —> reduced effect of drug

Question 18

Give some examples of drugs which inhibit CYP450 enzymes. What effect does this have on drugs metabolised by CYP450?

Answer 18

• omeprazole
• disulfarim
• erythromycin
• valproate
• isoniazid
• cimetidine (grapefruit juice)
• ciprofloxacin
• alcohol (acute)
• sulfonamides

Inhibition of CYP450 —> drugs metabolised by CYP450 more slowly —> increased effect of drug

Question 19

What are some important drug interactions with warfarin?

Answer 19

Aspirin:

• augments anti-thrombotic action of warfarin
• displaces warfarin from plasma proteins —> increases [warfarin]free

Cranberry juice:
- inhibits CYP isoform which metabolises warfarin —> reduced clearance of warfarin —> increased anticoagulant effect of warfarin

Question 20

How does renal disease affect drug ADME?

Answer 20

Reduces GFR (acute or chronic)

• > reduced clearance of renally excreted drugs e.g. digoxin, aminoglycoside antibiotics
• > disturbance of electrolytes
• > nephrotoxins e.g. aminoglycoside antibiotics

+ nephrotic syndrome —> hypoalbuminaemia —> competition between drugs for albumin binding sites

Question 21

How does hepatic disease affect drug ADME?

Answer 21

• reduced clearance of drugs metabolised in liver
• reduced CYP450 activity
• hypoalbuminaemia e.g. liver failure, malnutrition —> competition between drugs for albumin binding sites

Question 22

How does heart disease affect drug ADME?

Answer 22

Reduced cardiac output

• > excessive response to hypotensive agents
• > reduced hepatic perfusion —> reduced clearance
• > reduced renal perfusion —> reduced clearance
• > oedema in gut —> reduced absorption

Question 23

Define an adverse drug reaction.

Answer 23

Unwanted or harmful reaction which occurs after administration of a drug and is suspected or known to be due to drug(s)

Question 24

Contrast on target and off target ADRs.

Answer 24

On target ADRs = exaggerated therapeutic effect of drug

• most likely due to increased dose or factors affecting pharmacodynamics and pharmacokinetics
• e.g. hypotension caused by anti-hypertensives
• can affect same receptor in different tissues e.g. antihistamines also act in CNS to cause drowsiness

Off target ADRs = drugs interacting with other receptor types secondary to target receptors OR metabolites acting as toxins OR inappropriate immune response
- e.g. paracetamol overdose due to metabolite toxicity

Question 25

How can the different types of ADR be classified?

Answer 25

A-ugmented pharmacologic effects (dose-related) e. g. insulin causing hypoglycaemia, diarrhoea & rash with antibiotics - dose-dependent - predictable - common - high morbidity (usually mild), low mortality - genetic factors may be important - ~80% of all ADRs B-izzare effects (unpredictable) e. g. penicillin anaphylaxis, troglitazone (diabetic drug) withdrawn after causing liver disease - not expected from known pharmacology - independent of dose - rare - high mortality - usually dependent on uncharacteristic host factors - ~20% of all ADRs C-hronic effects (only occur after prolonged treatment) e.g. iatrogenic Cushing's caused by prednisolone D-elayed effects (occur a long time after treatment) e.g. secondary cancers caused by radiation for Hodgkin's lymphoma E-nd of treatment effects (occur when a drug is stopped) e.g. withdrawal seizures after anti-epileptics are stopped Components of ADRs: 1. Dose 2. Susceptibility of patient 3. Time course Severity: MAJOR = permanent/life-threatening MODERATE = requiring additional treatment MILD = trivial/unnoticeable

Question 26

Give some examples of factors which increase the risk of ADRs occurring.

Answer 26

- ignorant/inappropriate/reckless prescribing - polypharmacy - patients at extremes of age (co-morbidities, altered renal and hepatic states) - multiple medical problems - use of drugs with narrow therapeutic indices (increased risk of toxicity) - drugs used near their minimum effective concentration (increased risk of treatment failure if metabolism is increased)

Question 27

What are some classes of drugs which are frequently responsible for ADRs?

Answer 27

Anti-convulsants (esp. phenytoin and carbamezepine) Anti-coagulants e.g. warfarin Anti-biotics (esp. quinolones, macrolides, rifampicin) Anti-depressants/anti-psychotics e.g. MAO-inhibitors Anti-arrhythmics e.g. amiodarone

Question 28

What are some biological and pharmacological factors which cause variability in drug response?

