Therapeutics L4 Dr Monem Alshok 26\4\2011
Drugs Interactions :The modification of the effect of a drug by the prior or concomitant administration of another drug
Interactions may occur with other drugs or food .Drug interactions: the alteration of action of a drug by: Other prescribed drugs.OTC medications or Herbal therapies.
Two drugs together( e.g. ) Beta blockers (IV or PO) and verapamil (IV).
Phenytoin and the OCP.Ciprofloxacin and theophylline. Enzyme inducers vs. enzyme inhibitors.
Nutrition (e.g.)NG feeding and phenytoin
Diseases : Ampicillin and EBV
Interactions result in :
n Additive effect
n Synergistic effect
n Antagonistic effect
n Incompatibility
Types of DRUGS INTERACTIONS :
Pharmaceutical interactions,
pharmacodynamic interactions &
pharmacokinetic interactions.
Pharmaceutical interactions : are physicochemical interactions, either of a drug with an intravenous infusion solution or of two drugs in the same solution, resulting in the loss of activity of the drugs involved. Pharmaceutical interactions are too numerous to remember in detail, but they can be simply avoided: by giving intravenous drugs via bolus injection or an infusion burette or syringe pump ,by using only dextrose or saline for drug infusion ,by not mixing drugs in the same infusion solution, unless the mixture is known to be safe (e.g. potassium chloride with insulin).
Pharmacokinetic interactions : Pharmacokinetic interactions occur when the absorption, distribution or elimination (metabolism or excretion) of one drug is altered by another drug. Absorption interactions : Absorption interactions are seldom important. Exceptions include impaired absorption of tetracyclines, bisphosphonates and fluoroquinolones by chelation with divalent and trivalent cations. Parenteral metoclopramide increases the rate of gastric emptying and this hastens the absorption of analgesics in the treatment of an acute attack of migraine, a beneficial interaction.
Distribution interactions: protein-binding displacement . Protein-binding displacement causes an increase in the circulating concentration of unbound drug. However, this is only important if the object drug is highly protein-bound (greater than 90%) and is not widely distributed to body tissues. In practice, important interactions of this type occur with warfarin and phenytoin. When these drugs are displaced, their clearance rate increases in proportion to the degree of displacement, and so at steady state the total concentration of drug in the plasma falls to a new equilibrium value and the unbound concentration is the same as it was before the precipitant drug was introduced, in spite of an increase in the unbound fraction. This means that the interaction may not have significant clinical consequences, provided the patient can weather the increase in unbound concentration of the object drug until a new steady state is reached.
Metabolism interactions : Drug interactions involving metabolism are important. They occur when the metabolism of one drug is either inhibited or increased by another drug.There are two phases of hepatic drug metabolism.
Phase I metabolic reactions (for example, dealkylation, deamination, hydroxylation, sulphoxidation) are carried out by isoenzymes of the mixed-function oxidase (cytochrome p450 or CYP) system and are subject to interactions. Phase II reactions are conjugations (for example, acetylation, methylation, glucuronidation, sulphatation); they are not affected by interactions. Some drugs are metabolised by specific enzymes and may be the subject of interactions.
n Inhibition of drug metabolism. Drug metabolism can be reduced by inhibition of either CYP isoenzymes or other metabolic pathways. Examples of the former include inhibition of warfarin metabolism by chloramphenicol, cimetidine, erythromycin, ketoconazole, metronidazole and quinolones, inhibition of phenytoin metabolism by isoniazid, and inhibition of theophylline metabolism by quinolone and macrolide antibiotics (for example, erythromycin). Examples of the latter include inhibition by allopurinol of xanthine oxidase, inhibiting the metabolism of azathioprine and 6-mercaptopurine, and inhibition of the metabolism of dietary amines by monoamine oxidase inhibitors.
n Induction of the metabolism of a drug reduces the amount of drug in the body and therefore reduces its effects. An important example is unwanted pregnancy when an enzyme-inducing drug such as carbamazepine, phenytoin or rifampicin is taken along with an oral contraceptive.
