Pharma - 113 Drug Interactions PDF

# Dept. of Pharmacology & Therapeutics ## Pharma - 113 # Drug Interactions ## Objectives: - Define a drug interaction. - Describe the mechanism by which drug interactions occur, including the distinction between PK and PD interactions. - Differentiate between enzyme substrates, inducers, and inh...

# Dept. of Pharmacology & Therapeutics ## Pharma - 113 # Drug Interactions ## Objectives: - Define a drug interaction. - Describe the mechanism by which drug interactions occur, including the distinction between PK and PD interactions. - Differentiate between enzyme substrates, inducers, and inhibitors. - Provide examples of drug interactions caused by enzyme induction or inhibition and demonstrate how to avoid or manage these interactions. - Identify general strategies for the management or avoidance of drug interactions. # Types of drug interactions: - Drug-drug interactions, - Drug-food interactions, - Enteral feeding-drug interactions, - Nutrient-drug interactions, - Alcohol-drug interactions, - Tobacco-drug interactions, - Herbal-drug interactions, & - Drug-disease interactions. # Nomenclature: - **Precipitant (or perpetrator) drug:** a compound that is causing the interaction. - **Object (or victim) drug:** is the agent that is being affected in the interaction. - **Substrate for a particular enzyme:** the enzyme metabolizes this drug (substrate). - **Inhibitors:** are agents that block the action of an enzyme or transport protein. - **Inducers:** are compounds that stimulate the action of an enzyme or transport protein. # Definition: - Modification of the effects of one drug (i.e., the object drug) by the prior or concomitant administration of another (i.e., the precipitant drug). # Classification of drug interactions: - Drug interactions that occur in vivo are generally classified as PK or PD interactions. ## 1. PK interactions occur when there is: - Altered absorption, - Altered distribution (protein & tissue binding), - Altered metabolism, or - Altered renal excretion. ## 2. PD interactions produce: - antagonistic, - synergistic, or - additive effect. ## 3. Pharmacogenetic interactions occur when the PK effect of the drug is altered by genetic factors that affect the process of metabolism. ## 4. Pharmaceutical interactions are caused by a chemical or physical incompatibility when two or more drugs are mixed together. - **Examples:** - An i.v. sol of aminophylline has an alkaline pH and should not be mixed with drugs such as epinephrine, erythromycin gluceptate, or cephalothin-Na, which decompose in alkaline pH. - Phenytoin-Na will precipitate from a sol. that has an acid pH, such as dextrose 5%. # PK interactions: ## Absorption: - Drug interaction can affect the rate and extent of systemic drug absorption (bioavailability) from the absorption site, resulting in increased or decreased drug bioavailability. - The most common drug absorption site is in the GIT. - Absorption from other sites such as skin, can be affected by drug interactions. ## Mechanisms of altered GI absorption: - Complexation or chelation, - Alteration of gastric pH, - Adsorption, - Alteration of intestinal flora, - Alteration of GI motility, - Drug-induced mucosal damage, & - Inhibition of drug metabolism in intestinal cells ## Absorption (Cond): ### Alteration of gastric pH: - Non-ionized form of a drug is more lipid soluble & more readily absorbed from the GIT into the systemic circulation than the ionized form. - Weak acidic drugs tend to be absorbed in the upper portion of the GIT, where they are in an acidic medium. - The opposite is true of weak bases. - Antacids increase the gastric pH and may delay the absorp of certain drugs (e.g., ketoconazole). ### Alteration of gastric pH: - Administering antacids (NaHCO3) with ketoconazole may decrease the absorp of the antifungal agent by reducing its dissolution. - H₂-antagonists may reduce ketoconazole dissolution. - Antacids or H₂-antagonists should be given at least 2 h after the antifungal agent. ### Complexation or chelation: - Tetracycline when combined with other drugs (e.g., Fe preparations) or food (e.g., milk) in the GIT will form poorly absorbed complexes. - The interval between the administration of the two drugs should be increased by ~ 2-4 h. ### Complexation or chelation (Cond.): - Administering an Al-Mg-oH antacid with ciprofloxacin may drastically decrease the absorp of the antibiotic by about 85% (chelation). - Antacid should be given at least 6 h before or 2 h after ciprofloxacin. - Co-administering sucralfate or antacids with ciprofloxacin & norfloxacin will decrease the absorp of the antibiotics. ## Adsorption: - Cholestyramine decreases the absorp of exogenously administered thyroxine in the GIT. - Other agents that can interfere with drug absorp by binding to the object drug or by forming complexes or chelates with the object drug include: - activated charcoal, - antacids, - colestipol, and - polyvalent cations (e.g., Fe salts). ## Alteration of intestinal flora: - Antibiotic admin may decrease the number of bacteria in the GIT. - Some drugs have been shown to be affected by changes in the intestinal flora. - Drug interactions resulting from changes in the intestinal bacterial flora involve drugs that are: - incompletely absorbed from the upper GIT or - undergo enterohepatic recirculation. ## Alteration of intestinal flora (Cond,): - The onset and reversal of this interaction are delayed, requiring up to several weeks. - Adjusting the admin times of the two drugs would not alter interactions occurring by this mechanism. ## Alteration of intestinal flora (Cond,): - Digoxin (PO) is metabolized by GI flora to inactive digoxin reduction products. - Clarithromycin and erythromycin reverse this process by altering GI bacteria, allowing more digoxin to be absorbed. - The effects of this interaction may persist for weeks to months after erythromycin is discontinued. ## Alteration of Gl motility: - Changes in GI motility may increase or decrease absorp. - Increasing GI motility may decrease absorp by reducing the amount of time that an orally administered drug is in contact with the absorbing surface. - A decrease in bioavailability may result from slowing dissolution or delaying gastric emptying. ## Alteration of Gl motility (Cond.): - Anticholinergics + Acetaminophen → - Impact: Delay in absorp of acetaminophen. ## Alteration of Gl motility (Cond.): - Interactions occurring as a result of altered GI motility result from systemically administering the precipitant drug. - Separating the administration times of the interacting drugs would not prevent this interaction. ## Alteration of Gl motility (Cond.): - cyclosporine absorp. is increased when concurrently administered with metoclopramide (increases stomach emptying time). - Conversely, by increasing GI motility, metoclopramide may decrease the absorp of orally administered digoxin (tablet). - This interaction may not occur with digoxin formulations that have high bioavailability (e.g., digoxin caps or elixir). - Anticholinergic drugs (propantheline) are an example of a class of drugs that slow GI motility. ## Drug-induced mucosal damage: - Drugs (antineoplastic agents) that damage the GI mucosa may reduce the absorp of certain drugs. - Reduced GI absorp of certain digoxin preparations has been attributed to alterations in the intestinal mucosa induced by chemotherapeutic agents (e.g., cyclophosphamide, vincristine, procarbazine, plus prednisone). - The effects of this interaction appear to be minimized by administering digoxin caps or digitoxin. ## Inhibition of drug metabolism in intestinal cells: - Alteration of intestinal blood flow caused by drugs such as MAOIs (e.g., tranylcypromine, phenelzine). - These drugs can inhibit metabolism of albuterol and levalbuterol leading to hypertension. # Distribution interaction: - Clinically important interactions may result from protein displacement if displacement is accompanied by: - enzyme inhibition or - if the displaced drug has a small Vd, narrow therapeutic index, and rapid onset of action. ## Distribution interaction (Cond.): - Examples of drugs that are highly protein-bound include: - phenytoin (90%), - tolbutamide (96%), & - warfarin (99%). - Common precipitant drugs include: - sulfonamides (e.g., sulfisoxazole), - aspirin, & - phenylbutazone. - Phenylbutazone displaces warfarin from plasma protein, and inhibits its metabolism leading to an increased anticoagulant response. ## Distribution interaction (Cond.): - Example: Phenytoin + VPA - Impact: Protein binding of VPA is reduced and total Css decreased. # Metabolism: - Drugs may be substrates for more than one enzyme. - Imipramine is a substrate of CYP1A2, CYP2C19, & CYP2D6. - CYP2D6 isozyme is not present in 5 to 10% of Caucasians, who have been designated as poor metabolizers. - A drug may act as a competitive inhibitor of one enzyme while being metabolized by another. - E.g., mexiletine is an inhibitor of CYP1A2 but is a substrate for CYP2D6. - Quinidine inhibits CYP2D6 but is metabolized by CYP3A4. - Some drugs may act as both inhibitor & inducer. - Omeprazole is a CYP1A2 inducer but an inhibitor of CYP2C19. # CYP1A2 | Substrates | Inducers | Inhibitors | |------------------------|--------------------|---------------------------------| | Amitriptyline, Imipramine | Cigarette smoke | Amiodarone | | Fluvoxamine | Omeprazole | Ciprofloxacin, Norfloxacin | | Naproxen | Phenobarbital | Clarithromycin, Erythromycin | | Theophylline | Phenytoin | Fluvoxamine | | Verapamil | Ritonavir | ketoconazole | | R-warfarin | | | # CYP2C9 | Substrates | Inducers | Inhibitors | |------------------------|-----------------|--------------------------------------------------| | Amitriptyline | CBZ | Amiodarone | | Celecoxib | Ethanol | Fluvoxamine | | Glipizide | Phenobarbital | Ketoconazole, Fluconazole | | Phenytoin | Rifampicin | Omeprazole | | Valproic acid | Secobarbital | Sulfamethoxazole, Trimethoprim | | S-warfarin | | Phenylbutazone | # CYP2C19 | Substrates | Inducers | Inhibitors | |------------------------|-----------------|---------------------------------------------| | Amitriptyline, Imipramine | CBZ | Felbamate | | Diazepam | Norethindrone | Fluconazole, Ketoconazole | | Lansoprazole, Omeprazole | Prednisone | Indomethacin | | Phenobarbital, phenytoin | Rifampicin | Lansoprazole, Omeprazole | | Progesterone | | Probenecid | | R-warfarin | | Topiramate | # CYP2D6 | Substrates | Inducers | Inhibitors | |------------------------|-----------------------|-----------------| | Amiodarone | Dexamethasone | Amiodarone | | Amitriptyline | Rifampicin | Amitriptyline | | Captopril | | Cocaine | | Carvedilol | | Fluoxetine | | Codeine | | Imatinib | | Tramadol | | Quinidine | # CYP3A4 | Substrates | Inducers | Inhibitors | |------------------------|--------------------|------------------------------------------------| | Amiodarone | CBZ | Clarithromycin, Erythromycin | | CBZ | Phenobarb., Primidone | Ciprofloxacin, Norfloxacin | | Clarithromycin | PHT | Diltiazem, Verapamil | | Clonazepam, Diazepam | Rifampicin | Ketoconazole, Itraconazole | | Omeprazole | | Metronidazole | # Enzyme Induction (Cond.): - It results from increased production of proteins (enzymes). - It has a slow onset and may require up to 3 wks before the max. effect is observed. - The precipitant drug usually induces the enzymes that enhance the metabolism of the object drug. - Some drugs (e.g., CBZ) increase their own metabolism. - When the precipitant drug responsible for enzyme induction is discontinued, the process is reversed. - Reversal of enzyme induction often is a slower process than the onset. # Enzyme Induction (Cond.): - In patients receiving warfarin and phenytoin concurrently, bleeding could occur if the enzyme inducer, PHT, is discontinued without an adjustment in the anticoagulant dosage. - PHT increases the hepatic metabolism of mexiletine. - Theop & PHT increase the metabolism of each other. # Enzyme Induction (Cond.): - Example: Phenobarbital + Warfarin - Impact: Phenobarbital induces the metabolism of warfarin, resulting in reduced anti-coagulation. # Decreased metabolism (Enzyme Inhibition): - Enzyme inhibition usually results from competition between the precipitant & object drugs for binding sites on the enzyme. - The onset of interaction is more rapid than with enzyme induction, often occurring within hours. - Unless the precipitant drug has a long t1/2, enzyme inhibition generally reaches a max. effect within 24 h. - The inhibitory effect of the precipitant drug on the metabolism of the object drug is usually maximal within 3 t1/2. # Enzyme Inhibition (Cond.) - Example: Erythromycin + Theophylline - Impact: Erythromycin inhibits the metabolism of theophylline, resulting in increased theophylline levels. # Enzyme Inhibition (Cond.): - Upon discontinuing the enzyme-inhibiting drug, plasma concs of the object drug decrease, resulting in loss of efficacy unless appropriate action is taken. - When an enzyme inducer drug (e.g., CBZ) is administered with an enzyme inhibitor (e.g., verapamil), the effect of the inhibitor appears to predominate and the effect of the inducer is attenuated. # Renal excretion: - Various mechanisms may be involved with interactions affecting renal elimination, including: - competition for active tubular secretion, - pH-dependent renal tubular transport, - Increase renal blood flow. # Active tubular secretion: - Each protein has a unique affinity for an anion or cation. - drugs that use a similar system for transport appear to interact by competitive inhibition of transport proteins. - Saturation of the transport system by the precipitant drug may decrease the tubular secretion of the object drug. - Interactions resulting from this mechanism tend to occur rapidly. - Plasma concs of the object drug may be increased, producing an increase in therapeutic and toxic effects. # Active tubular secretion (Cond.): - Probenecid inhibits the tubular secretion of methotrexate. - Example: Probenecid + Penicillin - Impact: Probenecid prolongs the t1/2 of penicillin, allowing single-dose therapy. - Quinidine reduces the renal and biliary CL of digoxin by 30 – 40%, increasing serum digoxin concs. # Passive tubular reabsorption: - Weakly acidic drugs are reabsorbed from acidic urine, whereas basic drugs are excreted. - The opposite is true in alkaline urine. - Thiazide diuretics decrease renal Li+ clearance, producing toxicity. - NaHCO3 administration (5 h) increases Li+ clearance. - Chronic antacid therapy (Mg-Al-OH) is associated with increased salicylate clearance. # Passive tubular reabsorption (Cond.): - Example: Antacids + Aspirin - Impact: Antacids reduce the tubular reabsorption of salicylates via an increase in urine pH. # Increase renal blood flow - Example: Hydralazine + Digoxin - - Impact: Hydralazine increases the renal clearance of digoxin.