Answer 28

BIOLOGICAL = - body weight & size - age - sex - genetics (CYP polymorphisms) - health conditions - placebo effect PHARMACOLOGICAL = - dose, formulation, route of administration - drug resistance/tolerance - drug allergy - drug interactions (chemical/physical, GI absorption, protein binding/distribution, metabolism, excretion, receptors, changes in pH or electrolytes)

Question 29

Describe the mechanism of digoxin poisoning.

Answer 29

Properties of digoxin: - large apparent volume of distribution ---> long half life (~40hrs) - predominantly excreted by kidneys (therefore take age and renal function into account when prescribing) - time to steady state (5 half lives) ---> over 1 week (therefore loading dose used) Causes of digitoxin poisoning: - overdose - AKI (reduced clearance) S&S: - bradycardia - vomiting - xanthopsia (yellow vision)

Question 30

Why are some ADRs are not detected during testing?

Answer 30

Uncommon ADRs require a large amount of patients to trial the drug in order to detect e.g. ADRs with an incidence of 1/100 ---> once case of ADR detected when 300 patients take the drug, ADRs with an incidence of 1/10,000 ---> once case of ADR detected when 30,000 patients take the drug Some drugs only detected when drug is prescribed routinely (due to co-morbidities, longer duration of treatment)

Question 31

What are the limitations of pre-marketing clinical studies in identifying drug safety issues?

Answer 31

- selectively small no. of patients treated - frequent exclusion of patients who may be at an increased risk of ADRs (age, co-morbidities, polypharmacy) - structure of clinical studies = limited duration, experienced & specialist investigations

Question 32

In general, what are the different ways in which ADRs can be identified in routine practice?

Answer 32

Spontaneous reporting = recognition of possible ADR in clinical practice, establishing possible causal relationship, and reporting observations - post-marketing surveillance - publish case-reports or studies - MHRA via Yellow Card Scheme Cohort studies = identify group of patients exposed to a drug & compare to (non-randomised) control group, then observe to determine rate of occurrence of ADRs (prospective & retrospective) e.g. cimetidine cohort study showed increased morbidity and mortality (may be due to disease process) Case-control studies = select cases with ADRs/disease and match to controls without ADRs/disease, compare exposure (drug) to calculate odds ratio e.g. bleeding peptic ulcer associated with NSAIDs (increased risk with increased potency of NSAID)

Question 33

What are the advantages and disadvantages of identifying ADRs via spontaneous reporting?

Answer 33

Advantages: - operates as soon as drug is marketed - covers entire population receiving drug - involves all doctors - overlooks all drugs - detects common and rare reactions - continues indefinitely - inexpensive - may identify risk factors - may allow characterisation of ADR note: good at generating new ADR signals/hypotheses but does not usually confirm this Disadvantages: - gross under-reporting of possible ADRs (numerator unknown) - delays in reporting - poor quality data e.g. other drugs given not recorded, reaction not explained properly, timeline of drug therapy not given - misleading reports - difficulty recognising previously unknown ADRs - no control group - denominator data poor (population data) note: cannot calculate incidence as numerator & denominator are unknown

Question 34

What are the advantages and disadvantages of identifying ADRs using cohort studies?

Answer 34

Advantages: - allows hypothesis generation & testing e.g. type of ADR/death Disadvantages: - expensive (esp. prospective) - subjects lost to follow-up

Question 35

What are the advantages and disadvantages of case-control studies?

Answer 35

Advantages: - good for rare ADRs or where there is a long latency - can give a quick answer (if a suitable database is available) - low cost - indicate degree of increased risk Disadvantages: - requires prior hypothesis - suitable database often not available - many biases - expertise required - credibility

Question 36

Give some examples of Yellow Card scheme controversies.

Answer 36

Panorama programme highlighted increased suicide risk in adolescents treated with Paroxetine/Seroxat (has increased the rate of patients reporting ADRs - ?reduced quality of data) Under-reporting of ADRs: - FATAL (15% of PEs with OCP reported) - SERIOUS (35% of drug-induced neutropenias reported) - clinical studies (once case of ADR in practolol in pre-launch studies v.s. 200 within 5 weeks of publication) - audits (zero Yellow Cards completed for 2 serious ADRs in a population of 22 patients)

Question 37

What are some factors contributing to the under-reporting of ADRs?

Answer 37

FAILURE Failure of patient to report ADR (or be asked?) ADR too trivial Ignorance of reporting and its procedures Lack of time Uncertainty of relationship of drug to presentation Relating to duration of marketed drug Experience & familiarity with the ADR