Drug Interactions: Mechanisms and Potential Clinical Outcomes

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1 : Mechanisms and Potential Clinical Outcomes Alan P. Agins, Ph.D. President PRN Associates, Ltd Continuing Medical Education Tucson, AZ Objectives Specify the two major clinical outcomes of drug interactions as they relate to either s or toxicity. Understand pharmacokinetic interactions that can occur at the level of absorption, distribution and renal elimination. Compare and contrast cytochrome induction and inhibition as they relate to drug interactions. List a number of pharmacodynamic drug interactions that may occur from additive effects of multiple drugs chode 3rf.com Disclosures The speaker has no financial or other conflicts of interest to disclose How Common are? Estimates of - (DDIs) vary according to: Populations studied hospitalized, outpatient, elderly, CA, HIV, etc Method of data collection and analysis Types of interactions selected for inclusion theoretical vs. documented moderate vs. life threatening Identifying Potentially Major No current standard for rating drug interactions. Some interactions can be very severe but are uncommon. Many interactions are common but are not life-threatening. s most likely to be involved in interactions are: Those with a narrow margin between the and toxic dose Those requiring careful dosage control (TDM) Those which either induce or inhibit liver cytochrome enzymes Most likely classes: Anticonvulsants ( st generation) Cardiac drugs (warfarin, amiodarone, dig, verapamil) Antibiotics (just by sheer volume) Antiretrovirals Alan P. Agins, Ph.D. 06

Two Basic Outcomes of An interaction that increases the toxicity of one or more other drugs taken by a patient increased risk of morbidity or mortality Two Basic Outcomes of An interaction that

2 Two Basic Outcomes of An interaction that increases the toxicity of one or more other drugs taken by a patient increased risk of morbidity or mortality Two Basic Outcomes of An interaction that diminishes the benefit of one or more other drugs taken by a patient, allowing for disease progression with increased risk of morbidity or mortality Classic Examples of Deadly Combinations Types of Combination Emycin + Seldane Baycol + Lopid MAOI s + Tyramine Viagra + Nitroglycerin CNS depressants (Benzos + EtOH, etc.) Mechanism Arrhythmia (TdP) [PK + PD] Rhabdomyolysis [PK + PD] Hypertensive crisis [PK] Hypotension [PD] Respiratory depression [PD] Pharmacodynamic Pharmacodynamic Additive / Synergistic Pharmacological Physiological Antagonistic Pharmacological Physiological Additive / synergistic Pharmacological in nature Two or more drugs working directly on the same target / system Example: two CNS depressants tele5 3rf.com Alan P. Agins, Ph.D. 06

Pharmacodynamic Additive / synergistic Physiological in nature Two drugs working on different

Example: digoxin and furosemide Pharmacodynamic Antagonistic Pharmacological in nature

com Pharmacodynamic Antagonistic Physiological in nature opposing physiological processes

com Pharmacokinetic Alterations in drug concentration reaching its target site Absorption

Intestinal / hepatic transporters Distribution Displacement of protein binding Metabolism

Pharmacokinetic (chemical) Tetracyclines Quinolones Bisphosphonates Levothyroxine Levodopa

3 Pharmacodynamic Additive / synergistic Physiological in nature Two drugs working on different physiological processes but ultimately increasing risk of toxicity from one or both drugs Example: digoxin and furosemide Pharmacodynamic Antagonistic Pharmacological in nature Classic receptor antagonism Example: naloxone / morphine tele5 3rf.com Pharmacodynamic Antagonistic Physiological in nature opposing physiological processes Example: NSAIDs and ACEIs (on renal blood flow) Pharmacokinetic Adrian Brockwell 3rf.com Pharmacokinetic Alterations in drug concentration reaching its target site Absorption Altered gastric emptying, GI motility Altered stomach ph Chelation or adsorption Altered Intestinal / hepatic transporters Distribution Displacement of protein binding Metabolism Enzyme induction / inhibition Renal Excretion Inhibition of drug transporters Chelation IRON Pharmacokinetic (chemical) Tetracyclines Quinolones Bisphosphonates Levothyroxine Levodopa Penicillamine CALCIUM Tetracyclines Quinolones Bisphosphonates Levothyroxine Prevents Systemic Absorption Sebastian Kaulitzki 3rf.com Alan P. Agins, Ph.D. 06 3

Pharmacokinetic (chemical) Adsorption (Bile Acid Resins) Warfarin Thiazides Furosemide Propranolol Thyroxine Digoxin ASA / NSAIDs Fat Sol Vitamins A, D, E, K + + + + + - + - - - -

rilpivirine indinavir atazanavir nelfinavir griseofulvin iron salts vitamin B 3drenderings 3rf.

