PHA3320: Introduction to Drug Interactions

• Paapa Mensah-Kane presents an introduction to drug interactions for PHA3320: Principles of Drug Action Q3, Winter 2025.

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

Drug Interactions

• Generally refers to Drug-Drug Interactions (DDIs), but can extend to drug-food or drug-herb interactions.
• Clinical significance is the key consideration.
• Most published data comprises extensive reviews, establishing relevance is important.
• Interactions usually imply reciprocal effects, where drugs mutually affect each other.
• Some DDIs involve a one-way effect of a drug on another, categorizing them as non-reciprocal.
• DDIs can be deleterious (harmful) or beneficial.

Drug-Drug Interactions

• Focus on polypharmacy which involves factors like:
  • Multiple drug use.
  • Individual eating habits.
  • Use of OTCs, vitamins, and herbal supplements.

Effects of Drug-Drug Interactions

• Types of Drug Interactions include:
  • Antagonism.
  • Additive.
  • Synergistic.
  • Potentiation.
• Additive effect: combined drug effects equal the sum of each drug's effect alone, whether beneficial or harmful.
• Synergistic effect: combined drug effects exceed the sum of individual drug effects.
• Potentiation: one drug enhances the action of another, increasing its effect in the presence of the second drug.
• Antagonistic: one drug interferes with the action of another, resulting in a combined effect less than the sum of each drug's effect alone.

Mechanisms of Drug-Drug Interactions

• The mechanistics of drug-drug interactions are broken into two types:
  • Pharmacokinetic
  • Pharmacodynamic

Pharmacokinetic Drug-Drug Interactions

• Pharmacokinetic alteration in a drug due to another drug or substance which includes:
  • A: Chelation, gastric transit times, acidity effects.
  • D: Binding affinity to plasma proteins.
  • M: Extent of drug metabolism.
  • E: Acidity of urine, competition for transport.

Absorption

• Any drug affecting GI function can alter drug absorption.
• Drugs altering gastric transit time, GI motility, or pH levels can change absorption rate and extent.
• Ranitidine and antacids may affect the absorption of basic drugs like triazolam, by increasing pH levels.
• Expect ranitidine to increase the rate of GI absorption of triazolam.
• Tetracyclines can interact with antacids, forming poorly soluble complexes with polyvalent ions which reduces bioavailability.

Protein Binding Interactions

• It's relevant for drugs with high plasma protein binding.
• Aspirin, barbiturates, phenytoin, warfarin, and valproic acid affects the binding to proteins in plasma.
• Only free (unbound) drug is active.
• Acidic and neutral drugs typically bind to albumin.
• Basic drugs typically bind to alpha-1 acid glycoprotein.
• Toxic effects are amplified due to increases in free drug concentration.
• Binding sites may be displaced by other drugs.
• Hypoalbuminia examples include malnutrition, liver failure, nephrotic syndrome.
• Anticoagulant effect of warfarin is enhanced with concomitant valproic acid therapy, which makes patients more prone to bleeding.

Drug Metabolism

• Diazepam can become a toxic drug during metabolism
• Inducers and Inhibitors work against that metabolism.
• Key drug inducers (PS PORCS):
  • P – Phenytoin
  • S – Smoking
  • P - Phenobarbital
  • O – Oxcarbazepine
  • R – Rifampin (also rifabutin, rifapentine)
  • C - Carbamazepine
  • S – St. John's Wort
• Key Drug Inhibitors CYP3A4 (G PACMAN):
  • G - Grapefruit
  • P – Protease inhibitors (e.g., ritonavir, lopinavir)
  • A – Azole antifungals (e.g., ketoconazole, fluconazole)
  • C - Cimetidine
  • M - Macrolides (except azithromycin) (e.g., erythromycin, clarithromycin)
  • A - Amiodarone
  • N – Non-DHP CCBs (verapamil, diltiazem)

Metabolism Interactions

• Principally involving CYP450s with specific examples:
  • Induction of CYP450 specific isoenzymes.
  • Inhibition (including competition).
• Induction causes:
  • Increased gene expression of the target enzyme.
  • Increased clearance & reduced therapeutic efficacy.
  • Increased activation of prodrug (possible toxicity).
• CYP3A4 Example:
  • Anticonvulsants (anti-seizure) are often used in combination.
  • Some of their interactions are true reciprocal DDIs.
  • Reciprocal DDI: both drugs affect each other's efficacy or toxicity.
  • This can be very complex and need close monitoring of plasma concentrations.

Enzyme Inhibition Interactions

• Competitive inhibition (most common type) or irreversible inhibition is important.
• It has a typical result: reduced metabolism of drug and increased plasma concentration of the affected drugs.
• There are direct clinical consequences that are more likely to be clinically severe vs. inducers, because of a Faster onset
  • immediate (compared to induction): possibility of sudden/rapid precipitation of adverse effects

Enzyme Inhibitors (examples...)

