Adverse Drug Reaction: An unwanted, unintended or harmful reaction as a consequence of drug administration

Sakurai 2016

2017B 16: 44% of candidates passed this question.

Candidates should have provided a definition of adverse drug reactions and then a classification. There are at least two widely accepted systems for classification, either was acceptable; though candidates often switched between both which led to a less structured answer. The WHO classification is comprehensive and logical, though both Rang and Dale and Goodman and Gilman also have sections on this topic.
Common errors were the citing of examples with the incorrect mechanism, describing only drug interactions rather than all adverse reactions and focussing the answer on the 4 hypersensitivity reactions which could only score a low mark. Some candidates confused drug errors with adverse reactions.

2012A 14: 1 (10%) of candidates passed.

This question was very poorly answered. Textbooks give different classifications so some largesse was allowed, but both immunologic and physicochemical (kinetic and dynamic) were expected. Marks were allocated for both type and an example – some candidates failed to provide examples or listed a drug side effect without explanation. Some candidates were ‘creative’ with classification systems but where appropriate examples were given marks were awarded. No marks were gained for detailed descriptions of LD50 and therapeutic ratios.

Pharmaceutical interactions:

• Physicochemical incompatibility b/t drugs
  • causes precipitation of drug (Eg. STP (alkaline) + SCh (acidic))
• Absorption or binding to containers (Eg. GTN + PVC lines)
• Degradation of drug (Eg. insulin denatures in solution of dextrose)

Pharmacodynamic interactions:

• One drug alters the body’s response to another at a given plasma [drug] and can be either
  • antagonistic
    • Direct (morphine and naloxone) or indirect
  • additive
  • synergistic
    • Inhibition of enzymatic inactivation e.g. clavulanic acid and amoxicillin
    • Enhanced agent uptake e.g. gentamicin and penicillin
• Direct interaction
  • Drugs act at same receptor site for effect
    • naloxone + opioids → direct antagonism
    • N2O + volatiles → direct additivity
• Indirect interaction
  • Drugs act at different receptor sites for same effect
    • Opioids + volatiles → indirect synergism
    • atropine + neostigmine → indirect antagonism

Pharmacokinetic interactions:

• Absorption
  • Mainly due to altered oral absorption a/w:
    • Complex formation: tetracycline + Ca in milk/antacids
      • Altered gastric emptying/intestinal motility
      • opiates ↓ intestinal motility → ↓ absorption of drugs absorbed in small intestine (paracetamol)
    • metoclopramide ↑ intestinal motility → ↓ absorption of drugs absorbed in stomach (Eg. cimetidine)
    • Altered gastric and intestinal pH
      • ↑ gastric pH by antacids impairs absorption of weakly acidic drugs
  • Altered parental absorption a/w localised vasoconstriction (Eg. adrenaline + LA)
• Distribution
  • Competition by drugs for plasma protein binding site → affects drugs that:
    • Are highly protein-bound drugs (Eg. warfarin, diazepam, phenytoin)
      • → ↑ unbound % in plasma
    • Have enzyme system close to saturation or zero-order kinetics (Eg. phenytoin)
      • →↑ displacement of drug and ↑ unbound % cannot be cleared effectively
      • → large ↑ unbound % in plasma
  • Drugs that alter C.O. impact on distribution of drugs to target, peripheral tissues
    • β-blockers ↓ C.O. → slow onset/offset times of drugs reliant on distribution
• Metabolism
  • Inhibition/induction of microsomal enzymes (Eg. CYP450)
    • Enzyme induction → resulting in ↓ plasma [drug]
    • Enzyme inhibition → resulting in ↑ plasma [drug]
  • Inhibitors of non-microsomal enzymes (Eg. MAOi, COMTi)
• Elimination
  • ↓ urinary excretion
    • Competition for tubular transport system occurs with weak organic acids (Eg. probenecid + penicillin)
  • Changes in urine pH
    • Alkalinising agents (Eg. NaHCO3/acetazolamide) → ↑ excretion of weak acids
  • Changes in urine volume
  • Changes in biliary excretion
    • Phenobarbital ↑ bile flow and biliary conjugation of drugs

Gladwin 2016

2021B 15: 54% of candidates passed this question.
This question has been asked previously, the answer template expected some description rather than a list of drug interactions. Generally, examples were provided for each type of interaction. The examiners reported too many vague, factually incorrect descriptions of the mechanisms and in some cases a very limited classification.