Albumin Competition for Protein Binding Competition for Protein Binding Blood Vessel Bound drug Serum Albumin Tissue 00% increase in active drug concentrations Unlikely source for

4 Pharmacokinetic (chemical) Adsorption (Bile Acid Resins) Warfarin Thiazides Furosemide Propranolol Thyroxine Digoxin ASA / NSAIDs Fat Sol Vitamins A, D, E, K Pharmacokinetic Absorption s or liquids that increase gastric ph PPIs H- Antagonists Antacids may decrease rate or amount of absorption: itraconazole cefpodoxime ampicillin esters rilpivirine indinavir atazanavir nelfinavir griseofulvin iron salts vitamin B 3drenderings 3rf.com Pharmacokinetic Distribution Competition for Protein Binding Blood Vessel Tissue Blood Vessel Tissue Bound drug Free drug Bound drug Free drug Equilibrium Serum Albumin Serum Albumin Competition for Protein Binding Competition for Protein Binding Blood Vessel Bound drug Serum Albumin Tissue 00% increase in active drug concentrations Unlikely source for clinically relevant interactions in healthy adults with most drugs Greater risk in patients with low albumin elderly, malnurished, liver disease, alcoholics More likely to be clinically significant in cases where one or more drugs have a narrow index Alan P. Agins, Ph.D. 06 4

Pharmacokinetic Protein Binding Potential interactions between drugs that are highly protein bound warfarin NSAIDs COX s lorazepam diazepam fenofibric acid phenytoin valproic acid lamotrigine

5 Pharmacokinetic Protein Binding Potential interactions between drugs that are highly protein bound warfarin NSAIDs COX s lorazepam diazepam fenofibric acid phenytoin valproic acid lamotrigine glyburide glipizide glimepiride Cytochrome Probably the most common source of pharmacokinetic drug interactions Two mechanisms for interactions Induction Inhibition Guniita 3rf.com Reversible increase in enzyme concentration resulting from administration of certain drugs or other chemicals May increase the metabolism and clearance of other drugs taken concurrently 450 concentration Basal initiate inducing drug Time Systemic Circulation 450 concentration Discontinue inducing agent Basal initiate inducing agent Time Portal vein Guniita 3rf.com Alan P. Agins, Ph.D. 06 5

rivaroxaban apixaban rivaroxaban apixaban A s Metabolized The presence cannabis smoke A sub- sub- clozapine olanzepine

6 Systemic Circulation 3A4 sub- The presence Portal vein Guniita 3rf.com rivaroxaban apixaban 3A4 s Metabolized 3A4 Clinical example s Metabolized Increases the clearance of these sub- sub- rivaroxaban apixaban rivaroxaban apixaban A s Metabolized The presence cannabis smoke A sub- sub- clozapine olanzepine Antidepressants duloxetine mirtazapine Miscellaneous frovatriptan zolmitriptan tizanidine warfarin (R) theophylline caffeine Increases the clearance of these cannabis smoke Alan P. Agins, Ph.D. 06 6

Metabolized E ethanol Miscellaneous frovatriptan

caffeine ity acetaminophen isoniazid enflurane

Metabolism Acetaminophen ity Alcohol Induces E

get into active site and are slow to dissociate

toxic levels Sulfate Glutathione Competition for

7 Clinical example A clozapine olanzepine Antidepressants duloxetine mirtazapine sub-sub s Metabolized E ethanol Miscellaneous frovatriptan zolmitriptan tizanidine warfarin (R) theophylline caffeine ity acetaminophen isoniazid enflurane halothane cannabis smoke Inhibition of Cytochrome Metabolism Acetaminophen ity Alcohol Induces E overdose Due to two drugs competing for the same enzyme with greater affinity or higher concentration typically inhibits other Some drugs get into active site and are slow to dissociate Glucuronide that is not metabolized can build up to toxic levels Sulfate Glutathione Competition for Enzyme by Competition for Enzyme by M M M Tyler Olson 3rf.com Alan P. Agins, Ph.D. M Tyler Olson 3rf.com 06 7

8 3A4 3A4 The presence Decreases the clearance rivaroxaban apixaban rivaroxaban apixaban 3A4 Clinical example D6 The presence rivaroxaban apixaban D6 Decreases the clearance D6 Clinical example Alan P. Agins, Ph.D. 06 8