• CYP3A4 Inhibitors: Cimetidine, ketoconazole, erythromycin and grapefruit juice.
• CYP2D6 Inhibitors: fluoxetine, quinidine and haloperidol.
• CYP2C9 Inhibitors: fluconazole, amiodarone.
• CYP2C19 Inhibitors: Omeprazole, fluoxetine.

Enzyme Inhibitors (DDIs)

• Terfenadine can be metabolized into Fexofenadine through CYP3A4 which can be influenced by inhibitors.

Enzyme Inhibition (DDIs)

• L-DOPA is converted to dopamine by DOPA decarboxylase however carbidopa inhibits DOPA decarboxylase thus it may influence dopamine production.
• Sinemet can be perscribed when you need to increase levels of dopamine

Interactions of Excretion

• Alterations to the excretion of a drug due to the presence of another drug.
• Classic Example: penicillin and probenecid.
  • Penicillin is cleared via tubular secretion in the kidney.
  • Probenecid inhibits renal tubular transport thus increased plasma concentration of penicillin and increase in half life occurs.
• Urinary Acidity can be modify excretion:
  • Acidify: NH4Cl, vitamin C, cranberry juice
  • Alkalinize: NaHCO3, acetazolamide (historically)

Other Mechanism of DDI

• Interference with transporters.
• P-gp (P-glycoprotein): efflux pump.
  • Transports drugs back into the intestinal lumen.
  • Secretes substances into the renal lumen.
  • Prevents drugs from crossing the BBB.
• Co-administration of a P-gp inhibitor or substrate may cause an increase in absorption, increased brain penetrance, and/or reduced 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.

P-gp Inhibitor DDIs

• Quinidine blocks P-gp in intestine & renal tubule.
• Digoxin normally eliminated into intestine & urine by P-gp.
• Plasma conc. of digoxin can reach toxic levels when admin. w/ quinidine.

Drug-Food Interactions

• The Gl absorption of drugs may be affected by the concurrent use of substances that:
  • Alter gastric pH.
  • Affect transport proteins in the Gl.
  • Specifically bind or chelate drugs.
  • Have a large surface area upon which the drug can be adsorbed non-specific binding
  • Alter gastrointestinal motility.

Food Drug Interaction: Monoamine Oxidase Inhibitors (MAOIs)

• MAO breaks down biogenic amine neurotransmitters such as Dopamine (DA), Norepinephrine (NE), Epinephrine (EPI) and Serotonin (5-HT).
• It exists in two isoforms: MAO-A and MAO-B.
• MAO-B metabolizes tyramine, which causes the release of NE, EPI and DA.

MAOls & "Cheese Effect"

• Nonselective MAOIs (inhibit MAO-A & MAO-B) with the the key effect to monitor the food intake as food must be monitored for interactions

MAOIs & Food

• Tyramine is produced by bacterial fermentation of proteins containing tyrosine.
• It is generally metabolized in the gut by MAO.
• If MAO is inhibited due to competition, hypertensive effects ("cheese effect") may occur.

Drug-Herb Interaction

• Herbs are usually a mixture of several compounds, which presents a challenge with supplements that can be bought OTC.
  • Gingko biloba and NSAIDs: both inhibit platelet aggregation which may increase risk of bleeding.
  • Selective serotonin reuptake inhibitors (SSRIs) and St.Johns wort: prevents serotonin reuptake and increases serotonin levels, and the latter increases serotonin levels in the brain.
  • HIV protease inhibitors (indinavir, ritonavir) and St.Johns wort: reduces blood levels of the HIV drugs and potential loss of HIV suppression.

Mechanisms of DDIs

• The mechanistics of DDIs are broken into two types:
  • Pharmacokinetic
  • Pharmacodynamic

Pharmacodynamic DDIs

• Occurs when a drug changes the response of target or non target tissues to another drug.
  • Receptor mediated - the two drugs interact with the same receptor.
  • Non-receptor mediated - the two drugs affect the same target via different or complementary pathways.

Nitrates and Sildenafil

• Nitrates: such as Nitroglycerin (Nitrostat®), isosorbide dinitrate (Isordil®) stimulates guanylyl cyclase, increase cGMP and causes vasodilation and are used as angina pectoris.
• Sildenafil (Viagra®), inhibits PDE-5 (phosphodiesterase type 5), which increases concentration of cGMP in the corpus cavernosum and causes vasodilation; useful for erectile dysfunction.
• Co-administration significantly increases cGMP levels, can cause severe hypotension

MAOIs and Sympathomimetic

• MAOIs: Isocarboxazid, selegiline, tranylcypromine, Phenelzine which causes NE, E, DA accumulates
• Sympathomimetics: dopamine, ephedrine, phenylephrine, pseudoephedrine (Sudafed®) which Mimic NE and E
• Co-administration can cause severe hypertension, seizures, arrhythmias, death and should be avoided.

