Drug interactions

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Drug interactions

• BDS lecture

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Learning objectives.

• Characteristics of those drugs prone to adverse
  drug interaction.
• Pharmacokinetic and pharmacodynamic mechanisms.
• Characteristics of those patients most at risk.

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A couple of definitions

• The INDEX drug
• The drug which is effected by drug interaction
• The INTERACTING drug
• The drug that interacts with the index drug.
• Perhaps increasing clinical effects of the index
  drug (causing harm).
• Perhaps decreasing clinical effects of the index
  drug (causing harm).

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Characteristics of index drugs

• Effects on vital body systems
• E.g. clotting, blood pressure, cardiac
  conduction, (contraception).
• Small therapeutic index.
• Steep dose-response relationship.

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Characteristics of index drugs

• Effects on vital body systems
• E.g. clotting, blood pressure, cardiac
  conduction, (contraception).
• Small therapeutic index.
• Steep dose-response relationship.

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Therapeutic effect
Toxic effect
requiring dose to achieve effect
DRUG DOSE
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Characteristics of index drugs

• Effects on vital body systems
• E.g. clotting, blood pressure, cardiac
  conduction, (contraception).
• Small therapeutic index.
• Steep dose-response relationship.

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Shape of dose-response curves.
Effect
Log drug concentration
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Pharmacodynamic mechanisms

• Two drugs acting upon the same (or similar)
  mechanism in the same direction (i.e. two
  agonists).
• E.g. Two beta-blockers additive
• E.g. Morphine plus diazepam additive
• E.g. Pen-G plus gentamicin synergistic
• Two drugs acting upon the same (or similar)
  mechanism in opposite directions (i.e. agonist
  plus antagonist).
• E.g. Beta-blocker plus salbutamol antagonistic
• E.g. Frusemide plus NSAID indirectly antagonistic

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PHARMACOKINETIC MECHANISMS

• Probably no overlap in the therapeutic effects
  of the two drugs.
• Impossible to predict from first principles.
• Look up BNF Appendix 1.
• Absorption
• Distribution
• Metabolism
• Excretion

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Absorption

• From the gut, in the case of two drugs
  administered together.
• Chelating agents (e.g. calcium resonium).
• Resins (e.g. cholestyramine).

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Distribution plasma protein binding
R
Drug in free solution in plasma water
Albumin
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Distribution plasma protein binding
R
Drug in free solution in plasma water
Albumin
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Distribution.

• Examples
• Sulphonamide antimicrobials.
• Pre-term neonates.
• Bilirubin (kernicterus).

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METABOLISM.

• Characteristics of index drug
• Effects on vital body systems
• E.g. clotting, blood pressure, cardiac
  conduction, (contraception).
• Small therapeutic index.
• Steep dose-response relationship.
• Terminated by metabolism.

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METABOLISM

• Examples of INDEX drugs.
• Coumarin anticoagulants.
• ENHANCED EFFECTS bleeding
• REDUCED EFFECTS thrombosis-related issues
• Oestrogen component of the combined OCP
• REDUCED EFFECTS unplanned pregnancy
• The interactions usually involve the CYP450
  family of mixed-function oxidases.

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METABOLISM

• Examples of INTERACTING DRUGS
• CYP450 Inducers
• Increase cellular content of the protein.
• Thus interactions take time (several days) to
  envolve.
• Effects of the INDEX drug are reduced.
• Carbamazepine
• Rifampicin
• Phenobarbitone

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METABOLISM

• Examples of INTERACTING DRUGS
• CYP450 Inhibitors
• Compete with INDEX drug at enzymes active site.
• Thus interactions become apparent very fast
  (often within a day).
• Effects of the INDEX drug are enhanced.
• Erythromycin
• Metronidazole

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EXCRETION

• Characteristics of index drug
• Effects on vital body systems
• E.g. clotting, blood pressure, cardiac
  conduction, (contraception).
• Small therapeutic index.
• Steep dose-response relationship.
• Terminated by irreversible excretion.

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EXCRETION

• Some strong acids/bases are actively
  secreted/reabsorbed by renal tubules.
• Digoxin excretion may be reduced by verapamil and
  quinidine
• Some drugs sensitive to changes in urinary pH or
  sodium balance.
• Lithium excretion may be reduced by diuretics and
  NSAIDs