Adverse drug reaction and their mechanisms Drug interactions: Adverse drug reaction and their mechanisms Drug interactions BY M SAMEERA MPHARMACY(II SEM) Dept. Pharmacology SRR COLLEGE OF PHARMACY Adverse drug reaction : Adverse drug reaction Definition Severity of ADR’s Types of ADR: 1) type A reactions. 2) type B reactions. 3) type C reactions (chronic long term effects). 4) type D reactions (delayed effects). 5) type E reactions (end of use) and 6) type F reactions (failure of therapy). Type-A reactions: Type-A reactions They are predictable known pharmacology of the drugs. Dose dependant and can be alleviated by dose reduction. Example- 1) bradykinin with beta blockers. 2) postural hypertension with prazosin. Type-B reactions – They are less common but they are often serious and account for many deaths. Can’t be predicted from the pharmacology of the drug. Not dose dependant, host dependant factors important in pre-disposition. example- 1) anaphylaxis with pencillin . 2) anti- convulsant hypersensitivity . Type-C reactions: Type-C reactions Biological characterizations can be predicted from the chemical structure of the drug or metabolite. Example- paracetamol hepatotoxicity . Type-D reactions- Occur after many years of treatment, can be due to accumulation. Example- 1) secondary tumours after treatment with chemotherapy. 2) teratogenic effects of phenytoin taken during pregnancy. Type-E reactions- Occur on withdrawal especially when drug is stopped abruptly. Example - 1) withdrawal seizures on stopping phenytoin . 2) adrenalcortical insufficiency on withdrawal of steroids. Predisposing factors to ADR : Predisposing factors to ADR Multiple drug therapy. Age. Gender. Inter-current disease. Race and genetic polymorphism. Mechanisms of ADR’s: Mechanisms of ADR’s TYPE-A ADR’S- The individual response to drugs shows greater variation. This is a manifest either as different doses being required to produce the same pharmacological effect or as different responses to defined dose. Such inter-individual variation is the basis for type-A adverse reactions. Dose related adverse reactions may occur because of variations in pharmaceutical, pk or pd properties of a drug and are often due to underlying disease states. It is of two mainly causes- 1) pharmaceutical causes. 2) pharmacokinetic causes. Pharmaceutical causes-: Pharmaceutical causes- Adverse reactions can occur due to pharmaceutical aspects of a dosage from either because of alterations in the quantity of the drug present or in the release characteristics. Example- A rate controlled preparation of indomethacin was withdrawn following the receipt of a significant no. of reports of GIT bleeding and haemorrhage . Pharmacokinetic causes- Quantitative alterations in the absorption, distribution, metabolism and elimination of drugs may lead to alterations in the concentration of the drug at the site of action with the corresponding changes in its pharmacological effects. Such an alterations may produce either an exaggerated response or therapeutic failure as a consequence of abnormally low drug concentrations . Absorption-: Absorption - Differences in both rate and extent of drug absorption may cause adverse effects. Factors which can influence the extent of absorption of the drug include- 1) dosage 2) pharmaceutical factors 3) GIT motility 4) absorptive capacity of GIT mucosa 5) first pass metabolism in the liver and gut wall before it reaches the systemic circulation. The rate of absorption of orally administered drugs is largely determined by the rate of gastric emptying which is influenced by factors including the nature of gastric contents, disease and concomitant drugs. Distribution : Distribution The distribution of drugs to various tissues and organs is dependant on factors including- regional blood flow, plasma protein and tissue binding. Changes in how a drug is distributed may theoritically predispose to adverse effects, although the clinical importance of such mechanisms is unclear. Elimination- Most drugs are excreted in the urine or bile are metabolized by the liver to yield metabolites which are then excreted by the kidneys. Changes in the drug elimination rates are probably the most important cause of type-A adr’s . Reduced elimination leads to drug accumulation, with potential toxicity due to increased plasma and tissue levels. Conversely, enhanced elimination leads to reduced plasma and tissue drug levels, resulting therapeutic failure. RENAL EXCRETION: : RENAL EXCRETION: Impaired glomerular filteration leads to reduced elimination of drugs which undergo renal excretion. Individuals with reduced glomerular filtration ( patients with intrinsic renal disease, elderly and neonates) are liable to develop type-A adverse reactions to normal therapeutic doses of drugs which are mainly excreted by the kidneys. Most potentially toxic drugs are digoxin , ACE-inhibitors, aminoglycoside antibiotics and many cytotoxic agents. The occurrence of these ADR’s may be minimized by adjusting the dosage given to individual patients on the basis of their renal function. Drug metabolism- Metabolism occurs predominantly in the liver, although the kidneys, lungs, skin and gut also have some metabolizing capacity. Slide 11: Drug metabolism can be divided into two phases. Phase-I( oxidation, reduction or hydrolysis) exposes