Narcotics and Buprenorphine

• Narcotics drugs Bind to opioid receptors leading to euphoria
• Buprenorphine Partial agonist at opioid receptors that Binds with high affinity, and is Used as analgesic but more commonly to treat opioid addiction.
• Concomitant use can prevent euphoric effect of narcotics.

Prodrugs

• Prodrugs are inactive (or less active) bioreversible derivatives that must undergo enzymatic and/or chemical transformation in vivo to produce the active drug.
• Requires a functional group to be activated.

Learning Objectives for Prodrugs

• Define prodrug and explain the advantages of prodrugs.
• Describe various strategies to employ prodrugs.
• List common functional groups involved in prodrug metabolism and/or conversion.
• Describe physicochemical properties important for prodrug PK and PD.
• Provide examples of prodrug strategies and be familiar with their advantages and/or disadvantages.
• Prodrug activation converts the drug to its active form

Why use Prodrugs

• Improve physicochemical and pharmacokinetic (ADMET) properties by improving absorption, metabolic stability, minimizing adverse effects and providing specific targeting of drug

Benefits of Improving Duration of Action (DOA)

• Reducing the number or frequency of doses
  • Minimizing patient noncompliance
  • Eliminating the need for night time administration of drugs
• Eliminating the peaks & valleys of drug concentrations in the body
  • Reducing the potential for toxicity due to drug concentration peaks
  • Improving steady state concentration

Functional Groups Amenable to Making Prodrugs

• Includes releases are esterases, phosphatases, proteases, pH change, redox conditions

Some Common Prodrug Strategies

• Strategy includes: Improve oral delivery, improve parenteral delivery, improve topical delivery and other routes

Prodrugs to Improve Oral Delivery

• If drug is not hydrophilic enough: add ionizable groups
• If drug is too hydrophilic/polar: mask hydrogen bonding groups

Increased hydrophilicity

• Fosamprenavir (8x more water soluble), can be dosed QD or BID with a max tab = 4 tablet (700mg).
• Compared it's predecessor, Amprenavir(discontinued): requires a dose BID (16 capsules 150mg)
• Fosamprenavir is more water soluble and serves as a slow release version of Amprenavir and lowers the pill burden in HIV/AIDS patients and Patent on amprenavir expired 2013, fosamprenavir lasted until 2017.

Prodrugs to Improve Parenteral Administration

• Strategy for when: If drug cannot be taken orally due to absorption problems as e.g. absorption is poor PO or and if immediate action is required

Improving Aqueous Solubility; Phosphate ester. Example: Fosphenytoin

• Injectable salt requires 40% propylene glycol/Ethanol compared to Fosphenytoin which greater aqueous solubility no propylene glycol required

Enhancing aqueous solubility and taking advantage of the rate of conversion to active drug using a carbamate ester

• SN-38 (Active metabolite of irinotecan) has greater water solubility than camptothecin less toxicity profile.

Prodrugs to Improve Topical Treatment

• Dermal advantages: direct application to site however they have inappropriate physiochemical properties to effectively penetrate through the layers of the skin. Requires esterases
• Polar functional groups will prevent adequate dermal penetration and will require masking.
• Example:Tazarotene is used with ethyl ester to improve penetration and absorption, less skin irritation for skin conditions

Absorption: Esterification

• Enalapril is administered as prodrug due to better oral administration

Prodrugs and Drug Transporters

• Hijacking active transport to get drug into the CNS
• L-dopa / levodopa (Larodopa®):endogenous precursor to dopamine prodrug by active transport by CNS through L-amino

Route of Administration, and Bioconversion Selectivity

• Shows process of different bioconversion enzymes

Absorption/Metabolism: Improving metabolic stability

• Propranolol uses hemisuccinate to greatly reduce first past metabolism.

Absorption/Metabolism: Improving metabolic stability in Terbutaline

• (QD - once/day) terbutaline is created after Butyrylcholinesterase reacts with a Long acting form, bambuterol

Modifying rate of release of active drug for Lisdexamfetamine

• It requires ingestion for it to convert into the desired drug , therefore its not effective when sniffed.

Avoidance of Toxicity

• Using Nabumetone and Improve gastric irritancy profile,
• Inactive prodrug reduces direct GI irritation due to absence of acidic functional group and hinders secondary GI irritation due to lack.

Considerations About Prodrugs

• Factors for varying success includes: genetics through enzymatic breakdown, speed of reaction with different bodily reaction and speed of reaction with different bodily compounts