Drug Interactions Flashcards
What other factors (other than drug interactions) influence inter-individual variability in response to drugs?
- Age
- Gender
- Nutritional status (obesity)
- Smoking/Alcohol
- Disease states (kidney, liver)
- Genetic polymorphisms
Define pharmacodynamics and pharmacokinetics.
Pharmacodynamics are the effects of the drug on the body (competition at receptors)
Pharmacokinetics are how the body handles the drug (alterations in plasma levels and/or tissue concentrations)
What are the 4 processes of pharmacokinetics?
(ADME) Absorption Distribution Metabolism Excretion
What are mixed drug interactions?
Have both pharmacodynamic AND pharmacokinetic interactions
What are sporadic interactions?
Occur in small number and are not yet predicted from known properties of drugs
Ex: sporadic neurotoxicity on Lithium and Antipsychotics
Examples of things causing increased vs decreased absorption?
Increased: drugs that speed gastric emptying (metoclopramide) or inhibit motility (TCA’s, marijuana) or inhibit gut enzymes (MAO)
Decreased: Charcoal, Orlistat
Food (Increase Ziprasidone/Lurasidone, Effects thyroxine)
What are some things that affect drug distribution?
- Regional blood flow
- Lipophilicity
- Adipose/lean body mass
- Protein binding
- Drug transport proteins
What is the most important pharmacokinetic process in Psychiatry?
Metabolism
What are the 2 phases of metabolism?
Phase 1: Oxidation, reduction, hydrolysis
— Often rate-limiting, can produce active metabolites subject to phase 2 metabolism
Phase 2: Conjugation, acetylation
— Produce typically inactive metabolites which are ready for renal excretion
— Some agents undergo phase 2 metabolism only (Valproate, most Benzo’s)
Describe what happens when the metabolism of a substrate is inhibited vs induced?
Inhibited: rapid impact, substrate levels rise quickly
Induced: gradual impact, substrate levels decline slowly
- *Substrate: a drug metabolized by a given enzyme
- *Inhibitor/Inducer: drug that alters metabolic activity of enzyme
What are the mechanisms of Inhibition? Inducers?
Inhibition: Competitive inhibition, covalent binding, or enzyme destruction
Induction: up-regulation of transcription, enhanced synthesis of enzyme
Think induction when you see…
Carbamazepine Phenobarbitol Dilantin Primidone Prednisone Rifampin Chronic alcohol Chronic smoking Cruciferous veggies St Johns Wort
Think inhibition when you see…
Azoles Macrolides Fluoroquinolones Antiretrovirals Isoniazid Disulfiram (Antabuse) SSRI’s Valproic acid Duloxetine Wellbutrin Beta blockers Acute alcohol CCB’s Grapefruit juice Amiodarone
What percentage of drugs are Cytochrome P450 Isoenzymes responsible for metabolizing?
Greater than 80% of available drugs
Responsible for phase 1 metabolism of a wide variety of endogenous and xenobiotic substrates.
What accounts for individual differences in CYP450 activity?
- Genetics
- Disease states and environmental factors
What happens if you are genetically a poor metabolizer?
- Relatively insensitive to induction and inhibition
- Higher baseline concentrations of parent drug and lower levels of metabolite
- Exaggerates effects of certain drugs at low doses, and diminished effects of pro drugs
What other enzyme systems may be involved in Drug Metabolism?
- Flavin-containing monooxygenases (FMOs)
- Uridine diphosphate-glucuronosyl transferases (UGTs)
- Methyltransferases
- Sulfotransferases
**Drugs can be metabolized through multiple pathways
What are some drug interactions with Lithium?
Increased Lithium levels with:
- Thiazides
- ACE inhibitors/ARBs
- NSAIDs, COX-2 inhibitors
- Metronidazole, Tetracycline
What are some important drug interactions with Carbamazepine?
Reduced levels of OCP’s and CCBs
Can cause pregnancy!
What psychiatric drugs are affected by Oral contraceptives?
Inducers for Lamotrigine and Valproate
