Npsc521P Lecture 8 Clinic Implications, Drug Interactions

Front 1

Describe the clinical problems with drugs discussed in this study unit relative to :
a. Route of administration

Back 1

some patents cannot swallow tablets or capsules (may have had head or neck cancer). Think about liquids, suspensions or injections
i. E.g. American Heart Association recommends Ampicillin for patients predisposed to cardiac valvular endocarditis (IV or IM if they can’t oral)
ii. Ketorolac (toradol) is used in post-surgical dental pain. First dose = IM (other methods cause GI Bleeding) then oral tablets

Front 2

Describe the clinical problems with drugs discussed in this study unit relative to :
b. Absorption:

Back 2

Absorption from GI tract into blood stream can be affected by other drugs.
i. Antacids containing divalent ions, when taken with drugs such as tetracyclines (e.g. periostat doxycycline), will inhibit the gastrointestinal absorption of the tetracycline antibiotic thereby reducing the level in bloodstream and compromising the therapeutic effectiveness. BOARD QUESTION. Antiacids chelate with tetracycline producing large molecules that can’t be absorbed
ii. Ferrous sulfate (FE2+  iron pills) when taken with tetracycline will prevent the GI absorption of the antibiotic.
iii. Alcohol will enhance the GI absorption of diazepam (valium family) thereby increasing peak blood levels of the drug over a short time period. Keep in mind that Valium half life is 50 – 70 hours and patient should not take alcohol for at least 5 days

Front 3

Describe the clinical problems with drugs discussed in this study unit relative to :
c. Distribution:

Back 3

Plasma protein displacement of one drug by a second drug increases its free concentration in the bloodstream
i. Aspirin interacts with the coumarin anticoagulants by displacing coumarin from plasma protein binding sites, this leads to increased coumarin effect which has resulted in internal bleeding.
ii. Aspirin can also displace, from plasma protein the oral hypoglycemic drugs used to treat non-insulin dependent diabetes mellitus, resulting in an increased hypoglycemic effect.

Front 4

Describe the clinical problems with drugs discussed in this study unit relative to :
d. Drug metabolism:

Back 4

A decrease or inhibition in microsomal drug metabolizing enzymes by one drug will result in reduced biotransformation of other drugs. This may result in an increase in drug action due to the lack of metabolic inactivation.
i. Antibiotics erythromycin and clarithromycin are potent CYP3A4 inhibitors. Drugs which are substrates for CYP3A thus will not be metabolized as efficiently. This action may lead to increased serum levels of diazepam (Valium).
ii. Grapefruit juice inhibits CYP3A4 in the intestine. Drugs which are substrates for intestinal CYP3A4 thus will not be metabolized as efficiently leading to greater blood levels of parent drug. This action has lead to increased serum levels of nifedipine by grapefruit juice.

Front 5

1. Define drug interactions:

Back 5

When two or more drugs are taken at the same time by a patient, the resultant effects may often be different from the effects produced by each drug when given alone.

Front 6

2. Describe the classic interaction which defined this field in the 1950s

Back 6

a. The classic drug interaction observed in the 1950s which defined this field of adverse drug effects was the interaction between phenobarbital, a sedative, and warfarin (Coumadin), an anticoagulant.
b. The patient, medicated with phenobarbital, was given warfarin (Coumadin) at a dose to just barely affect the clotting process for protection against embolism formation. While at this dose of warfarin (Coumadin), the phenobarbital was withdrawn. Forty-eight hours later the patient experienced internal bleeding and near death from an apparent overdose effect of the warfarin (Coumadin).
c. The phenobarbital caused a certain rate of metabolism of the warfarin (Coumadin) in the liver while the two were taken simultaneously. When the phenobarbital was withdrawn, the rate of warfarin (Coumadin) metabolism decreased severely, resulting in significant blood levels of the anticoagulant. This caused the overdose effect of bleeding. It was discovered that the phenobarbital was the culprit.
d. Unknown to the physician, the warfarin (Coumadin) dose was arrived at on the basis of its phenobarbital-induced metabolism. With the phenobarbital absent, the “normal” warfarin (Coumadin) dose became an overdose.
e. So Phenobarbital had been elevating the CYP enzymes that metabolize Coumadin

Front 7

3. Describe the significance of drug interactions:

Back 7

a. In general, when an interaction occurs, the net drug response may result from enhancement of the effects of one or the other drug, the development of new effects that are not observed with the drug alone, or the inhibition of the effect of one drug by another.

Front 8

4. List the general mechanisms of drug interactions:

Back 8

a. Drugs having similar effects
b. Metabolism effects
c. Absorption effects
d. Displacement from plasma protein

Front 9

5. List an example for each mechanism of drug interactions.

Back 9

Drugs Having similar effects
i. Patient could be taking a tranquilizer known as Valium. This will be potentiated by the sedative effects of Benadryl, a common antihistamine  could result in serious motor impairment and inebriation.
b. Metabolism Effects:
i. Metabolism of one drug (A) by liver can be increased by concurrent administration of a second drug (B). In this way the effectiveness of drug (A) will be reduced. The more rapid metabolism of drug A results in the loss of its effect.
1. E.g. Warfarin (Coumadin) and Phenobarbital  Clot could form unexpectedly due to the loss of effectiveness of warfarin.
ii. Metabolism of one drug by liver can be decreased by concurrent administration of a second drug. So effectiveness of first drug is enhanced.
1. Erythromycin will increase the action of Theophylline because it inhibits the CYP family that metabolizes theophyline
c. Absorption effects:
i. The gastrointestinal absorption of drugs may be inhibited by binding resins such as cholestyramine and by certain metal ions that chelate the tetracycline antibiotics.
1. If cholestyramine (controls cholesterol) is given with digoxin (heart med), digoxin is not absorbed
2. If antiacid (Tums  calcium carbonate) is given with tetracycline then tetracycline is not absorbed
d. Displacement From Plasma protein
i. Some drugs compete with each other for binding sites on plasma proteins and if this happens the unbound concentration of one or both drugs might increase and thus the effects would also increase
1. Ingestion of tolbutamide (orinase)  diabetes and aspirine together causes displacement by aspirin and increased hypoglycemic reaction