Miscellaneous frovatriptan zolmitriptan tizanidine warfarin (R) theophylline caffeine The presence A clozapine olanzepine Antidepressants

9 D6 Sub- Pro-drug (need activation by D6) codeine diminished analgesia tamoxifen decreased protection Interesting caveat sertraline C9 The presence duloxetine C9 Decreases the clearance C9 Clinical example A clozapine olanzepine Antidepressants duloxetine mirtazapine Miscellaneous frovatriptan zolmitriptan tizanidine warfarin (R) theophylline caffeine The presence A clozapine olanzepine Antidepressants duloxetine mirtazapine Miscellaneous frovatriptan zolmitriptan tizanidine warfarin (R) theophylline caffeine Decreases the clearance Alan P. Agins, Ph.D. 06 9

A Clinical example clozapine olanzepine Antidepressants duloxetine mirtazapine Miscellaneous frovatriptan

the elimination of another Few noted at this level Potential for competition at renal drug transporters Oguzaral

tubule Anionic transporter (OAT) furosemide, thiazides penicillins NSAIDs methotrexate probenicid contrast media

(OCT) metformin contrast media (iodinated) cimetidine amiloride morphine procainamide quinidine Return to

morphine procainamide quinidine Pharmacodynamic Additive - Combining CNS depressants Alcohol Benzodiazepines

, zolpidem) Opioids Muscle relaxants Antihistamines ( st generation) Tricyclic antidepressants (3 o ) Sedation,

10 A Clinical example clozapine olanzepine Antidepressants duloxetine mirtazapine Miscellaneous frovatriptan zolmitriptan tizanidine warfarin (R) theophylline caffeine Pharmacokinetic Renal Elimination When one drug slows the elimination of another Few noted at this level Potential for competition at renal drug transporters Oguzaral 3rf.com Renal Transporters Active Secretion Renal Transporters Active Secretion Efferent arteriole Proximal renal tubule Anionic transporter (OAT) furosemide, thiazides penicillins NSAIDs methotrexate probenicid contrast media (iodinated) Efferent arteriole Proximal renal tubule Anionic transporter (OAT) furosemide, thiazides penicillins NSAIDs methotrexate probenicid contrast media (iodinated) Return to systemic circulation Cationic Transporter (OCT) metformin contrast media (iodinated) cimetidine amiloride morphine procainamide quinidine Return to systemic circulation Cationic Transporter (OCT) metformin contrast media (iodinated) cimetidine amiloride morphine procainamide quinidine Pharmacodynamic Additive - Combining CNS depressants Alcohol Benzodiazepines Z-hypnotics (ie., zolpidem) Opioids Muscle relaxants Antihistamines ( st generation) Tricyclic antidepressants (3 o ) Sedation, confusion, ataxia, Barbiturates amnesia, respiratory depression, coma, death chode 3rf.com Scott Betts 3rf.com Alan P. Agins, Ph.D. 06 0

Additive - Additive - Combining vasodilators or antihypertensives Nitroglycerin PDE-5 DHP-CCBs Alpha blockers

com ACEIs, ARBs Direct Renin Potassium-sparing diuretics (spironolactone, triamterene, amiloride) Potassium

SSRIs, SNRIs trazadone, mirtazepine vilazadone lithium dextromethorphan diphenhydramine, chlor/brompheniramine

??? Serotonin Syndrome Google images: Retrieved June 00 Additive - Antiplatlet s aspirin NSAIDs clopidogrel

inhibitors Misc Some cephalosporins SSRIs?

nd gen) Anti-emetics (5HT 3 -blockers) Opioids Methadone, Buprenorphine, Oxycodone Antidepressants TCAs,