functionally reactive groups or adds them to the molecule. Phase-II ( sulphation, glucourodination, acetylation or methylation) involves conjugation of the drug at a reactive site produced during phase-I. Drugs that already have reactive groups undergo phase-II reactions only. Others are sufficiently water-soluble after phase-I metabolism to be eliminated by renal excretion. Inter-individual difference or alterations in the rate at which drugs are metabolized result in appropriate variations in elimination rates. Reduced rates of metabolism may lead to drug accumulation and an increase risk of type-A adverse drug reactions, while enhanced rates of metabolism may result in therapeutic failure. Microsomal oxidation: Microsomal oxidation Drug oxidation occurs mainly in the smoothly endoplasmic reticulum of the liver by cytochrome p450 super-family. Four subfamilies of p450 iso -enzymes are thought to be responsible for most of the metabolism of commonly used drugs in humans cyp1, cyp2,cyp3 and cyp4. Poor metabolizes tend to have reduced first pass metabolism, increased plasma levels, and exaggerated pharmacological response to this drug, resulting in postural hypotension. Rapid metabolizes may require considerably higher doses for a standard effect. Hydrolysis- The hydrolysis is catalyzed by plasma pseudo cholinesterase which exists in several different genetically determined forms. Slide 13: Suxamethonium apnoea is the best known example of an alteration in drug response due to individual variation in drug hydrolysis. The neuromuscular blocking effects of suxamethonium are usually short lived,as the drug is rapidly inactivated in plasma by hydrolysis. Acetylation - A number of drugs are metabolized by acetylation including dapsone , isoniazid , hydralazine , phenalzine , procainamide and many suphonamides . Acetylation is under genetic control and shows a polymorphism such that individuals may be phenotyped as either slow or rapid acetylators . The variability is due to differences in the activity of the liver enzyme N- acetyltransferase . Slide 14: Slow acetylators are at increased risk of developing type-A ADR’s. Thus isoniazid –induced peripheral neuropathy, the haematological adverse effects of dapsone , and the adverse effects of sulphapyridine are more likely to occur in these individuals. Glucouronidation - Several drugs commonly used in clinical practise ( morphine, paracetamol and ethinylestradiol ) are eliminated at least partly by glucuronide conjugates. Pharmaco -dynamic causes- Many, if not most type-A ADR’s have a pk basis. some however, are due to enhanced sensitivity of target organs or tissues. The reasons why tissues form different individuals should respond differently to drugs are still largely unknown, but evidence is accumulating to show that target organ sensitivity is influenced by the drug receptors themselves, by physiological homeostatic mechanisms and by disease. Type- B ADR,s: Type- B ADR,s Type-B reactions are inexplicable in terms of the normal pharmacology of the drug. The cause may be pharmaceutical or pk or may lie in target organ response( pharmacodynamic ). They include- Pharmaceutical causes. Pk causes . Pharmacodynamic causes. Pharmaceutical causes- Pharmaceutical aspects of the medicine itself may be the cause of type-B ADR’s. Such reactions can occur due to the presence of degradation products of the active constituents, the effects if the non-drug components of the formulation, such as excipients and other compounds( colourings , preservatives and anti-oxidants) or the actions of the synthetic byproducts of the active constituents Pk causes: Pk causes There are no documented type-B adverse reactions that can be attributed to abnormalities of absorption or distribution. however there is emerging evidence that to suggest that the bio- activition of drugs to yield reactive species is responsible for a significant proportion of type-B adverse effects. Binding of such reactive metabolites may result in either direct or immune medicated toxicity. Examples- of type-B reactions postulated to occur as a result of bioactivation to reactivate metabolites include tacrine ( hepatotoxicity ) , clozapine ( agranulocytosis ) , halothane ( hepatotoxicity ) and carbamazepine ( hypersensitivity reactions). The reasons only why some individuals develop such type-B reactions remains unclear Pharmacodynamic causes: Pharmacodynamic causes Individual patients vary widely in their responses to drugs. Even after allowance has been made for the patient’s age, gender, body weight, disease state and concurrent drug regimens there is still variations between individuals. Qualitative differences in the target organ response to drugs may be considered as genetic or immunological, neoplastic or teratogenic . Genetic causes for abnormal response- Many type-B adverse reactions have been labelled as idiosyncratic reactions that were assumed to be due to some qualitative abnormality in the patient. until recently drug “idiosyncrasies” have tended to form a “dustbin” category for ADR’s that could not be classified under any other headings. Example - 1) methaenoglobin reductase -drug given is dapsone and the effect seen is methanoglobinaemia . Erythrocyte glucose-6- phosphate dehydrogenase(G6PD) deficiency: Erythrocyte glucose-6- phosphate dehydrogenase (G6PD) deficiency