(2) Lecture 2 - Drug interactions.pdf

Drug interactions Bashir Alsiddig Yousef B. Pharm., MSc. Molecular Medicine, Ph.D. Pharmacology Department of Pharmacology Email: [email protected] Introduction Drug interaction is one of the factors that can alter the response to drugs is the concurren...

Drug interactions Bashir Alsiddig Yousef B. Pharm., MSc. Molecular Medicine, Ph.D. Pharmacology Department of Pharmacology Email: [email protected] Introduction Drug interaction is one of the factors that can alter the response to drugs is the concurrent administration of other drugs. Many patients, especially the elderly, are treated continuously with one or more drugs for chronic diseases such as hypertension, heart failure, osteoarthritis and so on. Acute events (e.g. infections, myocardial infarction) are treated with additional drugs. The potential for drug interactions is therefore substantial, and poly-pharmacy is an important factor to consider when prescribing in this group. Drugs can also interact with other dietary constituents (e.g. grapefruit juice, which down-regulates expression of CYP3A4 in the gut) and herbal remedies (such as St John's wort).  There are several mechanisms by which drugs may interact. The administration of one drug (A) can alter the action of another (B) by one of two general mechanisms: 1. Modification of the pharmacological effect of B without altering its concentration in the tissue fluid (pharmacodynamic interaction) 2. Alteration of the concentration of B that reaches its site of action (pharmacokinetic interaction). Combined pharmacodynamics with pharmacokinetic interactions also may happen between two drugs when used concurrently. For such interactions to be important clinically, it is necessary that the therapeutic range of one drug is narrow (i.e. that a small reduction in effect will lead to loss of efficacy and/or a small increase in effect will lead to toxicity). Consequences of Drug Interactions Their effect on patients can vary greatly, from no untoward effects to the most extreme result of severe morbidity or death. Physicians face medical-legal liability if a poor patient outcome is the result of a known drug interaction. Health care facilities face increased consumption of resources and increased costs for diagnosing and treating patients with significant drug interactions. (One study found that hospitalized patients who received interacting drugs had a longer and more costly hospitalization than patients who did not experience such interactions). The pharmaceutical industry faces loss of investment, time, and financial resources if a drug is removed from the market, as well as potential litigation. Risk Factors Use of multiple prescribers and/or multiple pharmacies increases the odds that health professionals will have incomplete medical and drug information available to them, and raises the chance that a potential drug interaction may go undetected. Specific populations are at increased risk of experiencing drug interactions. For example, the elderly patients. The genetic makeup of an individual determines his or her complement of metabolizing enzymes and other proteins. Patients classified as slow metabolizers appear to be at less risk for drug interactions than extensive metabolizers or ultra-rapid metabolizers.  Number of chronic illnesses, increased drug usage to manage those illnesses, and age-related physiologic changes (e.g., decreased renal function, decreased protein binding), are at higher risk for drug interactions and adverse events. Obese patients have altered levels of metabolizing enzymes, making them more susceptible to drug interactions, as do malnourished patients. Other populations at risk include critically ill patients, patients with autoimmune disorders, and transplant recipients. Drugs with a narrow therapeutic index, a steep dose-response curve, or potent pharmacologic effects have been associated with greatest risk for significant drug interactions. Risk Factors for Drug Interactions  DRUG INTERACTIONS CLASSIFIED AS: ENHANCED EFFICACY A) USEFUL WITHOUT TOXICITY TOXICITY B) HARMFUL EFFICACY  Pharmacodynamic interaction Although most significant drug interactions involve a pharmacokinetic process, numerous pharmacodynamic interactions are clinically important as well. When two drugs with pharmacologic effects are administered concurrently, an additive, antagonistic or synergistic response is usually seen. The two drugs may or may not act on same receptor to produce such effects In theory, drugs acting on the same receptor or process are usually additive, eg, benzodiazepines plus barbiturates. Drugs acting on different receptors or sequential processes may be synergistic, e.g, nitrates plus sildenafil or sulfonamides plus trimethoprim. Conversely, drugs with opposing pharmacologic effects or blocking receptor may reduce the response (antagonize) to one or both drugs. A- Synergistic and additive Interactions 2 drugs with similar pharmacologic profiles when taken together can produce a response greater (may increase potency or toxicity) than that of either drug alone For example: 1- A patient taking amitriptyline for depression who is prescribed benztropine for Parkinson's disease may experience additive anticholinergic effects. These can manifest as severe constipation, dry mouth, worsening vision, or psychosis. 