PHA3320: Drug Interactions

• PHA3320: Drug Interactions is a principle of drug action, lectured winter 2025 by Paapa Mensah-Kane (Bpharm, Mphil, Ph.D)

Suggested Readings

• Golan; Chapter 06, Katzung; Chapter 56
• Goodman & Gillman's The Pharmacological Basis of Therapeutics; Chapter 03 (pages 73–81)
• Rang & Dale's Pharmacology; Chapter 57 (pages 692-702)

Learning Objectives

• Define additive, synergistic, potentiation, antagonistic
• Compare and contrast the different types and subtypes of drug interaction mechanisms
• Describe interactions relating to absorptive, distribution, metabolic, and elimination processes
• Provide examples of food-drug interactions
• Describe pharmacodynamic drug-drug interactions and provide examples

Drug Interactions (DDI)

• Drug interactions generally refer to DDIs
• This can also refer to drug-food or drug-herb interactions
• Consider clinical significance and relevance
• Interactions imply reciprocal effects from each drug
• Some DDIs only involve the effect of one drug on the other (non-reciprocal)
• DDIs can be deleterious (harmful) or beneficial

Polypharmacy

• People commonly use more than one drug
• People have individual eating habits
• People may use OTCs, vitamins, and/or herbal supplements

Effects of Drug-Drug Interactions

• Interactions can have additive, synergistic, potentiation, or antagonistic effects

Types of Drug-Drug Interactions

• Additive effect: combined effects of two drugs equals the sum of each drug's individual effect, and can be beneficial or harmful
• Synergistic effect: combined effects of two drugs exceeds the sum of each drug's effect
• Potentiation: a type of synergistic effect where one drug exerts action and its effect is made greater by the presence of the second drug
• Antagonistic: interference of one drug with the action of another and the combined effects of two drugs is less than the sum of the effect of each drug given alone

Mechanisms of Drug Interactions

• DDIs can take place via Pharmacokinetic or Pharmacodynamic mechanisms

Pharmacokinetic Drug-Drug Interactions

• Characterized by alteration in a drug's pharmacokinetics because of the presence of another drug (or substance)
• Drug interactions influence ADME (absorption, distribution, metabolism, excretion):
• A: chelation, effect on gastric transit times, or acidity
• D: binding to plasma proteins
• M: extent of metabolism
• E: effect on e.g. acidity of urine, competition for transport

Absorption Drug-Drug Interactions

• Normal GI function alterations can change absorption of drugs from the intestinal lumen
• Drugs affecting gastric transit time, GI motility, or pH influence the rate and extent of drug absorption
• Ranitidine, an H2 receptor antagonist, and other antacids raise GI pH and may affect absorption of basic drugs such as triazolam
• Antacids with tetracyclines form poorly soluble complexes with polyvalent ions and reduce tetracycline bioavailability

Protein Binding Interactions

• Relevant for drugs that have high plasma protein binding
• For drugs like aspirin, barbiturates, phenytoin, warfarin, and valproic acid
• Significance more relevant with low T.I. drugs like warfarin
• Active drug is free (unbound)
• Acidic and neutral drugs typically bind albumin
• Basic drugs typically bind alpha-1 acid glycoprotein
• Toxic effects can be amplified from increased free drug
• Displaced drugs from binding sites can cause toxicities
• Hypoalbuminia (malnutrition, liver failure, nephrotic syndrome)
• Enhanced anticoagulant effect of warfarin with concomitant valproic acid therapy
• Patients are more prone to bleeding with concomitant valproic acid therapy

Drug Metabolism

• Drug metabolism can be impacted by inducers or inhibitors, such as grapefruit juice, protease inhibitors, and azole antifungals
• Cytochrome P450 (CYP450) Inducers: "PS PORCS" - Phenytoin, Smoking, Phenobarbital, Oxcarbazepine, Rifampin, Carbamazepine, St. John's Wort
• Cytochrome P450 (CYP450) Inhibitors: "G PACMAN" - Grapefruit, Protease inhibitors, Azole antifungals, Cimetidine, Macrolides, Amiodarone, Non-DHP CCBs

Metabolism Interactions

• Primarily involves CYP450 enzymes and can occur via induction or inhibition
• Induction increases gene expression of the target enzyme, clearances, and activation of prodrugs (possible toxicity)
• Example: CYP3A4
• Anticonvulsants (anti-seizure) are commonly used in combination and can have reciprocal DDI