11 Additive - Additive - Combining vasodilators or antihypertensives Nitroglycerin PDE-5 DHP-CCBs Alpha blockers ACEI ARB Diuretics CCBs B-Blockers Thiazides Hypotension Syncope MI alexmit 3rf.com ACEIs, ARBs Direct Renin Potassium-sparing diuretics (spironolactone, triamterene, amiloride) Potassium supplements trimethoprim Azole antifungals NSAIDs Hyperkalemia Additive - Combining serotonin enhancing drugs SSRIs, SNRIs trazadone, mirtazepine vilazadone lithium dextromethorphan diphenhydramine, chlor/brompheniramine tramadol, tapentadol, methadone, meperidine lorcaserin triptans???? Serotonin Syndrome Google images: Retrieved June 00 Additive - Antiplatlet s aspirin NSAIDs clopidogrel dipyridamole Many dietary supplements Anticoagulants warfarin heparin, LMWH Direct Thrombin Factor Xa inhibitors Misc Some cephalosporins SSRIs??? Additive - Combining drugs that increase QT interval Anti-arrhythmics Fluoroquinolones Macrolides ( st gen > nd gen) Anti-emetics (5HT 3 -blockers) Opioids Methadone, Buprenorphine, Oxycodone Antidepressants TCAs, trazodone, citalopram Torsades de Pointes Fatal Arrhythmia Additive - Combining drugs that increase risk of myotoxicity Statins Niacin Fibrates NRTIs (nukes) Alcohol acute or chronic Glucocorticoids Antimalarials colchicine Myopathy Rhabdomyolysis phil holmes 3rf.com Alan P. Agins, Ph.D. 06

Additive - Combining s with Anticholinergic Side Effects Centrally-acting antiach drugs Overactive bladder drugs Antiemetics (ie.

Dry mouth, Urinary Retention, Confusion, Tachycardia Antagonistic / Competetive Pharmacological in nature Classic receptor antagonism

, donepezil) niacin (hyperglycemia) vs oral hypoglycemics Competitive (enzyme) inhibition override warfarin vs vitamin K (foods,

Limiting drug interactions Communication With patient - all things on the table!

com Limiting drug interactions Don't rely on memory to determine which drugs interact with which There are many commercial

12 Additive - Combining s with Anticholinergic Side Effects Centrally-acting antiach drugs Overactive bladder drugs Antiemetics (ie., meclizine, etc) Antispasmodics Respiratory anticholinergics Sedating antihistamines Tricyclic antidepressants Opioids Constipation, Dry mouth, Urinary Retention, Confusion, Tachycardia Antagonistic / Competetive Pharmacological in nature Classic receptor antagonism naloxone, buprenorphine vs morphine Opposing pharmacological effects anticholinergics (eg., oxybutynin) vs cholinesterase inhibitor (eg., donepezil) niacin (hyperglycemia) vs oral hypoglycemics Competitive (enzyme) inhibition override warfarin vs vitamin K (foods, supplements) Google images: Retrieved August 0 Summary Limiting drug interactions? Limiting drug interactions Communication With patient - all things on the table! With caregivers, parents With other healthcare professionals Ryzhkovoleksandr 3rf.com Wavebreak Media Ltd 3rf.com Limiting drug interactions Don't rely on memory to determine which drugs interact with which There are many commercial drug-interaction programs and apps available Limiting drug interactions Don't assume similar magnitude of interactions for all patients Varying underlying medical conditions Varying ages (very young to elderly) Genetic polymorphism (variability) Google images: Retrieved November 03 Alan P. Agins, Ph.D. 06

Limiting drug interactions Recognize patient & drug-related risks for interactions Acute medical conditions - fever,

medications/multiple prescribers Narrow range drugs s with very long half-lives Limiting drug interactions Remember not

.. Macrolides: Emycin and clarithyromycin inhibit 3A4; azithromycin does not Statins: Simvastatin, lovastatin,

Pravastatin and pitavastatin little or no involvement SSRIs: Fluoxetine & paroxetine inhibit of D6, others not Limiting

13 Limiting drug interactions Recognize patient & drug-related risks for interactions Acute medical conditions - fever, infection, dehydration Age extremes (very young, elderly) Documented renal or hepatic impairment Multiple medications/multiple prescribers Narrow range drugs s with very long half-lives Limiting drug interactions Remember not all drugs in a class interact the same way... Macrolides: Emycin and clarithyromycin inhibit 3A4; azithromycin does not Statins: Simvastatin, lovastatin, atorvastatin cleared by 3A4. Fluvastatin by C9. Rosuvastatin. Pravastatin and pitavastatin little or no involvement SSRIs: Fluoxetine & paroxetine inhibit of D6, others not Limiting drug interactions Take into consideration and educate patients re: all things that can interact with their medications - OTC drugs, lifestyle habits (alcohol and tobacco), dietary supplements, beverages, foods Questions? Thank YOU for listening. Alan Alan P. Agins, Ph.D. 06 3

Drug Interactions: Let me count the ways

Drug Interactions: Let me count the ways : Let me count the ways President: PRN Associates, Ltd. Continuing Education in Pharmacology Tucson, AZ Objectives At the conclusion of this continuing education lesson, the participant will be able to: