Drug Interactions

Drug Interactions

• occur when efficacy and/or toxicity of drug is changed by another medication, food, or drink that is consumed along with the drug

• best reserved for reactions that go on within the body of patient

• pharmaceutical incompatibility and drug interference with biochemical assays or other tests carried on body fluids are NOT considered drug interactions

Risk factors for drug interactions

• polypharmacy/multiple prescribers

• narrow therapeutic index

• OTC medications

• genetic disposition

• morbidity

• CHNET

• External

  • polypharmacy

  • environmental

  • diet

  • alcohol

  • herbal supplements

  • smoking

• Internal

  • age

  • gender

  • genetics

  • disease

  • pregnancy

CHNET interplays

• cytokine-hormone-neurotransmitter-enzyme-transporter

• disease, illness, and long-term concomitant use of certain meds alter the balanced network of CHNET and affects PK/PD of given drug

Pharmacokinetic interactions

• altered absorption, distribution, metabolism, or excretion

• results in either treatment failure (drug conc too low) or toxicity (drug conc too high)

Pharmacodynamic interactions

• direct effect on receptor functions

• interference with biological or physiological control process

• additive/opposed pharmacological effect

Absorption Interactions

• for drugs taken chronically, interaction affecting absorption rate has LITTLE impact on effect

• absorption rate indicates how quick drug can reach systemic circulation

• exception: analgesics where rapid response is needed

• factors that result in change in EXTENT of absorption have significant impact

  • affects bioavailability

Mechanisms involved in absorption interactions

• direct mechs:

  • Chelation

    • ex. tetracycline chelated by calcium

  • Binding

    • ex. cholestyramine binds to bile acids and other negatively charged drugs

• indirect mechs:

  • GI pH: affect drug dissolution and lipophilicity

  • GI motility: affect intestinal transit time

    • impact bioavailability of oral

    • slow intestinal motility, more absorption

  • active transporters: presence of inhibitors or inducers of efflux and influx active transporters in intestine

Grapefruit juice and Fexofenadine

• GFJ is rich in flavonoids and furanocoumarins

• inhibits activitys of CYP 3A4, P-glycoprotein, and Organic anion-transporting polypeptides

  • P-gp: efflux active transporter able to limit oral drug absorption and tissue distribution

  • OATPs: influx active transporters responsible for substance uptake

• Fexofenadine is substrate of both P-gp and OATPs

  • minimally metabolized

• GFJ is more potent OATP inhibitor than P-gp inhibitor

• concurrent admin of fexofenadine with GFJ reduces effect of fexofenadine by decreasing the oral bioavailability of fexofenadine

Distribution Interactions

• plasma protein binding

  • common but minor

  • only unbound drug molecules are pharmacologically active

  • displacement of plasma protein binding usually does NOT potentiate drug effects because unbound drug molecules are also free to be metabolized or excreted from the body

• tissue penetration

  • rare but important

  • inhibition or induction of active transporters comprising BBB may lead to increase in drug level in brain

  • Ex. Kava-Kava may increase brain concentration of SSRIs by inhibiting P-gp in the BBB

Metabolism Interaction

• phase I reactions: usually CYP450 enzymes involved

  • catechol reactions, functional groups changed

• phase II reactions: UGT, not common

  • conjugation reactions, parent drug unchanged but molecule added on

• Enzyme inhibition

  • competitive inhibition: 2 drugs metabolized by same enzyme system, and one of them has higher binding affinity for the enzyme protein, resulting in the inhibition of metabolism of the other drug

  • non-competitive (allosteric) inhibition: drug inhibits an enzyme that itself is not metabolized by or binds to a different binding site on an enzyme that reduces the metabolic/catabolic activity of the enzyme

• Enzyme induction

  • decreased plasma level of a drug due to induced enzyme activity by another drug

  • most cases are allosteric

  • rarely, a drug may induce enzyme system by which it is metabolized

Herbs that modulate metabolism

• Ginkgo

• Garlic

• Green Tea

• Ginger

• Rosemary

• Ginseng

• St. John’s wort

• grape seed extract

St. John’s Wort and Oral contraceptive interaction

• metabolism based

• St. John’s wort is inducer of CYP3A4 and P-gp

• concomitant use of St. John’s wort increases the clearance of norethindrone and reduces the half-life of ethinyl estradiol

• st. john’s wort increases the metabolism of ethinyl estradiol and norethindrone partly through abiltiy to induce CYP3A

• St John’s wort induces CYP 2C9, CYP 3A4, CYP 1A2, P-gp

Cheese reaction

• metabolism-based interaction

• tyramine interacts with MAO inhibitors (isocarboxazid, phenelzine, selegiline) causing a sudden increase in blood pressure

• tyramine-rich foods: aged cheese and meat, red wine

• isocarboxazid and phenelzine: antidepressants

• selegiline: Parkinson’s

• tyramine triggers noradrenaline release and inhibits noradrenaline metabolism by MAOA in peripheral adrenergic neurons

Excretion Interactions

• Renal Excretion

  • glomerular filtration

  • active tubular secretion

  • tubular reabsorption

• some herbal products may affect renal clearance by

  • displacement of plasma protein binding results in an increase in glomerular filtration of drug

  • acting as inhibitor or stimulator of active transporter to modulate active secretion

  • changing urine pH to alter tubular reabsorption

• Enterohepatic circulation

  • ex. Gnaphalium affine extract enhances the efficacy of benzbromarone through the inhibition of CYP2C enzymes leading to the increased bioavailability and enterohepatic recirculation of BBR

• Biliary Excretion

  • requires active transport

  • herbal products that are substrate or inhibitors of active transporters may affect

  • ex. Piperine and Capsaicin inhibit efflux transporters and decrease biliary excretion of doxorubicin

Pharmacodynamic interactions

• based on pharmacologic mechanisms of drugs having additive/synergistic effect or antagonistic effect on each other

• usually predictable based on understanding mechanisms of action

  • on-target toxicities

• predicting PD interactions can be challenging if our understanding of the mechanisms of action is incomplete

  • off-target toxicities, idiosyncratic reactions

• extent of drug interactions with herbs varies among individuals

Additive/Synergistic herb-drug interactions

• Serotonin Syndrome

  • caused by excessive serotonin in brain

  • PD interaction between St. John’s wort and SSRIs

  • St. John’s wort works similarly to SSRI

  • altered mental status, neuromuscular hyperactivity, autonomic stability

• Gingko-warfarin

  • gingko inhibitions platelet aggregation by inhibiting platelet activating factor activity

  • additive anticoagulant effect may lead to potential bleeding

Antagonistic herb-drug interactions

• Morindamorindiodes root, Morindalucida leaf, and Vernonia amygdalina lead exhibit anti-plasmodial effect

• used in combination with artesunate (first line treatment for severe marlaria), antimalarial efficacy of artesunate is reduced

• possible mechs: reduced bioavailability, development of drug resistance, competitive antagonism

Challenges in prediction of herbal drug interactions

• herbal meds contain 100s of constituents with differential quantitative presence of active constiuents along with inhibition and/or induction potency for drug-metabolizing enzymes, transporters, and receptors

• indirect HDI may occur bc of CHNET interplays

• inhibition and/or induction of CYPs and ABC transporters by herbal meds may vary based on confounding factors

• many herbal meds are used chronically, and interaction potential may not be replicated in experimental or clinical studies

• considerable variability in the active contents of herbal constituents due to the lack of standardized quality control