It is an enzyme required for the stability of the red blood cells. Individuals with the sex- linked inherited deficiency in this enzyme have weakened red cell membranes and are predisposed to haemolysis due to oxidant drugs such as primaquine, sulphonamides and sulphones and nitrofurantoins. The frequency of the enzyme deficiency also varies widely between and within various populations. The no. of currently available medicines with proven haemoytic potential in G6PD- deficient individuals is relatively small; primaquine is probably the best known example . Slide 19: Drugs that should be avoided in G6PD deficiency are- dapsone , niridazole , methylthioninium chloride ( methylene blue), primaquine , quinolones (ciprofloxacin, nalidixic acid , norfluoxacin , ofloxacin ), sulphonamides (co- trimoxazole ) Hereditary methaemoglobinaemias - An inherited deficiency of methaemoglobin reductase in erythrocyte renders affected individuals susceptible to the devlopment of methaemoglobinaemia and cyanosis in response to oxidant drugs. Drugs that are oxidizing agents, nitrites, dapsone , primaquine , niridazole , quinolones , sulphonamides etc.may have this effect. Porphyrias - They are heterogenous group of inherited disorders of haem biosynthesis. Slide 20: The effects of drugs are of most importance in patients with acute porphyrias , in whom certain commonly prescribed agents may precipitate life-threatening attacks. other trigger factors include alcohol and endogenous & exogenous steroid hormones. In the acute porphyrias patients develop abdominal and neuro-pschiatric disturbances and they excrete in their urine excessive amounts of porphyrin precursors 5-amino laevulinic acid(ALA) and porphobilinogen . Malignant hyperthermia- It is a rare but potentially fatal condition in which there is rapid rise in body temp( atleast 2 degrees per hr) occuring without obvious cause after administration of anesthetics or muscle relaxants. Slide 21: The condition usually follows the administration of an inhalational general anesthetic, often halothane in combination with suxamethonium . In addition to the temperature rise, the syndrome is characterized by stiffness of skeletal muscles, hyperventilation, acidosis, hyperkalemia and signs of increased activity of the sympathetic nervous system. It is likely that the condition is triggered by abnormal release of intracellular ionized calcium, which may be due to an inherited defect of cellular membranes. Glucocorticoid glaucoma- In genetically predisposed individual, glucocorticoids can cause a rise intraocular pressure leading to blindness. Development of increased intraocular pressure appears to be correlated with dosage and may persist for several months after stopping steroid treatment. It is important to remember that this complications may arise in patients treated with glucocorticoid eye drops. Cholestatic jaundice induced by oral contraceptives: Cholestatic jaundice induced by oral contraceptives These drugs are known to cause jaundice in some women especially during the first month of medication; this recovers rapidly on discontinuation of treatment. Available evidence suggest that a genetic component is important for the development of the reaction. The underlying mechanism for this reaction is unclear but it is likely that estrogen-induced changes in the composition of the hepatocyte membranes are involved. Immunological reasons for abnormal response: Immunological reasons for abnormal response Some drugs( peptides of foreign origin such as streptokinase) are immunogenic and may cause immunological reactions. Drug allergy is most frequently encountered type of immunological adverse reactions. The features of these reactions are— There is no relation to the usual pharmacological effects of the drug. There is often a delay between first exposure to the drug and the occurrence of the subsequent adverse reaction. Very small doses of the drug may elicit the reaction once allergies established. The reaction disappears on withdrawal of the drug. The illness is often recognizable as a form of immunological reaction. Slide 24: Allergic reactions vary from rash, serum sickness and angioedema to the life threatening bronchospasm and hypotension associated with anaphylaxis. Many factors influence the development of allergic reactions. Patients with the history of atopic or allegic disorders are at greatest risk. Ex- type-1 Ige mediated anaphylaxis for the drug pencillin . Delayed adverse effects of drugs- A no. of adverse effects may only become apparent after long term treatment, for ex-the relatively harmless melanin deposits in the lens and cornea that are seen after years of phenothiazine treatment and which should be distinguished from pigmentary retinopathy, a dose related adverse effect occuring within several months of initiation of treatment. Adverse effects associated with drug withdrawal: Adverse effects associated with drug withdrawal Some drugs cause symptoms when treatment is stopped abruptly, for ex-the benzodiazepine withdrawal syndrome ,rebound hypertension following discontinuation of anti- hypertensives such as clonidine and acute adrenal insufficiency that may be precipitated by the abrupt withdrawl of corticosteroids. these are all type-A reactions. Detection and monitoring of adverse drug reactions- By the time the drug receives a marketing authorization, It will usually have been given to an average of 1500 people and it is likely that clinical trials will a have detected only the most common adverse drug reactions. It follows the type-B reactions particularly those with an incidence of 1 in 500 or less, are unlikely to have been identified before the drug appears in the market. Slide 26:
