Week 9

• Drug interactions

  Pharmacokinetics or pharmacodynamics of one drug is altered by another
• It is important to consider drug interactions if concomitant drugs are started or stopped, or the dosage of one drug is changed
• The extent of a drug interaction will depend on the concentration of the interacting drug in the body
• Unidirectional interaction


  When drug A affects drug B
• Bidirectional interaction


  When drug A affects drug B and drug B affects drug A
• Mechanisms of drug interactions - Alterations in absorption

  • Complexation/chelation
  • Altered GI transit time
  • Altered gastric pH
  • Altered GI metabolism through enzyme inhibition or induction
  • Altered GI membrane transportation through transporter inhibition or induction
• Complexation/chelation


  • Antacids and tetracycline
• Complexation/chelation


  One drug forms an insoluble complex with another, reducing drug absorption
• Altered GI transit time


  May slow or hasten the absorption of other drugs
• Altered gastric pH


  • H2-blocker and ketoconazole
• Mechanisms of drug interactions - Alterations in membrane transporters

  • Altered GI absorption
  • Altered biliary excretion
  • Altered renal tubular secretion
• Mechanisms of drug interactions - Alterations in metabolism

  • Induction of metabolism
  • Inhibition of metabolism
  • Alterations in renal clearance
  • Alterations in plasma protein binding
• Induction of metabolism


  Enzyme induction leads to an increase in the synthesis or activity of a metabolic enzyme, which can lead to decreased serum concentration of drugs that are substrates for that enzyme
• Induction of metabolism can lead to a delay in the onset of the interaction as it may take several days for enzyme levels to be induced
• Inhibition of metabolism


  Enzyme inhibition leads to a decrease in the activity of a metabolic enzyme, which can lead to increased serum concentrations of drugs that are substrates for that enzyme
• Enzyme inhibition usually occurs faster than enzyme induction, and the degree of inhibition will be dependent on the plasma concentration of the interacting drug
• Altered renal blood flow

  Glomerular filtration is a passive process dependent upon the unbound fraction of drug in plasma and the renal blood flow
• Inhibition of active tubular secretion

  Tubular secretion is an active process involving several transporter systems which move substrates against a concentration gradient, and inhibition of this can prolong the half-life of a drug in the systemic circulation
• Altered tubular reabsorption

  Tubular reabsorption is generally a passive process that acts to keep drug within the circulation, and can be influenced by factors like pH
• Alterations in plasma protein binding

  One drug alters the plasma protein binding of another drug, which can change the free/unbound fraction and total drug concentration
• Major CYP450 isoenzymes responsible for drug metabolism

  • CYP1A2
  • CYP2C9
  • CYP2C19
  • CYP3A
  • CYP2E1
  • CYP2D6
• There is large variability between individuals in expression/activity of CYP450 enzymes
• Enzyme inducers

  Drugs or other compounds known to increase the synthesis or activity of a metabolic enzyme, leading to increased metabolism and lower plasma concentrations of enzyme substrates
• Enzyme inhibitors

  Drugs or other compounds known to decrease the activity of a metabolic enzyme, leading to decreased metabolism and higher plasma concentrations of enzyme substrates
• Drug interactions can also occur where one drug alters the renal clearance of another, through effects on glomerular filtration, tubular secretion, and tubular reabsorption
• Disease states that can cause pharmacokinetic variability

  • Renal disease
  • Hepatic disease
  • Congestive heart failure
  • Thyroid disorders
  • Gastrointestinal disorders
  • Respiratory disorders
  • Critical illness
• Renal disease

  Diabetic nephropathy, hypertension, glomerulonephritis
• To estimate renal function

  Calculate CrCL
• Dosage adjustment most important

  When drug >50% renally eliminated and renal function <50% of normal
• Direct decrease in renal clearance of drug and/or metabolites

  Has a predominate effect in PK
• Dosing in renal impairment

  1. Decreasing dose or increasing dosage intervals

  2. Dose recommendations based on degree of renal impairment: severe (CrCL <10mL/min), moderate (CrCL 10-25 mL/min), mild (CrCL 25-50 mL/min)

  3. Assume at least a mild degree of renal impairment in elderly patients above 65 years of age
• Hepatic disease

  Chronic liver disease involving cirrhosis effects PK more than any other form of liver disease
• No accurate overall marker of liver function - many different enzymes with x-selectivity for various substrates
• Effects of CLD on PK

  • Decreased hepatic CL
  • May increase F, secondary to decreased first pass effect
  • May increase V in patients with low albumin levels and ascites
  • Decreased CL, increased V can lead to increased half-life and time to reach steady-state
• Dosing in hepatic impairment

  1. Dose reductions may be necessary for extensively metabolised drugs, especially those with a low therapeutic index

  2. Avoid hepatically cleared agents where possible

  3. Monitor patient response closely and consider therapeutic drug monitoring
• Age

  • Pharmacokinetic variability is particularly important at the extremes of age
• Age and metabolic activity

  • Low in the foetus
  • Metabolic pathwayts immature in newborn
  • At 6 to 12 months of age metabolic activity may exceed that of an adult
  • After 5 years, metabolic activity may begin to decrease with puberty causing a decline to adult levels
  • Unique developmental patterns for each enzyme subfamily
• Ontogeny of selected metabolic enzymes
• Metabolic activity - Elderly

  • Acetylation and conjugation do not change appreciably in the elderly
  • Oxidative metabolism through CYP450 systemic does decrease in the elderly, resulting in decreased clearance of some drugs
  • Hepatic volume and blood flow may decrease in the elderly - extremely variable
• Overall hepatic metabolism of drugs generally decreases in the elderly. Dosage reduction of hepatically cleared drugs may be necessary (it may also depend on whether other factors are involved)