This chapter is related to one of the aims of Section D(iv) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe alterations to drug response due to pathological disturbance with particular reference to cardiac, respiratory, renal and hepatic disease". This is an expansive topic which would clearly cover pharmacokinetics and pharmacodynamics. Fortunately, no such SAQ has ever come up in the CICM primary or Fellowship exams. Ultimately, however, it is safest to assume that the examiners will one day come down upon their trainees with a question like "describe alterations to drug response due to critical illness", to which the unprepared candidate would not have a convenient response. Unless one is equipped with a suitable answer in short-term storage, this sort of thing would take much longer than ten minutes.

Historic SAQs not unlike the hypothetical one above have appeared in the exams.  Question 13 from the second Primary paper of 2013 and  Question 5 from the first Fellowship paper of 2011 both asked about the impact of critical illness on pharmacokinetics. In a written answer, pharmacokinetics probably occupies 90% of the response, and so the bulk of the discussion are exported to another pharmacokinetic-related chapter. Here, a tabulated structured answer is offered to the question, "how do pathological disturbance alter drug response". Where possible, references are noted to support the examples.

Influence of Organ System Pathology
on Pharmacodynamics and Pharmacokinetics
Pharmacokinetics Pharmacodynamics and interactions

Airway pathology

  • Absorption
    • Oral route may be impossible if swallowing is affected
    • Mucosal (buccal) absorption may be delayed following radiotherapy or oral surgery (eg. flap repair), or increased where there is airway hyperaemia (eg. airway burns)
  • Distribution
    • Distorted or abnormal airway anatomy may result in the deposition of aerosolised drug predominantly on the mucosa, bypassing first-pass metabolism
  • Elimination
    • Elimination of volatile anaesthetic agents is impeded by airway obstruction
  • Decreased physiological tolerance of sedative agents (eg. in OSA)
  • Increased airway smooth muscle reactivity (eg. from chronic smoke exposure) increases the sensitivity to other irritant substances
  • Drug effects (eg. antiocholinergic xerostomia) may influence the buccal absorption of other drugs

Respiratory pathology

  • Absorption
    • Inhaled route is obviously going to be ineffective if the patient is apnoeic
    • Poor respiratory function (eg. COPD) will result in decreased delivery of aerosolised particles (eg. of bronchodilator droplets)
  • Metabolism
    • Respiratory metabolism of many drugs (catecholamines, local anaesthetics, opioids, propanolol - Boer, 2003 ) is decreased when the lung is diseased (eg. ARDS or pneumonia)
  • Elimination
    • Elimination of volatile anaesthetic agents is obviously impossible if the patient is apnoeic
  • Respiratory pathology influences the response to induction agents (increased propensity to hypoxia)
  • Hypercapnia produces a narcosis which is additive with other sedative agents
  • Chronic exposure to beta-agonists, eg. in chronic asthma, may give rise to tolerance (Salpeter et al, 2004)

Cardiovascular pathology

  • Absorption
    • Decreased cardiac output decreases oral, gastrointestinal, intramuscular and subcutaneous absorption, and affects intravenous availability (eg. by prolonging  arm-brain circulation time)
  • Distribution
    • Volume of distribution may increase (eg. in fluid-overloaded cardiac disease) or decrease (eg. in haemorrhagic shock)
  • Metabolism
    • A low cardiac output reduces blood flow to clearance organs
    • This reduces the metabolism of drugs in the affected organ
    • Most affected are those drugs which have a high extraction ratio
  • Elimination
    • Decreased blood flow to organs of elimination obviously slows elimination
  • Cardiovascular disease increases the susceptibility to adverse effects (eg. QT prolongation, or hypotension from induction agents)
  • Chronic hypertension dampens clinical responses to routine doses of antihypertensive agents
  • Worsening CCF narrows the therapeutic window for beta-blockers and calcium channel blockers 
  • Maximal effect of diuretics is blunted by poor renal blood flow due to poor cardiac output (Lainscak et al, 2016)

Neurological pathology

  • Absorption
    • Intravenous drugs may be more bioavailable to the CNS tissues where the blood-brain barrier is broken, eg. malignancy or infection
  • Distribution
    • Changes in cerebral blood flow (eg. vasospasm following SAH) can decrease the delivery of drugs to brain parenchyma
  • Metabolism
    • Ischaemia oedema or infection can impair metabolism and transport of drugs at the choroid plexus (Ghersi-Egea et al, 2001)
    • Interaction between agents occurs at the level of metabolism (eg. MAOIs and sympathomimetics)
  • A decreased level of consciousness from primary CNS pathology is usually additive with the effects of sedatives
  • Change in receptor number or function through development of tolerance or sensitisation can decrease or increase the effects of CNS-active agents (eg. opiates)
  • Injuries to CNS can denervate large areas of muscle, giving rise to an increased number of NMJ receptors and an exaggerated response to suxamethonium