It is only after much wider use that rare reactions or those which occur predominantly in certain sub-groups within population, such as the elderly, are detected. It is therefore essential to monitor safety once the drug has been marketed. Some methods used commonly in post marketing surveillance are descried below- 1) case reports, 2) cohort studies, 3) case control studies, 4) spontaneous
schemes. Case reports- The publication of single case reports or case series of adverse drug reactions in the medical literature is an important means of detecting new and serious reactions, particularly type-B reactions.
Cohort studies: Cohort studies These are prospective studies which study the fate of a large group of patients taking a particular drug. They include ad hoc investigations set up to investigate specific problems. Case control studies – They compare the drug usage in a group of patients with a particular disease with use among a matched control group who are similar in potentially confounding factors but who do not have the disease. The prevalence of drug taking is then compared between the groups and a significant excess of drug takers in the disease group may be evidence of an association with the drug. this is a usual retrospective method which can provide valuable information on the incidence of type-B reactions and the association between the drugs and disease. Slide 28: It is not capable of detecting previously unsuspected adverse reactions. Spontaneous reporting schemes- Doctors and pharmacists are asked to report all suspected serious adverse reactions, and all suspected reactions to newer products marked with an inverted black triangle symbol in product information Spontaneous reporting schemes cant provide estimates of risk because the true no. of cases is invariably underestimated, and the denominator(total no. of patients treated with the drug in question).is not known. The main advantages of the scheme are : It is easily available for all doctors and pharmacists to report. It covers all therapeutic agents, including vaccines and herbal medicines. It is capable of detecting both rare and common reactions. It is relatively inexpensive to operate. Slide 29: The main disadvantage of the scheme is level of under reporting of reactions; it is likely that fewer than 10% of serious reactions are notified. The scheme operates on the basis that reports should me made despite uncertainaity about a casual relationship irrespective of whether or not the reaction is well recognized and regardless of other drugs having been given concurrently. Identification of adverse drug reactions- The establishment a casual relationship between a specific drug and a clinical event is a fundamental problem in adverse reaction assessment. First adverse drug reaction frequently mimic other diseases and, second many of the symptoms attributed to them occur commonly in healthy individuals taking no medication. Slide 30: Thus clinicians may fail to recognize the features of an adverse drug reaction because they don’t fit into a clearly defined pattern. When a suspected adverse drug reaction has occurred, it may be helpful to try to assess whether it is definitely, probably or possibly due to the drug. Factors taken into account when assessing the likely hood of an ADR: Where an adverse reaction is suspected a full history-in particular details of other drugs taken by the patient, including the over the counter and herbal medicines is important. The patient should be asked about the nature and timing of the symptoms or events and whether such events have occurred in the past. The temporal relationship of a suspected ADR is important . Slide 31: It is relatively easy to recognize an adverse reaction that occurs soon after drug administration However once more than a few weeks have elapsed the association between the drug and the event is more difficult. Patients and adverse dug reactions- There is some evidence that patients themselves are capable of correctly distinguishing probable adverse drug reactions from other types of adverse clinical events. In investigation of patients with ankolysing spondylitis 45% reported serious adverse drug reactions associated with their medication. They regarded insufficient information and inadequate monitoring by the doctor as important causes of ADR’s. Slide 32: It is found that most of the individuals wanted to be told of all possible adverse effects. It seems reasonable to expect that providing education for patients about their drug therapy could assist in preventing or minimizing ADR’s. Such intervention needs to be carefully constructed and balanced with risks and benefits kept in perspective. This type of educational initiation is costly but it could turn out be money well spent in the long term by reducing ADR’s and associated ADR’s. The pharmacist’s role: The pharmacist’s role Ensuring that the medicines are used safely in fundamental to the pharmacist’s role. Pharmacist’s involvement in patients care should result in prevention of some and early detection of other ADR’s. Recent studies have demonstrated that pharmacist involvement with patient’s averted a large no. of potential adverse reaction. Based on knowledge of relevant patient and medication factors pharmacists can ensure that prescribing is safe as reasonably possible. Medication counseling should include alerting the patient to potential adverse effects The pharmacists also has a significant role in the education of other health care professionals about the prevention, detection and reporting of ADR’s. Slide 34: Regulatory authorities in many countries accept reports of adverse reactions from pharmacists. In USA, pharmacists initiate most reports submitted to FDA via medwatch system . In UK the involvement of hospital pharmacists has been shown to increase the no. of yellow cards submitted to CSM with no difference in the quality of reports submitted from hospital doctors and hospital pharmacists. Conclusion- ADR’s are the inevitable risk associated with the use of modern medicines. However careful attention to the dosage, taking into account factors such as age, renal function in many patients. Genetic status should be taken into account in a few cases where this is appropriate and it is now possible to genotypic individuals, using recombinant DNA methods, for some of known polymorphisms. Drug interactions: Drug interactions An interaction is said to occur when the of one drug are changed by the presence of another drug, food, drink or an environmental chemical agent. The net effect of combination may be: 1) synergism or additive effect of one or more drugs 2) antagonism of effect of one or more drugs 3)alteration of effect of one or more drugs or the production of idiosyncratic effects. When a therapeutic combination could lead to an unexpected change or complication in the condition of the patient, this would be described as an interaction of potential clinical significance. Susceptible patients- Polypharmacy is common, and the more drugs a patient takes the greater is the likelihood of an ADR. Drug interactions are more likely to have serious consequences when they effect elderly or seriously ill patients. Slide 36: Patients at particular risk include those with hepatic or renal disease, those on long-term therapy for chronic disease, for example those with human immunodeficiency virus (HIV) infection, epilepsy or diabetes, those in intensive care, transplant recipients, patients undergoing complicated surgical procedures and those with more than one prescribing doctor. Critically ill and elderly patients are at increased risk not only because they take more medicines, but also because of impaired homeostatic mechanisms that might otherwise counteract some of the unwanted effects. The effects of interactions involving drug metabolism may vary greatly in individual patients because of differences in the rates of drug metabolism and in susceptibility to microsomal enzyme induction. Slide 37: SOME DRUGS WITH HIGH RISK OF INTERACTION: 1)concentration dependent toxicity- digoxin , lithium, warfarin etc. 2)steep dose- response curve – verapamil , sulphonylureas , levodopa 3)patient dependent on therapeutic effect – glucocorticoids , oral contraceptives, antiepiletics etc. 4) saturable hepatic metabolism – phenytoin , theophylline . Mechanisms of drug interactions- The mehanisms can be conveniently divided into those with a pharamacokinetic basis and those with a pharamacodynamic basis. Drug interactions often involve more than one mechanism. Pharmacokinetic interactions: Pharmacokinetic interactions Pharmacokinetic interactions are those which can effect the processes by which drugs are absorbed, distributed, metabolized or excreted. There is marked inter-individual variability in these processes, and although these interactions may be expected, their extent cannot easily be predicted. Absorption - Most drugs are given orally for absorption though the mucous membranes of the gastrointestinal tract. Most of the interactions which occur within the gut result in reduced rather than increased absorption. It is important to recognize that the majority result in changes in the absorption rate, although in some instances the total amount (i.e. the extent) Of drug absorbed is affected. Slide 39: For drugs which are given chronically on a multiple dose regimen (for example the oral anticoagulants) the rate of absorption is usually unimportant provided the total amount of drug absorbed is not markedly altered. On the other hand, delayed absorption can be clinically significant where the drug affected has a short half-life, or where it is important to achieve high plasma concentrations rapidly as there may be the case with analgesics or hypnotics. Drug absorption interactions can often be avoided if an interval of 2-3 hours is allowed between the administration of the interacting drugs. 1) changes in the GIT pH 2) adsorption, chelation an other complexing mechanisms. 3) drug effects on the GIT flora. 