Enzyme Inhibition Interactions

• Can be competitive or irreversible
• Reduced drug metabolism, increased plasma concentration
• Typical result: reduced metabolism of drug and increased plasma concentration of affected drugs
• Direct clinical consequences more likely to be severe compared to inducers
• This is due to faster onset of effects
• Enzyme Inhibitors - CYP3A4 Inhibitors:
  • Cimetidine, ketoconazole, erythromycin and grapefruit juice
• CYP2D6 Inhibitors:
  • fluoxetine, quinidine and haloperidol
• CYP2C9 Inhibitors :
• fluconazole, amiodarone
• CYP2C19 Inhibitors :
  • Omeprazole, fluoxetine
• Can be particularly hazardous with low T.I. drugs
  • warfarin & other anticoagulants, antiarrhythmics, digoxin
• Example: Terfenadine & Fexofenadine
• CYP3A4 Inhibitors: erythromycin and grapefruit juice

Enzyme Inhibition (DDIs)

• Example: L-DOPA and carbidopa.
• Levodopa, precursor to dopamine, can cross the blood-brain barrier, while dopamine cannot
• Carbidopa inhibits DOPA decarboxylase

Interactions of Excretion

• Alterations to the excretion of a drug due to another drug's presence
• Example: Penicillin and probenecid:
• Penicillin clears via tubular secretion in the kidney
• Probenecid inhibits renal tubular transport
• The result is an increase in plasma concentration of penicillin and increase in half-life
• Acidification: NH4Cl, vitamin C, cranberry juice
• Alkalinization: NaHCO3, acetazolamide (historically)

Other DDI Mechanisms

• Interference with transporters such as P-gp (P-glycoprotein): efflux pump
• Transports drugs back into the intestinal lumen and secretes substances into the renal lumen
• Prevents drugs from crossing the BBB
• Co-administration of a P-gp inhibitor or substrate may increase absorption, increase brain penetration and/or reduce renal secretion of a drug

P-gp Based DDIs

• P-gp substrates: loperamide, digoxin, fexofenadine, taxane anticancer agents, etc
• P-gp inhibitors: verapamil, quinidine sulfate, etc
• Will increase absorption and brain penetration of the drug
• May reduce renal secretion of a drug
• P-gp inducers: rifampin, St.Johns wort, Phenobarbital
• Will reduce the absorption and brain penetration of the drug
• May increase renal secretion of a drug
• Example: The P-gp inhibitor quinidine blocks the activity of P-gp in the intestine & renal tubule
• Digoxin is normally eliminated into intestine & urine by P-gp
• Concomitant administration can make the level of digoxin reach toxic drug levels

Drug-Food Interactions

• Gl absorption can be affected by concurrent use of substances that alter gastric pH, affect transport proteins, specifically bind or chelate drugs, have large surface area, and/or alter gastrointestinal motility

Monoamine Oxidase Inhibitors (MAOIs)

• MAOIs break down biogenic amine neurotransmitters
• Dopamine (DA), Norepinephrine (NE), Epinephrine (EPI), Serotonin (5-HT)
• Two isoforms: MAO-A and MAO-B
• MAO-B metabolizes tyramine
• Tyramine causes release of NE, EPI and DA

MAOIs & Food - The Cheese Effect

• Nonselective MAOIs (inhibit MAO-A & MAO-B)
• Food must be monitored
• Tyramine: an indirect sympathomimetic
• Promotes monoamine neurotransmitter release from adrenergic terminals
• Substrate for MAO (monoamine oxidase)
• Prolongs actions of adrenergic transmitters due to tyramine competition for MAO
• Foods with tyramine:
• aged cheeses: blue, brie, camembert, cheddar, emmenthaler, gruyere, parmesan, romano, sour cream, roquefort, & swiss
• aged or cured meats: fermented sausages (pepperoni, salami, etc.), other dried fish, pickled herring & shrimp paste
• Tyramine produced by bacteria (fermentation of proteins containing tyrosine) is generally metabolized in gut by MAO
• If MAO inhibited (due to competition): Can cause hypertensive effects, called the "cheese effect"

Drug-Herb Interaction

• Herbs are a mixture of several compounds, and may present challenges with supplements that do not need prescriptions
• Gingko biloba and NSAIDs: both inhibit platelet aggregation, which may increase risk of bleeding
• Selective serotonin reuptake inhibitors (SSRIs) and St.Johns wort
• SSRI prevents serotonin reuptake and increase serotonin levels, St. Johns wort increases serotonin levels in the brain, and the combination may lead to serotonin syndrome (shivering, muscle rigidity, fever and seizures)
• HIV protease inhibitors (indinavir, ritonavir) and St.Johns wort lead to blood level reductions

