Drug Interactions Flashcards
Two major mechanisms of drug interactions
Pharmacokinetic interaction - A change in the pharmacokinetics of one drug caused by the interacting drug e.g. an inducer of hepatic enzymes
Pharmacodynamic interaction - A change in the pharmacodynamics of one drug caused by the interacting drug. e.g. additive action of two drugs with similar effects.
The consequences of these interactions can be:
Additive - The effect of two drugs given together is equal to the sum of the responses to the same drugs given separately
Antagonistic - the effect of two drugs given together is less than the sum of the responses to the same doses given separately
Synergistic - the effect of two drugs given together is greater than the sum of the two responses when they are given separately.
What are drug incompatibilities
In vitro drug interactions (i.e. a drug precipitating in the presence of another)
What is ADME
Interactions based on absorption
Interactions based on Distribution and Binding
Interactions based on metabolic clearance
Interactions based on renal function (excrettion)
Characteristics of Interactions based on absorption
- have a large surface area upon which the drug can be adsorbed (drug:drug interactions)
- bind or chelate
- alter gastric pH
- alter gastrointestinal motility
- affect transport proteins such as P-glycoprotein and organic anion transporters.
How can changing stomach pH affect absorption
Increasing stomach pH can reduce absorption
EX: ranitidine can reduce bioavailability of ketoconazole
Characteristics of Interactions based on Distribution and Binding
- competition for plasma protein binding
- displacement from tissue binding sites
- alterations in local tissue barriers, eg, the blood-brain barrier
EX: Phenylbutazone can displace warfarin from binding sites on albumin and the free warfarin will cause excessive anti-coagulation.
Phase I vs Phase II
Phase I - Cyp enzymes
Phase II - glucuronidation and sulfation
What is P450 induction
Induction of P450’s in the liver occurs relatively slowly - 7-10 days, because new enzyme is synthesized and accumulated.
Examples of P450 inducers
barbiturates, carbamazepine, ethanol, phenytoin, primidone, and rifampin
What is inhibition of P450 inbhibition and how quick is it?
Inhibition of P450’s is more rapid because often the inhibiting drug binds to the P450 and the P450 can no longer function. The inhibiton occurs as long as it is present. However, if the half-life of the affected drug is long, it may take a week or more (three to four half-lives) to reach a new steady-state serum concentration
Examples of P450 inhibitors
cimetidine, disulfiram, erythromycin, fluconazole, furanocoumarins (substances in grapefruit juice), ketoconazole, proposyphene, sulfonamides.
Impact of drugs that reduce hepatic blood flow and example
Drugs that reduce hepatic blood flow may also reduce clearance of other drugs metabolized in the liver, especially those with flow-limited hepatic clearance like verapamil and morphine.
Propranolol
Drugs that interact with warfarin
How can renal clearance be affected
- Drugs that are weak acids or weak bases may be influenced by other drugs that affect urinary pH. EX: methamphetamine (excreted better in acidic urine)
- Active secretion (via P-glycoprotein, organic anion transporters, and organic cation transporters) into the renal tubules is an important elimination pathway. Inhibition of these transporters can inhibit renal elimination with attendant increase in serum drug concentrations.
Examples of drugs that are eliminated by P-glycoprotein
digoxin, cyclosporine, dabigatran, colchicine, daunorubicin, and tacrolimus. The plasma concentration of these drugs can be increased by inhibitors of P-glycoprotein including amiodarone, clarithromycin, erythromycin, ketoconazole, ritonavir, and quinidine.
Example of how blocking an organic ion transporter will affect drug levels
Two ways drugs can have pharmacodynamic effect
A. Interactions Based on Additive Effects
B. Interactions Based on Opposing Actions or Effects
Uses of St Johns Wart and interactions
St. John’s wort is most often used as a dietary supplement for depression. People also use it as a dietary supplement for other conditions, including menopausal symptoms, attention-deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder. It is used topically for wound healing.
St. John’s wort can interact in dangerous, sometimes life-threatening ways with a variety of medicines.
Uses of ginseng
Today, Asian ginseng is used as a dietary supplement to improve general well-being, physical stamina, and concentration; stimulate immune function; slow the aging process; and relieve various health problems such as respiratory disorders, cardiovascular disorders, depression, anxiety, erectile dysfunction, and menopausal hot flashes.
There’s currently no conclusive evidence supporting any health benefits of Asian ginseng.
The most common side effects of ginseng are headaches, sleep problems, and digestive problems.
Other herbal interactions
Major food interactions
grapefruit juice, as it irreversibly inhibits P450 3A4 (recall CYP450 3A4 plays a role in the biotransformation of 40-50% of the most commonly prescribed drugs). Particularly affected are the lipid lowering drugs (i.e. atorvastatin and simvastatin).
cruciferous vegetables* (i.e. broccoli, cauliflower, brussel sprouts) should not be mixed with blood thinners such as warfarin. These foods contain a lot of vitamin K, and can reduce warfarin’s ability to thin blood, thereby raising the risk of heart attack or stroke.
Interactions: Bananas, green leady vegetables, oranges, salt substitutes
Interaction: Real black licorice or supplements with licorice extract