Electrolyte and acid-base derangement

  • Absorption
    • Effect of electrolyte or acid-base derangement on intestinal absorption may be erratic (mainly as the upshot of decreased gut motility
  • Distribution
    • Effect of electrolyte derangement on fluid shifts will affect the volume of distribution
    • Acidosis or alkalois affects drug-protein binding, increasing or decreasing
  • Metabolism
    • Effects of acidosis or alkalosis on regional blood flow or cardiac output affects blood flow through  organs of metabolism 
  • Elimination
    • Elimination of one serum electrolyte may affect the elimination of another, eg. where one needs to replace magnesium in order to effectively correct hypokalemia (Whang et al , 1985
    • Effects of acidosis or alkalosis on regional blood flow or cardiac output can affect blood flow through  organs of elimination
  • Serum electrolyte concentration significantly affects the response to drugs which exert their effect by manipulating ion transactions across channels or pumps. An example is digoxin: hypokalemia greatly enhances its potential for adverse effects
  • Acid-base derangements affect the binding affinity of receptors for drugs. A good example  is the way acidosis affects the alpha-1 receptors: at a low pH (7.15), the affinity of noradrenaline for these receptors is reduced by 75%

Endocrine pathology or environmental effects

  • Absorption
    • Endocrine pathology can affect active transport of substances from the gut lumen (eg. vitamin D deficiency and calcium absorption)
  • Distribution
    • Endocrine pathology can give rise to changes in body water distribution and serum protein concentration, affecting volume of distribution and protein binding
  • Metabolism
    • Endocrine pathology can increase or decrease the cardiac output, blood flow to clearance organs or the metabolic function of those organs (eg. hyperthyroidism and myxoedema)
    • Hyperthermia can increase the metabolism of drugs, and hypothermia can decrease it
  • Elimination
    • Hypothermia-induced diuresis can increase renal drug clearance
    • Changes in cardiac output due to endocrine pathology (eg. phaeochromocytoma, hyperthyroidisim or hypothyroidism) can give rise to changes in the clearance organ blood flow 
  • Receptor sensitivity and expression is substantially influenced by endocrine pathology. Two decent examples are the influence of Type 2 diabetes on the response to insulin, and the effect og corticosteroids on the response to catecholamines. 
  • Hypothermia and hyperthermia can influence the affinity of drugs for their receptors. For instance, the affinity of opioids for the mu-receptor is decreased by about 450% at a temperature of 30º C. In other cases, drugs may lose their receptor selectivity under the effects of hypothermia (for example, dobutamine becomes more of an alpha-agonist). Both examples are from van der Broeck et al (2010)

Renal pathology

  • Absorption
    • Renal failure decreases the bioavailability of drugs by decreasing intestinal motility and by decreasing the activity of active transport proteins such as Pgp (Dreisbach et al, 2008).
  • Distribution
    • Fluid overload associated with chronic renal failure can give rise to changes to drug distribution (i.e. due to increased amount of body water).
    • Competition for protein binding sites with uraemic toxins and the effect of those toxins on protein structure teds to increase the free fraction (Dreisbach et al, 2008).
  • Metabolism
    • Renal failure affects CYP-mediated metabolism of drugs- production of CYP 450 enzymes is decreased, which is thought to be PTH and cytokine-mediated.
    • Renal metabolism of drugs sometimes contributes signficantly; for example, kidneys a responsible for the degradation of approximately 70% of insulin (Rabkin et al, 1984). 
  • Elimination
    • Obviously renal clearance of drugs will be affected (i.e. decreased or totally absent), and the characteristics of clearance of drugs by dialysis will be markedly different from normal patters
  • Chronic adaptation to renal failure can dampen responses to drugs via indirect mechanisms, eg. making the patient more resistent to the effects of antihypertensives by activiating the renin-angiotensin-aldosterone axis
  • Tubular pathology can lead to a decreased sensitivity of tubular cells to drugs which target them (i.e. larger doses of diuretics may be required)
  • The decreased elimination rate of some drugs may give rise to an increased pharmacodynamic effect, such that the same dose produces a greater response (renally cleared time-dependent killers such as penicillin and vancomycin are an example)

