Alterations to Drug Response

Define tachyphylaxis, tolerance, addiction, dependence and idiosyncrasy

There are four mechanisms which result in variable response to drug:

• Alteration in drug that reaches the receptor
  This is typically due to pharmacokinetic factors.
• Relative difference in presence of exogenous and endogenous ligands
  Antagonists will have a greater effect in the presence of high endogenous ligand concentration.
• Variation in receptor function and number
  Up-regulation and down-regulation of receptors may occur as a consequence of prolonged stimulus.
• Alteration in function distal to the receptor

Key Terms

• Tachyphylaxis is the rapid decrease in response to repeated dosing over a short time period, usually due to depletion of transmitter

• Desensitisation is the loss in response over a long time period, usually due to change in receptor morphology or loss in receptor numbers

• Withdrawal is a pathological response when a drug is ceased
  • During administration receptors may be:
    • Up-regulated in the continued presence of an antagonist
    • Down-regulated in the continued presence of an agonist
  • Loss of receptor numbers may precipitate withdrawal when the agonist or antagonist is ceased

• Addiction is a behavioural pattern characterised by compulsive use and fixation on acquiring and using a drug

• Idiosyncrasy is an individual patient response to a drug
  Typically mediated by a reactive metabolite rather than the drug itself.

Tolerance

Tolerance is the requirement for a larger dose to achieve the same effect, due to altered sensitivity of the receptors to the stimulant. Mechanisms can be classified into:

• Pharmacokinetic
  • Altered drug metabolism
    Metabolism may be increased or decreased:
    • Enzymatic induction and increased drug metabolism
      Increased hepatic enzyme pathway capacity increases metabolism and lowers plasma concentration.
    • Decreased metabolism
      Decreased metabolism of a prodrug can result in a reduced effect.

• Pharmacodynamic
  • Change in receptor morphology
    Can occur with ion-channel receptors and GPCRs:
    • Ion-channel receptors bind the ligand but do not open the channel
    • GPCR become 'uncoupled' - phosphorylation of the receptor makes it unable to activate second messenger cascade, though it can still bind the ligand.
  • Receptor down-regulation
    Prolonged exposure to agonists causes transmembrane (typically hormone) receptors to become internalised. This occurs more slowly than uncoupling.
  • Receptor up-regulation
    Prolonged exposure to antagonists causes an up-regulation of receptor.
    • Can lead to rebound effects when a drug is ceased (e.g. hypertension with cessation of clonidine)
  • Exhaustion of mediators
    Similar to tachyphylaxis - depletion of a mediating substance decreases the effect.
  • Physiological adaptation
    Actions of a drug may be countered by a compensatory homeostatic response.
  • Active removal of the drug from the cell

Alterations in Drug Response: Patient Factors

Pharmacokinetics and pharmacodynamics are affected in pregnancy and at extremes of age.

Pregnancy

• Absorption
  • Decreased gastric emptying
  • Nausea and vomiting
  • Increased cardiac output
    • Increases IM and SC absorption
  • Volatiles:
    • Increased onset due to increased MV and reduced FRC
    • Decreased onset due to increased CO

• Distribution
  • Increased V_D due to:
    • Increased TBW
    • Increased plasma volume
    • Increased fat mass
  • Decreased albumin and α₁-glycoprotein

• Metabolism
  • No change to HBF
  • Progesterone induces enzymes
  • Oestrogen competes for enzymes
  • Decreased plasma cholinesterase activity

• Elimination
  • Increased RBF
  • Increased GFR

• Pharmacodynamic
  • Decreased MAC
  • Increased LA sensitivity due to decreased α₁-glycoprotein

Foetus

Drugs that cross the placenta can be teratogenic to the foetus, besides exerting their usual pharmacological effects.

Pharmacokinetic factors predominantly affect placental transfer, and include:

• Lipid solubility
  Lipid soluble drugs diffuse more rapidly.
• Molecular size
  Drugs with a molecular weight >1000 dalton cross the placenta slowly.
• Protein binding
• Placental transporters
  Some medications are actively removed from foetal circulation.
• Placental metabolism
  The placenta can metabolise some medications, although in some cases results in toxic metabolites.

Maternal pharmacodynamic factors predominantly affect the uterus and breast, but major organ systems are not significantly affected.

Drugs that cross the placenta can have dramatic effects in the foetus. These include:

• Teratogenesis
  A drug which adversely affects foetal development causing a permanent abnormality. Multifactorial mechanisms that are not well understood.

Neonates

At < 1 year of age, pharmacokinetics are significantly altered:

• Absorption
  • Delayed gastric emptying, increasing absorption of drugs metabolised in the stomach
  • Decreased secretion of pancreatic enzymes and bile salts impairs absorption of lipid soluble medications
  • Smaller muscle mass and higher relative muscle blood flow increases IM onset
  • Increased V_A:FRC ratio increases onset of volatiles

• Distribution
  • TBW is 70-75% (compared to 50-60% for an adult), and extracellular water is 40% (compared to 20%), which typically increases V_D
  • Preterm infants have reduced body fat
  • Greater proportion of cardiac output goes to head, increasing onset of centrally acting (e.g. anaesthetic) drugs
  • Decreased albumin and α₁-glycoprotein
  • Immature BBB increases uptake of partially ionised drugs

• Metabolism
  • Enzymatic capacity of all pathways is reduced, which prolongs elimination half-lives and reduces clearance.
    • Hepatically metabolised drugs must be dose adjusted accordingly
      • The glucuronide pathway may not mature until age 4

• Excretion
  • GFR is proportionally lower and dose not reach adult equivalence until 6-12 months
    • GFR is further reduced in pre-term infants
    • GFR is increased in 1-3 year olds

• Pharmacodynamic
  • Smaller ACh reserves increase sensitivity to NMBs
  • Increased MAC but more rapid onset
  • NSAIDs cause closures of ductus arteriosus

Geriatric

Though there is a linear decrease in functional capacity of major systems beginning at 45, alterations are predominantly a consequence of polypharmacy and drug interactions.

• Absorption
  • Laxatives and prokinetic increase gastric emptying and reduce absorption of oral agents

• Distribution
  • There is a proportional increase in fat
  • There is a proportional decrease in:
    • Lean body mass
    • Total body water
    • Albumin

• Metabolism
  • ↓ Hepatic blood flow
  • ↓ Enzymatic activity
    Phase I > Phase II.

• Elimination
  • Loss of nephron number with age reduces renal clearance

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

Alterations in Drug Response: Disease Factors

Cardiac Disease

• 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 V_D

• 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

• Elimination
  • Decreased renal blood flow

Hepatic Disease

• Absorption
  • Porto-caval shunting
    Decreased first pass metabolism.

• Distribution
  • Impaired synthetic function reduces plasma proteins and increases unbound fraction
  • Increased V_D 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 V_D 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 V_D 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

1. Anderson C. Variability in Drug Response 1. ICU Primary Prep.
2. Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's Pharmacology. Sixth Edition. Churchill Livingstone.
3. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
4. CICM Examiner Report: Sep/Nov 2012
5. Alfred Anaesthetic Department Primary Exam Tutorial Series