2- Many diuretics (thiazide and loop diuretics) lower plasma K+ concentration, and thereby predispose to digoxin toxicity and to toxicity with type III antidysrhythmic drugs. 3- Warfarin competes with vitamin K, preventing hepatic synthesis of various coagulation factors. If vitamin K production in the intestine is inhibited (e.g. by antibiotics), the anticoagulant action of warfarin is increased. 4- Monoamine oxidase inhibitors increase the amount of noradrenaline (norepinephrine) stored in noradrenergic nerve terminals and interact dangerously with drugs, such as ephedrine or tyramine, that release stored noradrenaline. This can also occur with tyramine-rich foods-particularly fermented cheeses. 5- The risk of bleeding, especially from the stomach, caused by warfarin is increased by drugs that cause bleeding by different mechanisms (e.g. aspirin, which inhibits platelet thromboxane A2 biosynthesis and which can damage the stomach). 6- Sulfonamides prevent the synthesis of folic acid by bacteria and other micro- organisms; trimethoprim inhibits its reduction to tetrahydrofolate. Given together, the drugs have a synergistic action. 7- Histamine H1 receptor antagonists, such as promethazine, commonly cause drowsiness as an unwanted effect. This is more troublesome if such drugs are taken with alcohol, and it may lead to accidents at work or on the road. 8- Combination of an erectile dysfunction drugs such as sildenafil or tadalafil and a nitrate such as isosorbide mononitrate causes profound hypotension. These drugs reverse erectile dysfunction by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for the metabolism of cyclic guanosine monophosphate (cGMP), which cGMP causes vasodilation. Nitric oxide donors such as isosorbide mononitrate, nitroglycerin, or isosorbide dinitrate exert their vasodilatory effects by ultimately increasing cGMP levels. Because these two drug classes have additive effects on cGMP and blood pressure, the combination of a PDE5 inhibitor and any nitrate is contraindicated. B- Antagonistic Interactions When one drug in combined with another drug lead to decrease its potency, either by competing with its receptor or producing an effect that lead to decrease its response. For examples: 1- An antagonistic pharmacodynamic interaction is a degradation or blunting of the response to one or both interacting drugs. For example, corticosteroids can cause hyperglycemia, worsening blood glucose control for diabetic patients, which may require changes in insulin dosing. 2- Antidepressant mirtazapine has been reported to block α-receptors, causing loss of hypertensive control in patients taking clonidine. 3- Take the case of a patient with Alzheimer dementia who is receiving treatment with the cholinesterase inhibitor donepezil and is prescribed the anticholinergic drug tolterodine for urinary incontinence. (therefore cause failure of treatment). 4- NSAIDs such as ibuprofen or indomethacin, inhibit biosynthesis of prostaglandins, including renal vasodilator/natriuretic prostaglandins (PGE2, PGI2). If administered to patients receiving treatment for hypertension, they cause a variable but sometimes marked increase in blood pressure. 5- β-Adrenoceptor antagonists diminish the effectiveness of β- adrenoceptor agonists such as salbutamol. ANTAGONISM BY RECEPTOR BLOCK: Receptor block antagonism involves two important mechanisms: 1. reversible competitive antagonism 2. irreversible, or non-equilibrium, competitive antagonism Pharmacokinetic Interaction All the four major processes that determine pharmacokinetics- absorption, distribution, metabolism and excretion can be affected by drugs. Pharmacokinetic interactions have received a great deal of attention, it is medically very important.  Altered GIT absorption After oral administration, most drug absorption takes place in the proximal small intestine, where the large surface area facilitates this process. However, drug interactions that alter absorption may occur throughout the GI tract through a variety of mechanisms: 1- Altered gastric pH: The non-ionized form of a drug is more lipid soluble and more readily absorbed from the GIT than ionized form. Therefore change in pH could result in change in drug absorption. for example, ketoconazole, itraconazole, atazanavir, and iron supplements, require an acidic environment for optimal dissolution and absorption. Compounds that raise gastric pH such as H2 receptor blockers (e.g., cimetidine, ranitidine), proton pump inhibitors (e.g., omeprazole, lansoprazole), or antacids can reduce the absorption of these drugs, thereby decreasing their effectiveness. 2- Complexation or Chelation: Agents that form chemical complexes with drugs may cause lower rates of drug absorption. Cholestyramine (a bile acid–binding resins) binds to several drugs (digoxin, warfarin, levothyroxine, furosemide) decrease its absorption. The result is lowered serum concentration and reduced effectiveness. Divalent and trivalent metallic ions such as magnesium, aluminum, calcium, zinc, bismuth, and iron can form insoluble complexes with drugs, also resulting in reduced serum levels and possibly therapeutic failure. The quinolone antibiotics are highly susceptible to chelation sucralfate, most antacids, calcium acetate, and ferrous sulfate (including iron in multivitamins), as are many of the tetracycline antibiotics and penicillamine. 