Gastrointestinal pathology

  • Absorption
    • It stands to reason that the failure of any segment of the gastrointestinal tract will lead to the impaired absorption of those drugs which would normally be absorbed through that segment
    • Increased gut transit (eg. due to diarrhoea or high-output fistula) will reduce GI tract absorption of drugs
    • Slowed gastrioc emptying, ileus and constipation may decrease absorption of drugs due to their decreased delivery to the small bowel 
  • Metabolism
    • Certain substances (eg. catecholamines) undergo significant metabolism in the gut wall; this will be affected by gut wall diseases eg. colitis or ischaemia
  • Elimination
    • Gastrointestinal elimination of drugs may be affected by pathological changes in gut flora (eg. enterohepatic recirculation will be affected by concomitant infective colitis. 
  • Gastrointestinal drug receptor targets may respond differently in pathological states; for instance, following bowel resection the gut may have a greater propensity to develop ileus with doses of anticholinergic drugs which would usually be viewed as safe.
  • Critical illness may produce states of functional resistance to the effects of drugs which act on GI targets (eg. in the case of motilin receptors and erythromycin, or in the case of PPIs and stress ulceration). Increased doses may be required for the same functional effect.

Hepatic pathology (Morgan & McLean, 2012)

  • Absorption
    • High portal venous pressures in liver disease (as well as the use of drugs like terlipressin and octreotide) may impair gastrointestinal blood flow and decrease absorption
  • Distribution
    • Decreased serum albumin levels increase the free fraction of protein-bound drugs
    •  Fluid compartment changes and ascites associated with chronic liver disease alter the volume of distribution
  • Metabolism
    • The loss of hepatic enzymes due to liver disease results in slowed metabolism (i.e. there are fewer enzyme molecules to do the work).
    • This is also true in the case of circulating enzymes (eg. plasma esterases) which are synthesised in the liver
    • The presence of portosystemic shunts results in some fraction of the drug bypassing the hepatic clearance systems altogether
  • Elimination
    • Biliary excretion of drugs is obviously going to be somewhat impaired if your common bile duct is blocked. 
    • Hepatic parenchymal and canalicular disease will also decrease the active transport of drugs into the bile
  • Consequences of liver disease will produce pathological changes which can change the response to conventional drug doses; one example is the decreased need for anaesthetic induction agents in the presence of hepatic encephalopathy (they are already comatose, how much more do they need?)
  • Physiological adaptations to chronic liver disease produce homeostatic changes which may counteract the effects of some drugs (eg. diuretics)
  • Chronic sympathetic activation tends to dampen the response to beta-antagonists by decreasing the receptor sensitivity
  • Decreased synthetic function can decrease the synthesis of some notable drug targets, such as clotting factors. 

Haematological pathology

  • Absorption
    • High portal venous pressures in liver disease (as well as the use of drugs like terlipressin and octreotide) may impair gastrointestinal blood flow and decrease absorption
  • Distribution
    • Massive transfusion dilutes the circulating drug levels by direct replacement of blood volume with drug-free blood products
  • Metabolism
    • The reticuloendothelial system (including bone marrow and spleen) is responsible for some drug metabolism - notably, unfractionated heparin
    • Macrophages contribute to the metabolism of xenobiotics, which can have both positive and negative effects (eg. in Wickaramasinghe, 1987, where macrophages may activate some environmental procarcinogens)
  • Elimination
    •  Where the haematological pathology requires plasmapheresis or leukopheresis, plasma drug concentrations will be affected, i.e. drugs will be cleared by the process (Ibrahim et al, 2012)
  • Under some circumstances, haematological pathology may render the patient insensitive to normal doses of a drug. For instance, a large embolic burden in PE may require larger doses of heparin than would ordinarily be expected (Kandrotas, 1992)
  • In haematological disease, there may be a loss of drug targets rendering drugs less effective (eg. antithrombin-III deficiency and heparin), or the gain of drug targets which renders other drugs more effective (eg. the Philadelphia chromosome mutation in CLL)

Infectious pathology

  • Absorption
    • Infectious diseases in the critically ill may affect the route of administration (eg, abdominal sepsis) or decrease absorption from non-GI routes (eg. septic shock and subcutaneous administration)
  • Distribution
    • Distribution of antimicrobial agents to their site of action may be challenging in scenarios where the infection is in a "hard to reach place" (eg. CNS or  bone) 
  • Metabolism
    • Metabolism of drugs by intestinal bacteria can reduce the bioavailability of some drugs, or release toxic metabolites.  (Kobashi et al, 1992). Notably, post-mortem metabolism of benzodiazepines can fool the forensic pathologist into underestimating your overdose (Roberson et al, 1995)
  • Elimination
    •  As already mentioned, changes to bowel flora due to antibiotic use may produce changes to enterohepatic recirculation.
  • Severe bacterial infections can set up an environment where conventional antimicrobial drug doses have less effect (eg. the Eagle effect).
  • Adverse effects of antimicrobial agents (eg. encephalopathy, nephrotoxicity, QT prolongation) may be potentiated by the effect of severe sepsis

