Lecture 18_Drug Interactions

Question 1

Classification of drug interactions

Answer 1

• 1. Consequence: Beneficial or adverse?
• 2. Site: Are drugs mixed together outside the body (external) or inside the body (internal)?
• 3. Mechanism: Does drug B metabolize drug A (pharmacokinetics, pharmacodynamics, etc)

Question 2

Classification of drug interactions based on consequence are either enhanced or diminished. Give examples of each in terms of efficacy and toxicity.

Answer 2

• Enhanced Efficacy: Combination drug therapy in cancer, hypertension, angina, pectoris, infection.
• Enhanced Toxicity: CNS depressants + ethanol.
• Diminished Efficacy: Methotrexate effect negated by prior inhibition of thymidylate synthetase by 5-fluorouracil.
• Diminished Toxicity: Vasodilator + beta blocker, Naloxone + opiates, Thiazides + potassium, Carbidopa + L-dopa

Question 3

Classification based on site of interaction

Answer 3

• External: Physiochemical incompatibilities (eg., precipitation or inactivation) may prevent drugs from being mixed together in i.v. vials or syringes.
• Internal: Can refer to a body site (g.i. tract) or the site of action (cell membrane, receptor site).

Question 4

What are physiological interactions? Give an example.

Answer 4

• Physiological interactions are those in which the actions of drugs are mediated at different sites or organ systems but have the net effect of augmenting or offsetting each other.
• EX: Cardiac glycoside/diuretic scenario.

Question 5

Pharmacodynamic interactions are…

Answer 5

…those that occur when the effects of two drugs impinge on a common effector. The consequences of this are:
- Additive, Supra additive, infra additive.

Question 6

Pharmacodynamic interaction (guanethidine).

Answer 6

Complex interactions, involving regulation of neurotransmitter receptor numbers, can affect drug responses. Eg., Guanethidine (an antihypertensive) decreases the release of norepinephrine presynaptically; a consequence of NE receptor upregulation after chronic guanethidine treatment. If a patient taking guanethidine is also administered desipramine (an antidepressant that blocks NE uptake), this leads to significant increases in blood pressure.

Question 7

Pharmacokinetic interaction examples

Answer 7

• Absorption: Physiochemical interaction, G.I. motility, bacterial flora, mucosal function.
• Distribution: Blood flow, serum binding, tissue binding, active transport to site of action.
• Biotransformation: Hepatic, other sites.
• Excretion: Renal, biliary, other sites.

Question 8

Physiochemical interactions

Answer 8

Egs., Changes in g.i. pH produced by one drug (such as the H2 receptor antagonist cimetidine, or antacids) can affect the ionization of another drug; chelation of Ca2+ or Fe3+ by tetracycline; binding of warfarin by cholestyramine; adsorption of drug by activated charcoal in treatment of poisoning.

Question 9

Changes in g.i. motility

Answer 9

Changes in g.i. motility affect the rate and/or completeness of drug absorption. Egs., metoclopramide increases the rate of gastric emptying which can result in earlier and higher peak drug concentrations. Cathartics increase rate of intestinal motility, which decrease completeness of absorption. In contrast opioid analgesics and anticholinergics decrease the rate of gastric emptying, slowing absorption and decreasing the peak drug concentration.

Question 10

Drug-induced changes in mucosal function.

Answer 10

Drugs with g.i. toxicity (eg. colchicine) may damage the g.i. mucosa altering absorption of other drugs.

Question 11

Blood flow

Answer 11

Organ uptake and clearance of drugs depends on blood flow. Some drugs (like b-blockers and antiarrythmics) decrease cardiac output and thus the hepatic clearance of drugs such as lidocaine which have a high extraction rate in liver.

Question 12

Serum protein binding

Answer 12

Many drugs are bound to serum proteins, especially to albumin. Such drugs may be displaced by other highly bound drugs administered concurrently. When a displacing drug is added to therapy, it can in theory lead to the immediate appearance of toxicity to the first drug. Even a small amount of displacement of a highly bound drug can cause a large relative increase in free drug in serum.

Question 13

Clinically important pharmacokinetic interactions due to displacement from plasma proteins will occur when:

Answer 13

• 1.) Administration of the displacing drug is started in high doses during chronic administration of displaced drug
• 2.) The Volume of distribution of the displaced drug is small
• 3.) The response to the displaced drug occurs faster than redistribution or enhanced elimination.

Question 14

Biotransformation

Answer 14

Pharmacokinetic interactions between drugs can occur by one drug either inducing or inhibiting an enzyme that metabolizes another. This is particularly true for the cytochrome P450 family of enzymes, responsible for the metabolism of many drugs.

Question 15

Enzyme induction

Answer 15

Hundreds of drugs such as analgesics, anticonvulsants, oral hypoglycemics, sedatives and tranquilizers stimulate the biotransformation of either themselves or other drugs.

Question 16

Consequences of enzyme induction are:

Answer 16

• 1.) Increased rate of hepatic biotransformation of drug
• 2.) Increased rate of production of metabolites
• 3.) Increased hepatic drug clearance
• 4.) Decreased serum drug half-life
• 5.) Decreased serum total and free drug concentrations.
• 6.) Decreased pharmacological effects if metabolites are inactive.

Question 17

Enzyme inhibition. Clinically important inhibitors of drug biotransformation are:

Answer 17

• Acute ethanol exposure which inhibits propranolol, diazepam and chlordiazepoxide metabolism.
• Cimetidine (decreases gastric acid secretion) is a potent cytochrome P450 inhibitor and inhibits biotransformation of acetaminophen, diazepam, digoxin, phenytoin and warfarin among other drugs.
• Disulfuram inhibits aldehyde dehydrogenase, causing acetaldehyde accumulation after alcohol consumption.
• Grapefruit juice contains a bioflavonoid that is transformed in the liver to naringenin. This is a potent inhibitor of CYP3A4, CYP1A2 and CYP2A6, and reduces the first-pass metabolism of a number of drugs including calcium channel blockers, cyclosporine, midazolam and caffeine.

Question 18

Inhibition of drug biotransformation is the clinically _______ important mechanism of pharmacokinetic interactions

Answer 18

most important.

Question 19

Excretion. Theoretically, drug interactions could alter rates of excretion by any route, but the only careful studies of these phenomena have been performed involving renal excretion. The following phenomena have been observed:

Answer 19

• 1.) Glomerular filtration of drugs is increased by displacement from albumin binding sites.
• 2.) Tubular reabsorption of drugs is decreased by diuretics (sometimes), urine alkylinizers (for weakly acidic drugs such as ASA and barbiturates) or urine acidifiers (for weak amines such as amphetamine or methadone)
• 3.) Tubular secretion of drugs is decreased by competition for active transport systems. Probenicid was used to block penicillin G secretion during World War II.