3- Altered GIT motility: Many drugs alter gastrointestinal motility. (altered GI motility affects drug absorption is difficult to predict). Narcotics or drugs with anticholinergic effects (e.g., tricyclic antidepressants, phenothiazines, oxybutynin, tolterodine) can slow GI motility. Metoclopramide (pro-kinetic drug), erythromycin, and some laxatives can increase GI motility. Slowing motility may enhance drug absorption by allowing more time for drug dissolution and prolonged contact with absorptive surface of small intestine. Alternatively, slowed motility may prolong exposure to intestinal enzymes, reducing the amount of drug available for absorption. Enhanced motility may speed the transit of drugs through the GI tract, decreasing medication absorption. This is particularly important for drugs that require prolonged contact with the absorptive surface. Sustained-release products and enteric-coated drugs may also undergo decreased absorption if GI motility is increased. 4- Altered intestinal bacterial flora: Gut flora play important roles in metabolizing of some drugs. Example: A- 40% or more of the administered digoxin dose is metabolized by the intestinal flora. Antibiotics kill a large number of the normal flora of the intestine lead to increase digoxin concentration and toxicity. B- Antibiotic disrupt the enterohepatic circulation of oral contraceptives, in wich micro-flora are required to cause optimum blood concentration of OCs. Therefore, lead to failure of OCs. 5- Altered Drug Transport Two types of transport proteins are present in the intestinal mucosa— those that are involved in the transport of compounds from the lumen of the intestine into the portal bloodstream, and those that are involved in the efflux of compounds from the intestinal mucosa back into the gut lumen. Of these, efflux transporters, particularly P-glycoprotein (Pgp). Co-administration of a Pgp inhibitor such as verapamil increases the amount of substrate available for absorption and may elevate the serum drug concentration. Increase expression of Pgp (rifampin, Pgp inducer) leads to enhanced efflux of the substrate into the gut lumen, and lower serum levels of the substrate 6- Drug-induced mucosal damage: Drug may injury the epithelial barrier of the GIT lead to increase absorption of the other drugs. Example, use of antineoplastic agents increase absorption of other drugs. 7- Decrease the blood supply: Decrease in the blood supply lead to reduction in adsorbed drug. Example is the addition of adrenaline to local anaesthetic injections; the resulting vasoconstriction slows the absorption of the anaesthetic, thus prolonging its local effect Distribution One drug may alter the distribution of another, which is also clinically important. The mechanisms by which drug interactions alter drug distribution include: (1) Competition for plasma protein binding, (2) Displacement from tissue binding sites (3) Alterations in local tissue barriers, eg, P-glycoprotein inhibition in the blood-brain barrier.  The main mechanism for drug interaction at the distribution stage is (Displacement of a drug from protein-binding sites). This displacement in cause transiently increases the concentration of free (unbound) drug, which lead to toxicity from the transient increase in concentration of free drug. Displacement occurs if both drugs are highly protein bound (>90%), due to competition between the two drugs for the same protein-binding site can lead to displacement. Examples: sulfonamides and chloral hydrate cause displacement of other clinically important drug such as warfarin and phenytoin lead to increase it toxicity.  Drug metabolism Pharmacokinetic interactions that involve changes in metabolism account for most therapeutically important drug interactions. The liver is main organ for drug metabolism, but also other organ can also included such as GIT, skin, lung an WBCs. The 2 main types of hepatic drug metabolism are phase I and phase II reactions. Phase I oxidative reactions are the initial step in drug biotransformation, and are mediated by the cytochrome P-450 (CYP) system. This complex superfamily of enzymes has been sub-classified into numerous enzymatic subfamilies. The most common CYP subfamilies include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. These enzymes may be induced or inhibited by other agents, thereby leading to an increase or decrease in the metabolism of the primary drug. 1- Enzyme induction: A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself. e.g. barbiturates, ethanol, rifampicin, carbamazepine, phenytoin. Over 200 drugs cause enzyme induction and thereby decrease the pharmacological activity of a range of other drugs. This can cause pharmacokinetic kind of tolerance, lead to gradually increased over a period of a few weeks, during which it induces its own metabolism. Such as in alcohol and carbamazepine. Enzyme induction involves protein synthesis. Therefore, it needs time up to 1 - 2 weeks to reach its effect.  Examples of drugs cause induction (stimulation) of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, phenytoin, primidone, rifampin, rifabutin, and St. John’s wort. Enzyme induction is isoezyme selective: Rifampicin (CYP3A4), Barbiturates (CYP3A4,CYP2C19), Carbamazepine (CYP3A4), Ethanol chronic use (CYP2E1), smoking (CYP1A2). Enzyme inducers can also increase the activity of phase II metabolism such as glucuronidation. Enzyme induction is exploited therapeutically by administering phenobarbital to premature babies to induce glucuronyltransferase, thereby increasing bilirubin conjugation and reducing the risk of kernicterus. 