4) effects on GIT motility Changes in gastrointestinal pH.: Changes in gastrointestinal pH . The absorption of a drug across mucous membrane depends on the extent to which it exists in the non-ionized, lipid-soluble form. The ionization state depends on the pH of its milieu, the pKa of the drug and the formulation factors. Weakly acidic drugs, such as the salicylates, are better absorbed at low pH because the ionized form predominates. An alteration in gastric pH due to antacids, histamine H2 antagonists or proton pump inhibitors therefore has the potential to affect the absorption of other drugs. Changes in gastric pH tend to affect the rate of absorption rather than the total availability, provided that the drug is acid liable. Slide 41: Antacids, histamine H2 antagonists and omeprazole can significantly decrease the bioavailability of ketoconazole and itraconazole , as both require gastric acidity for optimal absorption. The absorbtion of flucanazole , however, is not significantly altered by changes in gastric pH. Absorption, chelation and other complexing mechanisms- Certain drugs react directly within the gastrointestinal tract to form chelates and complexes which are not absorbed. The drugs most commonly implicated in this type of interaction include tetracyclines and the quinolone antibiotics which can complex with iron, and antacids containing calcium, magnesium and aluminium . Tetracyclines can chelate with divalent or trivalent metal cations such as calcium, aluminium , bismuth and iron to form insoluble complexes, resulting in greatly reduced serum tetracycline concentrations. .: . Biophosphates such as etidronate are often co-prescribed with calcium supplements in the treatment of osteoporosis. If these are ingested concomitantly, the bioavailability of both is significantly reduced with the possibility of therapeutic failure. The absorption of some drugs may be reduced if they are given with adsorbents such as charcoal or kaolin, or anionic exchange resins such as colestyramine or colestipol. The adsorption of propanolol, digoxin, warfarin, tricyclic antidepressants , ciclosporin and thyroxine is reduced by colestyramine. Acarbose, an agent used in the management of diabetes mellitus, inhibits intestinal alpha glucosidase, thereby delaying the digestion and absorption of starch and sucrose. Slide 43: Case reports suggest that this drug can significantly decrease plasma concentrations of digoxin . Digoxin levels increased to within the therapeutic range after acarbose was discontinued. Patients taking both acarbose and digoxin should separate dosing by an interval of atleast 6 hours. Most chelation and absorption interactions can be circumvented by separating doses of the interacting drugs by a period of several hours. Drug effects on the gastrointestinal flora- Bacterial flora predominate in the large bowel, and are present in much smaller numbers in the stomach and small bowel. Thus drugs which are well absorbed from the small bowel are less likely to be affected by changes in gut flora. Slide 44: About 10% of individuals a substantial amount of digoxin is inactivated by gut bacteria, and the introduction of a broad-spectrum antibiotic may lead to substantially increased plasma digoxin concentrations. Antibiotics may also prevent the intestinal bacterial hydrolysis of drug conjugates secreted into bile and thus reduce reabsorption of the active parent drug. Effects on gastrointestinal motility- Since most drugs are largely absorbed in the upper part of the small intestine, drugs which alter the rate at which the stomach empties its contents can affect absorption. Anticholinergic drugs delay gastric emptying. These drugs are commonly used in the control of movement disorder but they have been shown to reduce the bioavailability of levodopa by as much as 50% and to reduce plasma chlorpromazine concentrations significantly. Slide 45: Opioids such as diamorphine and pethidine strongly inhibit gastric emptying and greatly reduce the absorption rate of paracetamol . Metoclopramide increases gastric emptying and increases the absorption rate of paracetamol , an effect which is used to therapeutic advantage in the treatment of migraine. Drug displacement(protein-binding)interactions - Once absorbed a drug is distributed to its site of action and during this process it may interact with other drugs. The main mechanism behind such interactions is displacement from protein-binding sites. A drug displacement interaction is defined as a reduction in the extent of plasma protein binding of one drug caused by the presence of another drug, resulting in an increased free or unbound fraction of the displaced drug. Slide 46: Many drugs and their metabolites are highly bound to plasma proteins. Albumin is the main plasma protein to which acidic drugs such as warfarin are bound, while basic drugs, such as tricyclic antidepressants, lidocaine(lignocaine), disopyramide and propanolol, are generally bound to alpha-1 acid glycoprotein. For most drugs, if displacement occurs, then the concentration of free drug will rise temporarily, but metabolism and distribution will return the free concentration to its life of the displaced drug. Drug metabolism: Drug metabolism Most clinically important interactions involve the effect of one drug on the metabolism of another. Metabolism refers to the process by which drugs and other compounds are biochemically modified to facilitate their degradation and subsequent removal from the body. The liver is the principal site of drug metabolism although other organs, such as the gut, kidneys, lung, skin and