Mechanisms of DDIs recap

• DDIs can take place via Pharmacokinetic or Pharmacodynamic mechanisms

Pharmacodynamic DDIs

• Interactions that occur when a drug changes the response of target or non-target tissues to another drug
• -Receptor mediated – both drugs interact with the same receptor
• -Non-receptor mediated - drugs affect the same target via different or complementary pathways

Examples of Pharmacodynamic DDIs

• Nitrates and Sildenafil: nitrates stimulate guanylyl cyclase, increasing cGMP. Sildenafil prevents its breakdown by inhibiting PDE-5. This combination significantly increases cGMP levels, causes severe hypotension, and is a pharmacodynamic (non-receptor) interaction
• MAOIs and Sympathomimetics: isocarboxazid, selegiline, tranylcypromine, phenelzine prevent breakdown of dopamine, NE, and E, and when combined with dopamine, ephedrine, phenylephrine, and pseudoephedrine, it can mimic NE and E, resulting in potentially fatal hypertension and death. This is a pharmacodynamic (non-receptor) interaction
• Narcotics and Buprenorphine: narcotics drugs bind the opioid receptors and, when combined with the partial opioid agonist Buprenorphine, which has high affinity, they can prevent the euphoric effects of narcotics. This is a pharmacodynamic (receptor) interaction

Prodrugs

• These must undergo enzymatic and/or chemical transformation in vivo to produce the active drug
• Prodrugs are usually employed to improve the physicochemical and pharmacokinetic (ADMET) properties of a drug candidate
• 20% of new small molecule drugs approved from 2000-2008 were prodrugs
• 10% of all marketed medicines are prodrugs
• Examples: Improve absorption (lipid or aqueous solubility) & transport, Metabolic stability (duration of action: “DOA"), Minimize adverse effects, Patient acceptability & formulation issues, Specific targeting of tissues, Managing the life cycle of a drug

Improvements From Prodrugs

• Reduced drug toxicity, Minimizing patient noncompliance by reducing the frequency of needed doses, Reducing the potential for toxicity due to drug concentration peaks, Improving steady-state concentrations
• Prodrugs are made with functional groups commonly used to make prodrugs, where drug release is triggered by e.g. esterases, phosphatases, proteases, pH change, redox conditions

Common Prodrug Strategies

• Common prodrug strategies affect oral, parenteral, and topical administrations

Improving Oral Delivery

• To improve oral delivery, add ionizable groups if the drug is not hydrophilic enough or mask hydrogen bonds if the drug is too hydrophilic/polar

Improvement Via Prodrug

• Ex: Fosamprenavir is an 8x more water-soluble prodrug of Amprenavir, allowing for oral dosing QD or BID rather than BID (16 capsules 150mg).

Improving Aqueous Solubility

• Prodrugs can provide increased water solubility for injectibles
• E.g. Fosphenytoin sodium is a water-soluble prodrug of phenytoin, allowing more concentrated IV dosing w/o propylene glycol

Enhancing water solubility prodrug

• Irinotecan HCI: water-soluble prodrug that is more favorable in terms of its toxicity profile
  • Irinotecan provides a slower release of SN-38, but is prone to variability from patient-to-patient

Improving Topical Administration

• Dermal Advantages:
• Direct Application to site
• Polar Functional Groups need to be masked
• Topical Tazarotene reduces acne symptoms and facial wrinkles due to its quick liberation in the skin

Absorption: Esterification and Prodrug

• Oral enalapril is an ineffective ACE inhibitor following IV administration because its prodrug’s carboxylic acid is rapidly processed

Hijacking Transporters

• L-dopa: prodrug of dopamine crosses the Blood-brain barrier through active transport using L-amino acid transporters

Route of Administration/Biotransformation Selectivity:

• Fluorouracil is administered for its bioconversion selectivity
  • Selectivity to eliminate dihydrofluorouracil in the patient’s system, while also serving as the basis for combination therapies

Improving Metabolic Stability

• Reductions in first-pass effects
• Greater availability due to well-absorbed substrates
• Masking of metabolically labile substances (ester and functional groups) to improve oral administration

Examples Of Exploiting Metabolic Stability

• Prodrug Terbutaline exploits first pass esterases for more effective release
• Lisdexamfetamine, a prodrug of amphetamine, is metabolized more slowly (less abuse potential)

Toxicity Avoidance

• Some prodrugs, like nabumetone for NSAID Improved Gastric Irritation or has inactive properties towards GI mucosa function Cytochrome expression (1A2) allows for enhanced liver conversion

Considerations About Prodrugs

• Inter-individual variations in response and bio-activating enzyme systems
• Hydrolysis-catalyzing enzymes, CYPs, and ubiquitously expressed (low potential saturation) enzymes must also be considered