Drug-drug interactions

Drug Drug Interactions (DDI) Include:

-Prescription Drugs over the counter drugs illicit drugs food/nutritional supplements natural health products environmental chemicals

Classification of Drug Interactions (3 types)

1. unintentional vs intentional 2. direct vs indirect 3. pharmacodynamic vs pharmacokinetic

Location within the body that drug interactions can occur

1. the same site on the same receptor 2. different sites on the same receptor 3. distinct locations in the body

PD interactions greater effects

1. duplications 2. additive effects 3. synergistic effects

Duplication (drug interaction) with example

leads to greater effect. same drug in two different product ex. tylenol and neocitran both contain acetaminophen

Additive effects with example

drugs are different but they have the same effect ex. both propanolo and timolol both bind to the same beta adrenergic receptor

synergistic effect with example

(AKA supra-additive) both drugs have similar effects on the body and lead to an effect greater than just additive ex. ethanol + diazepam both have a sedative effect

PD interactions lesser effects

antagonistic competitve binding and negative allosteric modulator

Interactions affecting absorption (6 things)

• physiochemical interactions mucosal damage GI motility Altered bacterial flora Gastric ph Drug transporters

Ion exchange binding

drugs with opposite charges are attracted to each other and may not be absorbed when paired drugs may also stick to delivery system and reduce absorption

dissolution and complexation

the therapeutic agent may dissolve in a material that is not absorbed or bind to something that prevents their absorption

examples of dissolution and complexation

reduction in absorption of fat soluble vitamins when taken with mineral oil antibiotics form complexes with the metals in some antacids both reduce absorption

mucosal damage (what drugs cause mucosal damage)

some drugs impair the barrier function of the GI tract NSAIDS (nonsteroidal anti-infammatory drugs) sometimes damage the GI mucosa making it easier for other drugs to enter

GI motility, what are drugs that increase and decrease it

drugs that speed up or slow down GI motility can affet the rate of absorption cathartics increase GI motility opioids decrease GI motility

drug metabolism examples

• antibiotics can kill the helpful bacteria in the gut reducing bacterial metabolism of other drugs such as digoxin first pass effect can be modified by other drugs

acidic drug ionization equation

R-COOH -> R-COO- + H+ as you increase the pH above the pka, a greater amount is charged

basic drug ionization equation

R-NH3+ -> R-NH2 + H+ as you increase pH above the pKa, more of the drug is uncharged

Uptake transporters

OAT, OATP, OCT, OCTN

Efflux Transporters

MDR, MRP BCRP

explain digoxin +propafenone interaction

MDR1 receptor is an efflux receptor (pgp) and digoxin is a substrate of it, however propafenone is a pgp inhibitor

Fexofenadine + Grapefruit Juice interaction, (and what transporter)

OATP1A2 is an uptake transporter in the intestine. grapefruit juice inhibits OATP1A2, which means less fexofenadine is absorbed (which is an allergry drug)

Interactions affecting distribution (6 things)

Displacement from plasma proteins, displacement from tissue binding sites, chelation, alterations in blood flow, alterations in local tissue barriers, interactions at drug transporters,

Phenytoin and warfarin protein binding

they both bind to albumin and compete for binding sites. displacement increases free drug levels leading to toxicity risk

Chelation

the molecules of a chelating agent can form bonds with a metal ion

loperamide +quinidine

MDR1. loperamide is a substrate and quinidine is an inhibitor. Quinidine increases loperamide absorption, leading to higher plasma concentrations and risk of CNS toxicity (sedation, respiratory depression, coma).

Inhibition of drug metabolizing enzymes

acts within hours to days as a function of their half-lives, which determine when they are able to gain access to and then inhibit the enzymes

induction of drug metabolizing enzymes

may take several days to weeks for maximal effect

Interactions involving excretion

Alterations in pH Inhibition of drug transporters Induction of drug transporters

Penicillin and probenecid interaction

Its renal excretion can be inhibited by probenecid, leading to drug interactions

Example of induction of drug transporter

st johns wort induces pgp, and were also taking cyclosporine, which wasnt working as effectively because of the same transporter.