placenta are involved. Drug metabolism consists of phase-1 reactions, such as oxidation, hydrolysis and reduction, and phase-2 reactions, which primarily involve conjugation of the drug with substances such as glucouronic acid and sulphuric acid. Phase-1 metabolism generally involves the hepatic CYP450 mixed function oxidase system. Cytochrome P450 isoenzymes: Cytochrome P450 isoenzymes The cytochrome P450 system comprises about 40-50 isoenzymes each derived from the expression of an individual gene. Four main subfamilies of P450 isoenzymes are thought to be responsible for most(about 90%) of the metabolism of commonly used drugs in humans, CYP1, CYP2, CYP3 and CYP4. Individual isoenzymes that have been specifically identified are given a further number(eg.CYP2D6;this is the most extensively studied isoenzyme, debrisoquine hydroxylase). Some people have CYP2D6 isoenzymes with decreased or absent activity and so have reduced capacity to metabolize drugs, such as nortriptyline, that are substrates for this enzyme, leading to accumulation during therapy and an increased risk of adverse effects. Slide 49: If a drug is metabolized primarily by a single CYP isoenzyme, inhibition or induction of this enzyme would have a major effect on the plasma concentrations of the drug. For example, if erythromycin(an inhibitor of CYP3A4) is taken by a patient being given carbamazepine(which is extensively metabolized by CYP3A4), this may lead to toxicity due to higher concentrations of carbamazepine. Slide 50: P-450 isoform substrate Inducer Inhibitor CYP1A2 Amitrypline Imipramine Theophylline Omeprazole Cigarette smoke Cimetidine ciprofloxacin CYP2A6 Halothane phenytoin Tranylcypromine Enzyme induction: Enzyme induction The most powerful enzyme inducers in clinical use are antibiotic rifampicin and anti-epileptic agents such as barbiturates, phenytoin and carbamazepine, the last being to induce its own metabolism ( auto-induction) Enzyme inducing drugs with short half- lives( nifampicin) will induce metabolism more rapidly than inducers with long half- lives( phenytoin) as they reach steady state concentration more rapidly. Slide 52: Drug affected Inducing agent Oral contraceptives Rifampicin Rifabutin Paracetamol Phenytoin Carbamazepine Enzyme inhibition: Enzyme inhibition Enzyme inhibition is an extremely common mechanism behind drug interactions. Just as some drugs can stimulate the activity of CYP450 enzymes, there are many which have the opposite effect and act as inhibitors. The rate of metabolism of drugs given concurrently can be reduced and they begin to accumulate within the body. Enzyme inhibition appears to be dose-related; inhibition of the metabolism of the affected drug begins as soon as sufficient concentrations of the inhibitor appear in the liver, and the effects are usually maximal when the new steady state plasma concentration is achieved. For drugs with short half-life, the effects may be seen within a few days of administration of the inhibitor. Slide 54: The effects are not seen until later for drugs with a long half-life. The clinical significance of this type of interaction depends on various factors, includindg dosage(of both drugs), alterations in the pharmacokinetic properties of the affected drug, such as a half-life, and patient characteristics such as disease state. Interactions of this type are again most likely to affect drugs with a narrow therapeutic range, such as theophylline, ciclosporin, oral anticoagulants and phenytoin. For example, the initiation of treatment with an enzyme inhibitor such as ciprofloxacin or cimetidine in a patient taking chronic theophylline could result in doubling of plasma concentrations. The ability to inhibit drug metabolism may be related to specific chemical structures.. For example, a number of known enzyme inhibitors contain an imidazole ring, including cimetidine, ketoconazole, itraconazole, metronidazole and omeprazole . Predicting interactions involving metabolism: Predicting interactions involving metabolism Predicting drug interactions is not easy because individual drugs in the same class may have different effects on an isoenzyme . The quinolone antibiotics ciprofloxacin and norfloxacin inhibit CYP1A2 and have been reported to increase plasma theophylline levels, whereas lomefloxacin is a much weak inhibitor and appears not to interact in this way. Drug transportation- P-glycoprotein(P- gp ) is now known to have a role in drug interactions. A recognized cause of multiple drug resistance in malignant disease, more recent work indicates that P- gp also mediates the transcellular transport of many drugs. It acts as a drug transporter pump in the gut, kidneys and many other organs. There have been several published case reports of macrolide antibiotics increasing blood concentrations of digoxin . Slide 56: Other common substrates for p- gp are cyclosporins , fluoroquinolones , protease inhibitors, lignocaine , quinidine and ranitidine. Common inhibitors are diltiazem , verapamil and macrolide inhibitors. Elimination interactions- Most drugs are excreted either in the bile or in the urine. Blood entering the kidneys is delivered to the glomeruli of tubules where molecules small enough to pass across the pores of glomerular membrane are filtered through into the lumen of the tubules. Larger molecules such as plasma