2017A 03: 44% of candidates passed this question.

Candidates with a well organised answer scored highly. A list of drug interactions was not sufficient to pass, as the question asked to ‘describe’ the mechanism of drug interactions. Some candidates described the interaction but did not give examples. Common mistakes included using incorrect examples for a particular mechanism and describing the mechanism of action of drugs instead of drug interactions.

2015A 09: 33 % of candidates passed this question.

This question was best approached by classifying drug interactions as physicochemical or pharmaceutical, then pharmacokinetic and finally pharmacodynamic. Pharmacokinetic drug interactions could then be further sub classified into those affecting the rate and extent of absorption of other drugs by mechanisms such as surface adsorption, chelation, altering gastric pH and altering gastrointestinal motility. Drug interactions affecting the distribution of drugs mainly involve competition for protein binding and the displacement of highly protein bound drugs. Drug metabolism interactions usually involve drug induction or inhibition of hepatic microsomal enzymes either increasing or decreasing the metabolism of other drugs.
Examples of drug interactions affecting drug excretion include drugs altering urinary pH or drugs altering the tubular rate of secretion of other drugs. Pharmacodynamic drug interactions include potentiation of one drug by another, antagonism and combined toxicity at the tissue level. Combined toxicity can be due to the potentiation of adverse effects of two drugs.This is a broad question with plenty of opportunity to score marks. A structured approach such as that described above and providing an example for each mechanism was important.

Pharmacokinetic:

• Absorption
  • Skin: Faster absorption of transdermal drugs such as Fentanyl
  • GIT:
    • Less gut motility may delay absorption
    • Laxatives and prokinetics increase gastric emptying and reduce absorption of oral agents
• Distribution
  • Less total body water and lean body mass
    • water soluble drugs (digoxin) have smaller Vd
    • higher central compartment concentration
  • Increased fat content %
    • fat soluble drugs (diazepam) have higher Vd
  • Reduced albumin
    • the free fraction of protein bound drugs (warfarin) is increased
  • Reduced cardiac output
    • reduced organ ­flow
    • altered redistribution phase
    • important in drug termination (thiopentone)
• Metabolism
  • ↓ Hepatic blood flow – high Extraction drugs (CCB) have ↓ clearance
  • ↓ Enzymatic activity
    Phase I > Phase II.
• Elimination
  • Loss of nephron number with age reduces renal clearance
  • Reduced GFR / nephrons / renal blood ­ow
    • renal drug excretion slowed
    • un-metabolised drugs (aminoglycosides) or active metabolites have prolonged activity

Pharmacodynamic:

• Increased sensitivity to sedatives, opioids, and hypnotics
• Decreased sensitivity to β-agonists and antagonists
• Decreased MAC
• Polypharmacy increases potential for drug interactions

JC 2019

2010B 20: 8 (53%) of candidates passed this question.

As the general population ages, and many elderly are admitted to intensive care units and/or encountered during intensive care ward consultations, this topic is highly relevant. Unfortunately candidate performance generally lacked sufficient depth and breadth in this area. Good answers were expected to mention changes in body compartments (eg total body water, lean body mass decrease, etc), consequences of changes in organ function (eg deteriorating glomerular filtration rate, reduced liver blood flow, etc), alterations in protein levels and binding, increased likelihood of drug interactions and the influence of disease states.
Syllabus: Generic Pharmacology III2d. References: Millers’ Anaesthesia Chp 19

Pharmacokinetics:

Absorption:

• ↓ Oral absorption
  • ↑ N/V
  • ↓ gastric emptying during labour
  • ↓ gastric motility 2° to intestinal compression
  • ↑ gastric absorption
  • ↓intestinal absorption due to ↓ intestinal blood flow
• ↑ IM/SC/transdermal absorption
  • ↑ skin blood flow
    • ↑ C.O. (by 30-40%)
    • ↓ SVR
• IV (↑ onset)
• Neuraxial
  • ↓ epidural space 2° to EDVs
  • ↓ spinal and epidural doses
• Inhalational
  • Progesterone-mediated ↑ MV (by 50-70%)
  • ↑ FA/FI ratio (= uptake

Distribution:

• ↑ VD (↑ TBW/ECF and fat)
  • ↑ TBW/ECF (by 50%) (important for polar/ionized drugs)
  • ↑ body fat % (important for lipid soluble drugs)
• ↓ plasma protein 2° to dilutional effect
  • ↓ albumin →
    • ↑ free % of acidic drugs (Eg. STP, propofol)
    • ↓ dose required
    • ↑ transplacental transfer of drug.
  • ↓ A1AGP (by 30%) →
    • ↑ free % of basic drugs (Eg. LA, β blockers)
    • ↓ dose required
    • ↑ transplacental transfer of drug
• Ionisation (mild ↑pH alters ionisation based on pKa)
  • ↑ MV = mild respiratory alkalosis
    • ↑ transplacental transfer of basic drugs as they will have ↑ % in unionized form
      • (Base in base is less ionised)
  • ↑ ion trapping in more acidotic foetal circulation

Metabolism:

• Progesterone:oestrogen ratio
  • Progesterone → induces hepatic enzymes
  • Oestrogen → inhibits hepatic enzymes
• ↓ plasma cholinesterase (30%)
• Placenta metabolises some drugs
• Foetal liver has functioning CYP450
  • Can metabolise drugs
  • But requires transfer back to maternal circ for conjugation

Excretion:

• ↑ RBF/GFR (50%)
  • ↑ clearance/↓ elimination t1⁄2 of water-soluble drugs
• ↑ MV/↓FRC
  • ↑ washout of volatile agents

Pharmacodynamics:

• Decreased MAC – Increased sensitivity to volatile anaesthetics
• Increased LA sensitivity due to decreased α1-glycoprotein
• Increased sensitivity to IV anaesthetics

Gladwin / JC 2019

2020A 09: 7% of candidates passed this question.

Answers framed around absorption, distribution, metabolism and excretion performed better. Some brief comments on physiology are required as the basis for pharmacokinetic change, but discussion of physiology that was not then specifically related to pharmacology did not score marks. Specific ‘real life’ examples necessitating change in practice or prescribing were well regarded e.g. reduction in spinal/epidural local anaesthetic dosing. Vague statements about possible or theoretical changes were less well regarded.

2016B 16: 84% of candidates passed this question.

The best answers used tables and key pharmacological headings for comparisons, and avoided long sentences/ paragraphs.
An answer that correctly considered the following sections would be awarded a very good pass: Presentation, pharmacodynamics, mechanism of action, organ effects, side effects and pharmacokinetics.
Many candidates failed to identify agents as natural / synthetic catecholamines.
Few answers correctly mentioned the available preparations of these drugs or considered the structure activity relationships. Only 3 candidates commented that dobutamine is a racemic mixture.
Intracellular second messenger pathways were often incorrectly recounted or not mentioned at all. Pharmacodynamic effects on all organ systems, and all CVS parameters (HR, inotropy, PVR, SVR, SBP/DBP/MAP, regional circulations) should be considered. Metabolic fate and clinical dosage ranges were frequently incorrectly quoted.

2011A 11: 4 (33%) of candidates passed this question.

Answers framed around the structure of absorption, distribution, metabolism and excretion performed better. An approach based on the physiologic changes of pregnancy performed less well because important areas of pharmacokinetics were omitted. The effects of pregnancy on oral absorption should have included a discussion of gastrointestinal motility, nausea and vomiting and gut blood flow. Absorption from sites other than the gastrointestinal tract, such as skin, lung and the epidural space and the effect of pregnancy on these should have been mentioned. Many answers were vague on the effects of increases in total body water and plasma volume and cardiac output and changes in plasma protein binding on the distribution of drugs. Most answers did not provide enough specific examples. The effect of pregnancy hormones on liver enzyme activity were mentioned by few.
Syllabus: Generic Pharmacology III 2d
Recommended sources: Foundations of Anaesthesia: Basic clinical Science.
Hemmings and Hopkins, and Anaesthesia, Miller.