This is perhaps the sort of thing which calls for a tabulated answer. The approach of the Part One authors is laudable, and 

  • Absorption
    • Decreased cardiac output decreases PO absorption due to decreased gradient
  • Distribution
    • Decreased CO prolongs arm-brain circulation time
    • Increased α1-glycoprotein increasing binding of basic drugs
    • Decreased VD
  • Metabolism
    • Low-cardiac output states reduce hepatic flow and will reduce metabolism of drugs with a high extraction ratio
    • High-output states have the opposite effect

Hepatic Disease

  • Absorption
    • Porto-caval shunting
      Decreased first pass metabolism.
  • Distribution
    • Impaired synthetic function reduces plasma proteins and increases unbound fraction
    • Increased VD due to fluid retention
    • Metabolic acidosis changes ionised fraction
  • Metabolism
    • Impaired phase I and II reactions
    • Reduced plasma esterase levels
  • Elimination
    • Reduced biliary excretion
  • Pharmacodynamics
    • Hepatic encephalopathy increases sensitivity to sedatives and hypnotics

Renal Disease

  • Absorption
    • Uraemia prolongs gastric emptying
  • Distribution
    • Increased VD due to fluid retention
    • Metabolic acidosis adjusts ionised fraction
  • Metabolism
    • Buildup of toxic metabolites may inhibit drug transporters
    • Uraemic toxins inhibit enzymes and drug transporters
  • Elimination
    • Reduced clearance of active metabolites/active drug cleared renally

Obesity

  • Absorption:
    • Delayed gastric emptying
    • Decreased subcutaneous blood flow
    • Practical difficulty with IM administration
  • Distribution:
    • Increased VD of lipid soluble drugs
      • Dosing of lipid-soluble drugs by actual body weight
      • Dosing of water-soluble drugs by lean body weight
    • Increased CO
    • Increased α1-glycoprotein
    • Increased blood volume
    • Greater lipid binding to plasma proteins, increasing free drug fractions
  • Metabolism:
    • Increased plasma and tissue esterase levels
    • Normal or increased hepatic enzymes
  • Elimination
    • Increased renal clearance due to increased CO

Non-Specific Alterations to Drug Response

  • Absorption:

    • Site of administration
      Drugs given centrally will act faster than those given into peripheral veins.
    • Rate of administration
      Faster rate of administration will increase rate of onset.
  • Pharmacodynamic

    • Drug tolerance Increase requirement of drug.
      • e.g. induction anaesthetic agents in patients tolerant to CNS depressants.
        • Drug interaction
          May be:
        • Synergistic
        • Additive
        • Antagonistic

References

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Beckett, Arnold H., and R. D. Hossie. "Buccal absorption of drugs." Concepts in Biochemical Pharmacology. Springer, Berlin, Heidelberg, 1971. 25-46.

Shojaei, Amir H. "Buccal mucosa as a route for systemic drug delivery: a review." J Pharm Pharm Sci 1.1 (1998): 15-30.

Boer, F. "Drug handling by the lungs." British journal of anaesthesia 91.1 (2003): 50-60.

Hochhaus, Günther, et al. "Pharmacokinetics and pharmacodynamics of drugs delivered to the lungs." Pharmaceutical Inhalation Aerosol Technology, Second Edition. CRC Press, 2016. 222-257.

Salpeter, Shelley R., Thomas M. Ormiston, and Edwin E. Salpeter. "Meta-analysis: respiratory tolerance to regular β2-agonist use in patients with asthma." Annals of internal medicine 140.10 (2004): 802-813.

Lainscak, Mitja, et al. "Pharmacokinetics and pharmacodynamics of cardiovascular drugs in chronic heart failure." International journal of cardiology 224 (2016): 191-198.

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Sundar, S., D. P. Burma, and S. K. Vaish. "Digoxin toxicity and electrolytes: a correlative study." Acta cardiologica 38.2 (1983): 115-123.

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Keller, Frieder, and Alexander Hann. "Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease." Clinical Journal of the American Society of Nephrology 13.9 (2018): 1413-1420.

Aymanns, Christian, et al. "Review on pharmacokinetics and pharmacodynamics and the aging kidney." Clinical Journal of the American Society of Nephrology 5.2 (2010): 314-327.

Dreisbach, Albert W., and Juan JL Lertora. "The effect of chronic renal failure on drug metabolism and transport." Expert opinion on drug metabolism & toxicology 4.8 (2008): 1065-1074.

Rabkin, R., M. P. Ryan, and William C. Duckworth. "The renal metabolism of insulin." Diabetologia 27.3 (1984): 351-357.

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