proteins and blood cells, are retained. The blood then flows to other parts of the kidney tubules where drugs and their metabolites are removed, secreted or reabsorbed into the tubular filtrate by active and passive transport system. Interactions can occur when drug interfere with kidney tubule fluid pH, active transport systems, or blood flow to the kidneys there by altering the excretion of other drugs. Changes in the urinary pH: Changes in the urinary pH As with the drug absorption in the gut, passive reabsorption of drugs depend on the extent to which the drug exists in the non-ionized lipid soluble form. Only the unionized form is lipid soluble and able to diffuse back into the tubule cell membrane. Thus at alkaline pH weakly acidic drugs(pka-3-7.5) largely exist as ionized lipid in-soluble molecules which are unable to diffuse into the tubule cells and will therefore be lost in the urine. The renal clearance of these drugs will be increased if the urine is made more alkaline. Conversely, the clearance of the weak bases(pka 7.5-10) is higher in acidic urine. Strong acids and bases are completely ionized over the physiological range of urine pH and their clearance is unaffected by pH changes. Changes in active renal tubule excretion: Changes in active renal tubule excretion Drugs which use the same active transport systems in the kidney tubules can compete with one another for excretion. Such competition between drugs can be used to therapeutic advantage. ex- probenecid may be given to increase the serum concentrations of pencillins by delaying their renal excretion. Changes in the renal blood flow- Blood flow through the kidney is partially controlled by the production of renal vasodilatory prostaglandins. If the synthesis of these prostaglandins is inhibited( eg-indomethacin ) the renal excretion of lithium is reduced with a subsequent rise in serum levels. pharmacodynamics: pharmacodynamics They generally involve additive, synergistic or antagonistic effects of drugs acting on the same receptors or physiological systems. These interactions are much less easy to classify than those with a pk basis. In includes: Antagonistic interaction. Additive or synergistic interactions. Interactions due to changes in drug transport mechanisms. Interactions due to disturbances in fluid and electrolyte balance. Indirect pharmacodynamic interactions. Antagonists interactions- It is to be expected that a drug with an agonist action at a particular receptor type will interact with antagonists at that receptor. For ex- the bronchodilator actions of the selective beta 2 adrenoceptor agonists such as salbutamol will be antagonized by beta-2 antagonists. Additive or synergistic interactions: Additive or synergistic interactions If two drugs with similar pharmacological effects are given together, the effects can be additive. Although not strictly drug interactions, the mechanism frequently contributes of adverse drug reactions. For ex-concurrent use of drugs with CNS, depressant effects such as antidepressants, hypnotics, anti-epileptics, antihistamines may lead to excessive drowsiness, yet such combinations are frequently encountered. Interactions due to changes in drug transport mechanisms- TCA also prevent the reuptake of noradrenaline into peripheral adrenergic neurons, so that its presser effects are increased. Interactions due to disturbances in fluid and electrolyte balance: Interactions due to disturbances in fluid and electrolyte balance Changes in the electrolyte balance may alter the effects of drugs, particularly those acting on myocardium, neuromuscular transmission and the kidney. An important interaction is the potentiation of digoxin by diuretics and other drugs which decrease plasma potassium concentrations. Indirect pharmacodynamic interactions- In insulin dependant diabetics, the normal recovery from an episode of hypoglycemia may be impaired to some extent by propanolol . MONOAMINE-OXIDASE INHIBITORS: they reduce the breakdown of nor-adrenaline in the adrenergic nerve endings. This leads to the nerve ending having large stores of noradrenaline , which can be released into the synaptic cleft in response to either a neuronal discharge or an indirectly acting amine. Slide 62: SERATONIN SYNDROME : it is a rare syndrome which is becoming increasingly well recognized in patients receiving combinations of seratonergic drugs. It can occur when two or more drugs affecting seratonin are given at the same time or after one seratonergic drug is stopped and other is started. This syndrome is characterized by symptoms including-confusion, disorientation, abnormal movements, exaggerated reflexes, fever, sweating, diarrhoea and hypertension or hypotension. conclusion: conclusion It is impossible to remember all drug interactions of potential clinical significance. Practitioners should be continually alert to the possibility of drug interactions and take appropriate steps to minimize their occurrence. Patients should be advised to seek guidance about their medication if they plan to stop smoking or start a herbal remedy, as they may need close monitoring during the transition . References : References Clinical pharmacology and therapeutics-edited by ROGER & WALKER(3 rd edition).pg no-(21-43) Biopharmaceutics and pharmacokinetics-BRAHMANKAR. pg no-(224-234) Slide 65: THANQ