Physiological factors

• Drug transfer via diffusion, facilitated diffusion, secondary active transport, pinocytosis (e.g. immunoglobulins)/
• Diffusion according to Fick’s Law (see eqn):
  where
  • MW = Molecular weight
    • Drugs <500da freely permeable
  • Δ[Drug] = Concentration gradient between maternal anf foetal blood
  • SA = Surface area for diffusion
    • 16m² compared to alveolar surface area of 60m²
  • h = thickness of diffusion membrane
    • 3.5 microns compared with 0.5 for alveolar diffusion membrane

• Drug delivery to uterus
  • Blood flow ~750ml/min (Aprrox 600ml/min to placenta)
  • No autoregulatory mechanisms
• Placental transporters
  • MDR1 and p-glycoprotein efflux drugs out of foetal circulation
• Placental metabolism
  • P450 reactions
    • Pentobarbitol metabolized by placenta

Drug factors

• Drug size
  • Heparin too large to permeate (Warfarin can)
• Lipophilicity
  • Highly lipophilic drugs more permeable (Fentanyl > morphine)
• Ionization
  • Charged molecules less permeable (Glycopyrrolate < atropine)
  • Ionization trapping
    • Alfentanyl (pKa 6.5) ~90% unionized at physiological pH → more permeable
    • As alfentanyl crosses into foetal circulation, becomes more ionized in lower pH → trapped in foetal circulation
• Protein binding
  • Reduces permeability

Disease factors

• Inflammation of placental barrier increases permeability of drugs

Sakurai 2016

2009A 24: Pass rate: 30%

Good answers showed an understanding of diffusion, the influence on transfer of lipid solubility, molecular size, degree of ionisation and protein binding. They also made reference to placental transporters and placental metabolism. Extra points were scored for mentioning that the real concern is teratogenicity to the foetus.
Syllabus O2 2d
Reference: Katzung 10th edition p 971-973.

2008A 22: No candidates (0%) passed this question.

The main points candidates were expected to know included the passive and active mechanisms that regulate the transfer of drugs across placenta and the potential clinical implications of drugs use in pregnancy in order to pass this question.
Good answers to this question included examples to all the possible mechanisms that can affect the transport of drugs across placenta.
The common omissions were degree of ionisation, active transporters, placental metabolism, explanation on the interaction between protein binding and ionisation of a drug in regulating placenta transfer, and the expected molecular size or weight of a drug that affects passive placental transfer of the drug.

Pharmacodynamics

• Receptor resistance
  • Insulin resistance secondary to obesity

Pharmacokinetics

Absorption

• Increased cardiac output
  → Delayed onset of action of inhalational agents (volatile anaesthetic agents)
• Decreased subcutaneous absorption due to tissue binding (heparin)
• Failure of IM administration due to increased depth (adrenaline is anaphylaxis)

Distribution

• Increased total body fat
  • Increased volume of distribution of lipophillic drugs
    • Barbiturates, benzodiazepines → should be administered according to actual weight
    • Lipid insoluble drugs should be dosed according to ideal weight
• Decreased fractional proportion of total body water
• Increased blood volume and cardiac output
  • May require increased loading dose for therapeutic effect (thiopentone)
• Displacement of protein bound drug due by fatty acids (propofol)

Metabolism

• Decreased hepatic function due to non-alcoholic steatohepatitis
  • Increased T_1/2b of drugs metabolized by liver
• Increased plasma and tissue esterases
  • Increased metabolism of suxamethonium, remifentanyl

Excretion

• Increased cardiac output
  → Increased renal blood flow
  → Increased GFR
  → Increased tubular secretion
  → Increased renal clearance
• Increased T_1/2b  due to accumulation of lipid soluble drugs in fat, and slow redristribution into central component
  • Propofol, volatile anaesthetics

Sakurai 2016

2012B 13: 8 (36.4%) of candidates passed

This question could be approached by describing the effects of obesity on drug distribution, binding and elimination. Candidates that took this approach generally did better than those with a less structured approach. With obesity, fat body mass increases relative to the increase in lean body mass leading to an increased volume of distribution particularly for highly lipid soluble drugs, e.g. midazolam. However, the dosing of non-lipid soluble drugs, e.g. non-depolarising muscle relaxants, should be based on ideal body weight. An increase in blood volume and cardiac output associated with obesity may require an increased loading dose to achieve a therapeutic effect, e.g. thiopentone. Plasma protein binding of drugs may be decreased due to an increased binding of lipids to plasma proteins, resulting in an increased free fraction of drug. A reduction in plasma protein concentration due to an increase in acute phase proteins may also result in decreased plasma protein drug binding and increased free fraction of drug. Pseudocholinesterase levels are increased in obesity and therefore the dose of suxamethonium should be based on total body weight. Plasma and tissue esterase levels are increased resulting in the increased clearance of drugs by these enzymes e.g. remifentanil. Hepatic clearance is usually normal but may be impaired in liver disease caused by obesity. Renal clearance is usually increased due to increased body weight, increased renal blood flow and increased glomerular filtration rate. Renal clearance may be impaired in renal disease caused by obesity related diseases, e.g. diabetes. Insulin doses may be increased due to peripheral insulin resistance in type 2 diabetes caused by obesity. Most answers were deficient in examples of drugs to illustrate the effects of obesity on drug pharmacology

