Drug Interactions

Thursday, August 1, 2002 9:00 a.m. 10:00 a.m. Robert G. Lamb, Ph.D. E-mail Address: rglamb@vcu.edu Post a question to the bulletin board

Lecture Outline:
Objectives | Required Reading | Terminology of drug interactions | | Interactions associated with alterations in drug absorption | Interactions associated with drug excretion | | Interactions associated with drug metabolism | Interactions associated with drug distribution | | Receptor interactions in various tissues | An example of how drug combinations influence drug response (problem) | | Drugs to Remember |

OBJECTIVES After studying the material of this lecture, the student should be able to: 1. Define the terms used to describe drug interactions. Give specific examples of each drug interaction and explain the mechanism by which the interactions occur. 2. List specific examples of the so-called ADME drug interactions. 3. Explain how important drug interactions are in effective drug therapy 4. List some examples of both adverse and beneficial drug interactions. Required Reading Katzungs Clinical Pharmacology, 8th Edition., pp. pp 1122-1133.

Drug interactions occur whenever the effect of a drug is modified by the presence of another exogenous agent. The agent may be another drug (prescription or over the counter) or a sub-stance encountered in the diet or environment. Drug interactions may be beneficial, hazardous or of no clinical significance. Most drug interactions are a result of changes in drug absorption, distribution, metabolism and excretion [ADME]. Drug interactions are common in the elderly due to age-associated changes in pharmacokinetics, pharmacodynamics and high use of prescription drugs. Drug interactions rank at least 6th among U.S. causes of death. I. TERMINOLOGY OF DRUG INTERACTIONS A. Summation is the mathematical addition of individual drug effects.

B. C.

Synergism (potentiation) results in an effect greater than the individual drug effects. Antagonism (inhibition) results in an effect less than the individual drug effects 1. 2. Physiologic - depressant (alcohol) + stimulant (caffeine) Biochemical - inducer (Phenobarbital [CNS depressant]) + inhibitor (cimetidine [treatment of ulcers])

3. 4.

Chemical cholestyramine [cholesterol lowering agent] adsorbs dicumarol [anticoagulant] (reduced absorption) Pharmacological - receptor interaction in salivary gland, acetylcholine (stimulates) + atropine (inhibits) salivation.

II.

INTERACTIONS ASSOCIATED WITH ALTERATIONS IN DRUG ABSORPTION. A. Chelation is the interaction of metals (Mg2+, Ca2+, Fe2+, Al3+, Zn2+, etc.) with drugs. 1. EDTA chelates toxic metals such as lead and reduces toxicity.

2.

Tetracyclines and Quinolones [antibiotics] chelate metals and form an insoluble complex that reduces their absorption.

B.

Adsorption is the nonspecific binding of a drug to another agent. 1. Cholestyramine adsorbs may drugs such as dicumarol, methotrexate [cancer chemotherapy] and digitoxin [congestive heart failure] and de-creases their absorption. Antacids decrease digoxin and iron [Ca] absorption by adsorption.

2. C.

pH changes alter the absorption of drugs by changing ionization. 1. 2. Antacids (increased pH) will decrease the absorption of weak acids and increase the absorption of weak bases. Infections (decreased pH) will increase the absorption of weak acids and decrease the absorption of weak bases.

D.

Alterations in the transit time of drugs through the GI tract. 1. Gastric emptying time (GET) is the time required to empty the stomach and decreases in GET will increase drug absorption whereas an increase in GET will decrease drug absorption. a. b. 2. GET is increased by food and morphine GET is decreased by fasting and antacids

Intestinal peristalsis regulates the passage of drugs through the intestine. a. Laxatives will cause drugs to move through the intestine so rap-idly that they are poorly absorbed.

E.

Increases in blood flow will increase drug absorption whereas a decrease in blood flow will decrease drug absorption. 1. Epinephrine reduces blood flow and is used in combination with local anesthetics [lidocaine and procaine] to decrease their absorption into the blood (rapidly hydrolyzed) and to prolong their duration of action.

III.

INTERACTIONS ASSOCIATED WITH DRUG EXCRETION A. Renal tubular reabsorption of drugs is altered by drug ionization. 1. Reabsorption of bases (antihistamines, amphetamines, etc.) is decreased by NH4Cl (decreased pH) and increased by NaHC03 (increased pH). Reabsorption of acids (aspirin, phenobarbital, etc.) is decreased by NaHCO3 (increased pH) and increased by NH4Cl (decreased pH).

2.

B.

Renal tubular secretion is altered by drug competition for carriers. 1. Organic acids (penicillin, methotrexate, salicylates, probenecid [gout, blocks secretion of acidic drugs]) compete for specific acid carriers and when two acids are present simultaneously they will alter renal drug clearance. Organic bases (acetylcholine, histamine, morphine, atropine, etc.) compete for base carriers and when two bases are present simultaneously they will alter renal drug clearance.

2.

IV.

INTERACTIONS ASSOCIATED WITH DRUG METABOLISM A. Inhibition of drug metabolism rapidly increases the half-life (t 1/2) of various drugs. A reduction in drug dose is necessary to maintain the appropriate drug response.

1.

Alcohol is both an inducer (chronic) and inhibitor (acute). a. Chronic alcohol intake induces (CytP450) drug metabolism. 1. Disulfiram is used to discourage alcohol consumption since this agent inhibits acetaldehyde dehydrogenase (ethanol metabolism) and causes acetaldehyde to accumulate (toxic).

b. 2.