2- Enzyme inhibition: It is the decrease of the rate of metabolism of a drug by another one. This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity. Such effects can be clinically important and are major considerations in the treatment of patients with HIV infection with triple and quadruple therapy, because some protease inhibitors are potent inhibitors of P450 enzymes. Antihistamine terfenadine and imidazole antifungal drugs such as ketoconazole. Grapefruit juice reduces the metabolism of many drugs. Inhibition of the enzyme may be due to the competition on its binding sites, so the onset of action is short may be within 24 h. Stereochemistry play important roles for selectivity of inhibition for drug metabolism (esomeprazole, the (S)-isomer of omeprazole)  Examples of drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. Enzyme inhibition is isoezyme selective: Cimetidine (CYP3A4), Quinidine (CYP2D6), Chloramphenicol (CYP2B1), Ketoconazole (CYP3A4). 3- Haemodynamic effects: Variations in hepatic blood flow influence the rate of inactivation of drugs that are subject to extensive pre-systemic hepatic metabolism. e.g. lidocaine and propranolol: A reduced cardiac output reduces hepatic blood flow, so negative inotropes (e.g. propranolol) reduce the rate of metabolism of lidocaine by this mechanism. Drug excretion With exception of inhaled anesthetics, most drugs or drug metabolites are eliminated from the body via the urine or the bile. Other means of elimination are possible, for e.g., via sweat, saliva, or in the breast milk of nursing mothers. For renal elimination drug interaction may occur at several points, namely, interference with the passive diffusion (Glomerular filtration), active tubular secretion, or active reabsorption of drugs. The main mechanisms by which one drug can affect the rate of renal excretion of another are by: 1. Altering protein binding, and hence filtration 2. Inhibiting tubular secretion 3. Altering urine flow and/or urine pH. 1- Inhibition of tubular secretion: It occur in the proximal tubules, in which drug combines with a specific protein to pass through proximal tubules. Probenecid was developed to inhibit penicillin secretion and thus prolong its action. It also inhibits the excretion of other drugs, including zidovudine, methotrexate and acyclovir. Because diuretics act from within the tubular lumen, drugs that inhibit their secretion into the tubular fluid, such as NSAIDs, reduce their effect. 2- Alteration of urine flow and pH: Excretion and reabsorption of drugs occur in the tubules by passive diffusion which is regulated by concentration and lipid solubility. Diuretics tend to increase the urinary excretion of other drugs, but this is seldom clinically important. Conversely, loop and thiazide diuretics indirectly increase the proximal tubular reabsorption of lithium (which is handled in a similar way as Na+), and this can cause lithium toxicity in patients treated with lithium carbonate for mood disorders. The effect of urinary pH on the excretion of weak acids and bases is put to use in the treatment of poisoning with salicylate and phenobarbital.  Drug-food interaction Food–drug interactions are extensive and in some ways more complex than drug–drug interactions. The presence or absence of food, the composition of the meal and its size, the formulation of the drug, and even the age of the patient all factor into food– drug interactions. The impact of food on drugs may be pharmacokinetic or pharmacodynamic in nature. The most important pharmacokinetic food–drug interactions are those that alter the absorption of a drug (chelation, adsorption, changes in gastric pH, altered GI motility, altered gut metabolism, or altered transport across the gastric mucosa). Herb–Drug Interactions Herbs may mimic, magnify, or oppose the effects of many drugs. Herbal medicines are mixtures of more than one active ingredient. The multitude of pharmacologically active compounds obviously increases the likelihood of interactions taking place. Herbs & drugs may interact either pharmacokinetically or pharmacodynamically. Induction of cytochrome P450 enzymes and/or P-glycoprotein, some herbal products (e.g., St John’s wort) have been shown to lower the plasma conc (and/or the pharmacological effect) of a number of conventional drugs, including cyclosporine, indinavir, nevirapine, oral contraceptives, and digoxin.  Bleeding may occur when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), or danshen (Salvia miltiorrhiza). Induction of mania may be seen in depressed patients who mix antidepressants and Panax ginseng. Exacerbation of extrapyramidal effects is possible with neuroleptic drugs and betel nut (Areca catechu). Increased risk of hypertension is imminent when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe). Potentiation of oral and topical effects of corticosteroids is certain bylicorice (Glycyrrhiza glabra). Anthranoid-containing plants, including senna (Cassia senna) and cascara (Rhamnus purshiana), and soluble fibers, including guar gum and psyllium, can decrease the absorption of other drugs.