Absorption

• IV
  • Unchanged
• Oral
  • If GI inflammation → increased GI absorption (aminoglycosides)
  • Concomittant drug administration may inhibit intestinal transporters (amiodarone inhibits p-glycoprotein) or hepatic enzymes (valproate inhibits P450 enzymes) à Variable effect on bioavailability
  • If hepatic failure (i.e. ischaemic hepatopathy) → Decreased hepatic first pass effect → Increased oral bioavailability (aspirin)
  • Decreased splanchnic bloodflow (due to vasopressor agents, shock) → Decreased drug absorption → Decreased bioavailability
• IM/Subcut
  • Decreased peripheral blood flow due to shock, vasopressors → Delayed absorption (IM suxamethonium will delay onset)

Distribution

• Protein binding → albumin decreases as an acute phase reactant → Increased free drug fraction of protein bound drugs (propofol)
• pKa
  • Acids are ionized when pH >pKa, bases ionized when pH < pKa → acid base disturbances will alter drug ionization → permeability through cell membranes (Na channel blockers are less effective in acid environments)
• Volume of distribution
  • Renal failure, hepatic failure, heart failure + overzealous fluid resuscitation → increased total body water → Increased volume of distribution of drugs distributed to extracellular compartment

Metabolism

• Hepatic phase I (zone III) susceptible to ischaemia
  • Decreased phase I metabolism in shock (fentanyl metabolized by CYP450 3A4)
  • More global reduction of hepatic function in global hepatic failure
• Butylcholinesterase produced by liver → decreased levels in hepatic failure → decreased metabolism (suxamethonium → more drug delivery to NMJ)

Excretion

• Renal
  • Shock → decreased renal perfusion pressure (although renal blood flow may actually increase in distributive shock) → decreased glomerular filtration of drugs → Decreased clearance
  • Decreased plasma protein will promote glomerular filtration and filtration of free drug
  • Acute tubular necrosis → decreased tubular secretion of drugs → Decreased clearance
• Biliary
  • Hepatic failure → decreased biliary secretion

Mooney 2016

2022A 01: 47% of candidates passed this question.
The effects of critical illness on the physiological factors that influence drug pharmacokinetics was used to analyse the candidates understanding of this core pharmacological principle. Better responses were able to identify the key elements perturbed by critical illness as well as outlining outline the potential cause and effect on the specific PK aspect being discussed. Stronger answers also included specific drug examples. The failure to utilise a structure (absorption, distribution, metabolism, and elimination) with very superficial detail and limited examples limited marks and was common in poorly scoring answers.

2013A 13:
Most candidates answered the question under the subheadings absorption, distribution, metabolism and elimination. However, they didn’t give any details of the direction or mechanism of change, often used vague statements without specifically addressing the question and failed to give examples. The impact of the shock state on different kinetic parameters including absorption from skin, tissue, muscles, enteral absorption and inhalational was often overlooked. Similarly, the consequences of changes in volume of distribution, protein binding (e.g. albumin and globulin, ionisation) was poorly understood as was alteration in liver and kidney function. Although this topic is very broad candidates were asked to only outline the details of this topic.

Tolerance

Decreased pharmacological response of drug on repeated exposure, requiring larger subsequent doses for the same effect.