Acute alcohol intake inhibits the metabolism of drugs.

Monoamine oxidase inhibitors (Pargyline [antidepressant]) inhibit metabolism. a. Sympathomimetic amines (amphetamine, ephedrine [antidepressant] , etc.) accumulate and produce greater response (hypertension). Foods containing tyramine (chocolate, wines, cheeses, etc.) also produce hypertension.

b.

3.

Tricyclic antidepressants (Imipramine) reduce the inactivation of epinephrine and produce hypertension when epinephrine is administered. Chloramphenicol [antibiotic, DM inhibitor], cimetidine, allopurinol [gout, DM inhibitor] and disulfiram are a few of the drugs that rapidly inhibit drug metabolism.

4.

B.

Stimulation (induction) of drug metabolism is slow (days) and results in a re-duction in the half-life (t ) of drugs. More drug must be administered to maintain the appropriate drug response. 1. Phenobarbital, rifampin [antibiotic] and phenytoin [anticonvulsant] are a few of the drugs that induce their own metabolism as well as many other agents. Smoking and chronic alcohol intake are other common inducers.

2.

V.

INTERACTIONS ASSOCIATED WITH DRUG DISTRIBUTION A. Albumin binds many drugs (inactive) which can be displaced (active) by various drugs to produce a significant increase in drug response. 1. Plasma bilirubin is high in infants at birth and is primarily bound to albumin. However, sulfonamides [antibiotics] and salicylates can displace bilirubin and cause brain dysfunction (kernicterus). Dicumarol (anticoagulant) is highly bound to albumin and readily displaced (causes hemorrhage) by sulfonamides and salicylates. Tolbutamide (reduces blood sugar) is also highly bound to albumin and readily displaced (hypoglycemic shock) by salicylates and sulfonamides.

2. 3.

VI.

RECEPTOR INTERACTIONS IN VARIOUS TISSUES. A. B. C. Acetylcholine (agonist) increased salivation blocked by atropine (antagonist). Norepinephrine (agonist) causes contraction of arterial vasculature, which is blocked by [vasodilator, antihypertensive agent] (antagonist). Isoproterenol [increased heart rate, shock] (agonist) increased heart rate blocked by propranolol [decreased heart rate, ischemic heart disease] (antagonist). CNS Depressants (barbiturates) are antagonized by CNS stimulants (amphetamine, caffeine). Combinations of CNS depressants (alcohol, barbiturates and antihistamines) produced marked CNS depression.

D. E.

VII.

AN EXAMPLE OF HOW DRUG COMBINATIONS INFLUENCE DRUG RESPONSE (PROBLEM). A. Drug A 1. 2. Drug A is administered by iv infusion (no absorption effects). Drug A is a weak acid. a. 3. Drug A's ionization will be altered by changes in pH.

Drug A is highly bound (90%) by plasma albumin. a. Drug A can be displaced by other drugs.

4.

Drug A is rapidly metabolized by the liver. a. Inhibition or activation of metabolism will alter Drug A clearance.

5.

Drug A is secreted rapidly by the kidney. a. Competition between acid drugs for secretion.

6.

All drugs are administered at the points indicated by the arrows. Explain the potential interactions between Drug A and the other drugs that might explain the alterations in drug A's response and plasma levels.

B.

Drug B's effect could be a result of 1. Decreased drug metabolism;

2. 3. 4. C.

Displacement of drug from albumin; Decreased renal drug secretion (competition); Increased renal reabsorption of drug (ionization);

Drug C's effect could be a result of: 1. Decreased renal reabsorption

D. E.

Drug D's effect is an example of potentiation or synergism. Drug Es effect is an example of antagonism.

DRUGS TO REMEMBER: Alcohol [CNS depressant, chronic DM inducer, acute DM inhibitor] Caffeine [CNS stimulant], Phenobarbital [CNS depressant, inducer of DM], Cimetidine [treatment of ulcers, DM inhibitor], Cholestyramine [cholesterol lowering agent, adsorbs drugs in GI], Dicumarol [anticoagulant], Acetylcholine [neurotransmitter, blocks salivation], EDTA [metal chelator, treatment of Pb poisoning], Tetracycline [antibiotic], Quinolones [antiobiotic], Digitoxin [congestive heart failure], Morphine [analgesic], Antacids [peptic ulcers], Epinephrine [neurotransmitter, vasoconstrictor], Antihistamines [reduce allergic reactions], Amphetamines [CNS stimulant], Aspirin and Salicylates [analgesic, antipyretic], Penicillin [antibiotic], Methotrexate [cancer chemotherapy], Probenecid [gout, blocks secretion of acidic drugs], Histamine [neurotransmitter, inflammation], Morphine [opiod analgesic], Atropine [eye dilator, reduces salivation, etc.] Disulfiram [drinking deterrent, inhibits DM], Pargyline [antidepressant], Ephedrine [vasoconstrictor, broncodilator] Imipramine [antidepressant], Chloramphenicol [antibiotic, DM inhibitor], Allopurinol [gout, DM inhibitor], Rifampin [antibiotic, DM inducer], Phenytoin [anticonvulsant, DM inducer] Sulfonamides [antibiotics], Norepinephrine [neurotransmitter, vasoconstrictor], Prazosin [vasodilator, antihypertensive agent], Isoproterenol [increased heart rate, shock] , Propranolol [decreased heart rate, ischemic heart disease], Iron [anemia], NH4Cl [urine acidifier] and NaHCO3 [urine alkalinizer]