Valentovic - Drug Interactions Flashcards
Facts:
- Interactions lead to adverse reactions
- Over 2 MILLION serious drug interactions/year
- 2.8% of hospital admissions
- 100,000 DEATHS annually
- $136 BILLION annually
- Theoretical vs. clinical impact
The following are risk factors, predisposing patients to _______.
– Multiple medications
– Female gender –> oral contraceptives + Rifampin, antibiotics or St. John’s wort
– Extremes of age (babies - lower protein binding to drugs)
– Major organ dysfunction
– Genetic polymorphisms
– Metabolic and endocrine dysfunction (altered metabolic rates!)
– Other medical issues
Drug Interactions
What term?
– “what the body does to the drug”
– follows “ADME” model
- Change in absorption, distribution, metabolism, excretion
- Affecting its delivery to the site
Pharmacokinetic
What term?
– “what the drug does to the body”
– Additive/antagonistic/synergistic
- Affecting its Mechanism of action
– Can occur at receptor or during signal transduction
– Precipitant/causing drug (Drug A) modifies the object drug (Drug B) even at normal drug concentrations (alcohol & APAP or benzodiazepines)
Drug A: Alcohol —–> Drug B: Acetaminophen (tylenol)
Pharmacodynamics
What is the pharmacodynamic effect seen with alcohol and benzodiazepines?
Additive effect
What is the pharmacodynamic effect seen with diazepam (BZD) and flumazenil?
i.e. Naloxone and Oxycodone - competing at the receptor
Antagonistic effect
What drug worsens respiratory depression in surgery with anesthesia?
- Have nondepolarizing neuromuscular activity (presynaptic ↓Ach & ↓ postsynaptic activation of receptor) = lower respiration
- Respiratory paralysis can happen alone
- Drug interaction with *Succinylcholine increases risk of respiratory depression (magnifies its effect)
- Reverse with Neostigmine**
Aminoglycosides (especially Tobramycin), possibly taking for infection
What are the 4 Pharmacokinetic mechanisms of drug interactions?
Absorption, Distribution, Metabolism, Elimination
Pharmokinetic Mechanism
Absorption mechanism:
- Drug-drug, drug-food interactions can cause a change in _____, ______, _____ or _______.
- Complexes with other drugs
- binds drugs in stomach
- prevents either drug from being absorbed
- pH
- Transport (p-glycoprotein - grapefruit blocks efflux in the GI tract)
- Chelation (calcium and tetracycline - binds it and lowers levels)
- Metabolism
How can you overcome the problem of drug interactions with absorption?
Stagger the doses of the two drugs!
Problems with absorption:
-
Antacids of calcium, magnesium, or aluminum (precipitant drugs - form complexes) can interact with what drug?
- What antifungal agents need an acid environment?
- Cholestyramine (resin binds acidic drugs) can interact with what drug(s)?
- > What should you do to solve this problem?
- Ferrous sulfate, calcium, magnesium, or aluminum can interact with what immunosuppressive agent diminsing immune suppression?
*All prevent absorption!
- Tetracycline
- Ketoconazoles
- Digoxin, Warfarin
- stagger the drugs
- Mycophenolate mofetil (inhibitor of Inosine monophosphate dehydrogenase - IMPDH)
Changes in GI motility may change the ______ of absorption, but not the _______ of absorption!
- Shift in the peak time, but not in the bioavailability!
- Decreased gastric motility - examples?
- > Dec rate of absorption
- > No change in extent of absorption (Bioavailability)
- Increased gastric motility - example?
- >shorter peak time; greater peak effect
- ->no net change in absorption (bioavailability)
Rate
Total Extent
Amitriptyline (Anticholinergic effects), Morphine
Metoclopramide
Some drugs require acidic environment of the stomach to be absorbed - pH may change!
- H2 agonists (cimetidine, ranitidine) decrease absorption of ____ and _____
- PPI (omeprazole) decrease absorption of _____, ___ and ______
*** Increased pH, more ionized drug, less drug absorption aka lower blood levels –> Therapeutic failure more likely!
- Ketoconazole, Intraconazole
- Atazanavir (HIV protease inhibitor), Ketoconazole, Intraconazole
What is the ATP-dependent molecular transport that protects the body from harmful substances?
- “Gatekeepers” of metabolism
- Transport lipophilic molecules
- Apical membrane of enterocytes of small intestine epithelium
- exporting
- Helps facilitate excretion of drugs into gut lumen, bile, urine, out of brain
P-glycoprotein (PGP)
What are some inhibitors of P-glycoprotein?
So, p-glycoprotein inhibitors result in more bioavailability bc you have blocked the export in the small intestine.
***Some inhibitors of CYP3A4 also inhibit P-glycoprotein
Inhibitors: ketoconazole/itraconazole, erythromycin, grapefruit juice, clarithromycin
Drug transporters:
- ______ and _______ are inhibited by Ketoconazole and itraconazole
- Therefore, the efflux transporters are BLOCKED resulting in more absorption! what happens to the half life of drugs?
- CYP3A4, P-glycoprotein
- Half life is increased! Increased bioavailability
What is the relationship between oral contraceptives and antibiotics?
– Enterohepatic circulation
– Estrogen hydrolysis
greater therapeutic failure if OC’s taken with antibiotics (erythromycin)
What pharmacokinetic interaction?
-
Involves protein binding sites - mostly binding displacement
– Drug must be >90% bound******** (10% free fraction)
– Increased free serum drug concentration - distributes in the tissues
– Not always clinically significant
* Drugs that have limited distribution * More likely with drugs with **narrow therapeutic window** – **Warfarin 99% bound, 1% Free Fraction** (unbound drug distributes in to tissue)
– Sulfamethoxazole-trimethoprim (Abx) increase INR >6
Distribution
What metabolic component?
- Present in the endoplasmic reticulum
- Primarily Phase 1 metabolism (biotransformations)
Cytochrome P450 system
What type of CYP450 interaction?
– Increased concentration of object drug (Inc. t1/2 of the drug)
– Known examples:
*****Ketoconazole, cimetidine, erythromycin, grapefruit juice (furanocoumarins & naringin), clarithromycin
Inhibition
What are some inhibitors of CYP450? ****
Ketoconazole, cimetidine, erythromycin, grapefruit juice (furanocoumarins & naringin), clarithromycin
What type of CYP450 interaction?
– Decreased concentration of object drug (blood level goes down bc increased clearance)
– Known examples: phenytoin, rifampin, carbamazepine, St. john’s Wort
Inducers
What are some inducers of CYP450?
phenytoin, rifampin, carbamazepine, St. john’s Wort
What CYP isoenzyme?
Substrate: Theophylline
Inhibitor: Amiodarone
Inducer: Phenobarbitol
CYP1A2