Tachyphylaxis

When tolerance occurs rapidly, in a dose-independent manner

Mechanisms

• Tolerance
  • Pharmacodynamic tolerance
    Persistent, high concentrations of ligand, causes receptor downregulation (decreased expression, affinity or activity)
    • e.g. Opioid tolerance → continual exposure leads to receptor de-coupling with the G-Protein, or decreased endocytosis-cycling leading to decreased second messenger pathway on ligand binding
  • Pharmacokinetic tolerance
    Persistent exposure to drug may induce expression of clearance mechanisms (induction of CYP450 enzymes in liver) leading to decreased drug reaching effect site
    • e.g. Ethanol tolerance → Induction of alcohol dehydrogenase reduce bioavailability of alcohol due to increased first pass metabolism
  • Behavioral tolerance
    Diminution of a drug-induced disruption of a goal-oriented behavior that is dependent on a learning process
    • e.g. Psychoactive drugs

• Tachyphylaxis
  • Depletion of intracellular stores of an effector, before resynthesis may occur
    • e.g. Ephedrine tachyphylaxis occurs due to depletion of stored noradrenaline

Sakurai 2016

2014B 15: 15% of candidates passed this question.

Tolerance is the requirement of higher doses of a drug to produce a given response. When this develops rapidly (with only a few administrations of the drug) this is termed tachyphylaxis. Various mechanisms exist by which tolerance occurs and these include cellular tolerance (e.g. neuronal adaptation to opioids or alcohol), enzyme induction and depletion of neurotransmitters. Few candidates knew a comprehensive list or had a classification system for the different types of tolerance. No candidate had a good definition of tachyphylaxis.

Pharmacokinetic factors

(Amount of drug reaching the receptor)

• Absorption
  • IV dose so should be 100%
  • dose variability between patients
• Distribution
  • Volume of distrib:
    • Body mass and ratio of fat:muscle di­fferences
    • pregnancy, cardiac output states
  • Protein binding:
    • low albumin states, other protein bound drugs
    • propofol has 98% protein binding and will be influenced
  • Blood pH
    • affects degree unionised which can cross lipid membranes
    • eg alkalotic state with thiopentone pKa 7.6
• Metabolism
  • Hepatic factors
    • liver disease may reduce metabolism
    • CYP enzymes (inhibited or upregulated) eg Ketamine
• Excretion
  • Renal impairment: on­set of eff­ect more dependent of redistribution, but can be prolonged if renally excreted

Pharmacodynamic factors

• Presence of endogenous or exogenous ligands
  • Endogenous: increased catecholamines may necessitate a higher induction dose
  • Exogenous:
    • medications which potentiate sedation opioids, benzodiazepines, volatiles
    • medications which reduce sedation – amphetamines
  • Variation in the number of receptors
    • Extremes of age
    • Previous exposure to the drug or similar – tolerance, tachyphylaxis

Variability in the response distal to the receptor

• Pharmocogenetic factors
  • idiosyncrasy
  • anaphylaxis
• Pathological and physiological factors
  • sepsis
  • CNS function

JC 2019

2011B 02: 15 (60%) of candidates passed this question.

This was a broad question that required some structure and organisation to score well. The issues around variability in both pharmacokinetics and pharmacodynamics, of which there are many, needed be covered. For example variability due to differences in organ function, age, metabolism, body composition, were just a few of the factors expected to be mentioned.

2008B 23: 2 (40%) candidates passed this question

This question required the candidate to provide some detail why a given dose of intravenous anaesthetic administered for the purpose of induction may result in a variable response between individuals. A logical division into pharmacokinetic and pharmacodynamic factors pertaining to the drug and how these are impacted by patient physiology, citing appropriate examples, was expected. Extremes of age, pregnancy, low and high cardiac output states, sympathetic tone, body habitus and factors impacting on drug redistribution and elimination should have been addressed. Extra marks were awarded for relevant discussion of pharmacogenetics. Discussion of the “bolus effect” versus slow infusion of an induction drug, relative to these factors should have been included. Mention of drug interactions, idiosyncratic reactions and relevant pathophysiology impairing organ function reserve was appropriate. The consequences of variability in drug response in terms of over- / underdosing, haemodynamic compromise, respiratory depression, delayed recovery and allergic reactions needed emphasis to demonstrate understanding of the significance of predisposing factors.
Effective answers to this question utilised either clear headings, or a tabular format, dividing what is a large topic into discrete areas. The lack of a structured approach to this question was invariably unsuccessful.
Syllabus Ref: G2a 2.c,d,e,f,g
Suggested Reading: Pharmacology and Physiology in Anaesthetic Practice / R K Stoelting –
4th ed – 2006. Chapters 4,6.