Pharmacokinetic interactions( Excretion interactions ) Competition for renal tubular secretion reduces drug excretion. For example, probenecid inhibits the tubular secretion of penicillin, increasing the blood concentration of penicillin and prolonging its therapeutic effects: a beneficial interaction. Amiodarone, quinidine and verapamil inhibit the tubular secretion of digoxin by inhibiting the transport protein P glycoprotein, increasing plasma digoxin concentrations and potentially causing toxicity.
Pharmacodynamic interactions : In pharmacodynamic interactions the effect of a drug is altered at its site of action. Such interactions are either direct or indirect.
Direct pharmacodynamic interactions : occur when two drugs either act at the same site (antagonism or synergism) or act at two different sites with a similar end result. For example, naloxone reverses the effects of opiates and vitamin K reverses the effects of warfarin. The anticoagulant effects of warfarin are increased in direct synergistic interactions with anabolic steroids and tetracyclines. Any drug that has a depressant action on central nervous function can potentiate the effect of another such drug, whether or not the two drugs have effects on the same receptors; for example, alcohol potentiates the action of any other centrally acting drug.
Indirect pharmacodynamic interactions : occur when one drug affects the pharmacological, therapeutic or toxic effect of another drug, but the two effects are independent. For example, the effects of anticoagulants can be increased by three indirect effects: reduced platelet aggregation (due for example to salicylates, dipyridamole, clopidogrel and NSAID) ,GIT ulceration (due, for example, to NSAID) ,increased fibrinolysis (due, for example, to metformin). Diuretic-induced alterations in fluid and electrolyte balance (especially potassium) increase the effects of cardiac glycosides and class I anti-arrhythmic drugs (for example, lidocaine, quinidine, flecainide and phenytoin.
Pharmacodynamic interactions in general these are interactions between drugs which have similar or antagonistic pharmacological effects or side-effects. They may be due to competition at receptor sites, or occur between drugs acting on the same physiological system. They are usually predictable from a knowledge of the pharmacology of the interacting drugs; in general, those demonstrated with one drug are likely to occur with related drugs
Pharmacokinetic interactions in general : Affecting absorption,Due to changes in protein binding ,Affecting metabolism & Affecting renal excretion (Drugs are eliminated through the kidney both by glomerular filtration and by active tubular secretion. Competition occurs between those which share active transport mechanisms in the proximal tubule. For example, salicylates and some other NSAIDs delay the excretion of methotrexate; serious methotrexate toxicity is possible. Pharmacokinetic interactions occurring with one drug cannot be assumed to occur with related drugs unless their pharmacokinetic properties are known to be similar . They are not easily predicted and many of them affect only a small proportion of patients taking the combination of drugs.
Importance of interactions :
1 . Many drug interactions are harmless and many of those which are potentially harmful only occur in a small proportion of patients; moreover, the severity of an interaction varies from one patient to another.
2 . Drugs with a small therapeutic ratio (e.g. phenytoin) and those which require careful control of dosage (e.g. anticoagulants, antihypertensives, and antidiabetics) are most often involved .
3 . Patients at increased risk from drug interactions include the elderly and those with impaired renal or liver function.
Management of drug interactions requires:
Knowledge of monitoring that could be planned to check for toxicity
What to monitor & When to monitor? For example:
Amiodarone enhances effect of warfarin. If patient needs both drugs, could use a lower loading dose, INR can be checked more frequently until stabilised (both when starting and stopping amiodarone)
Knowledge of all drugs in a particular class Do they all interact in the same way? For example: Cimetidine is a liver enzyme inhibitor . Is ranitidine?
Knowledge of contra-indications and cautions for drugs that you prescribe
For example:Opiates can be a problem in liver failure because they are metabolised in the liver . NSAIDS can be a problem in liver failure because
NSAIDs can cause bleeding and renal failure . Liver failure causes abnormal blood clotting and a tendency to hepatorenal syndrome.
Avoiding adverse drug interactions :The simple way of avoiding adverse drug interactions is to avoid combinations that are known to be dangerous. If that is not possible, the dosage of the object drug should be reduced in advance of starting the precipitant drug and the precipitant drug should be introduced slowly. When a theoretical interaction is anticipated on the basis of the known properties of two drugs, even if it has not been previously described, careful monitoring may help recognise adverse effects early.
Table to demonstrate Examples of drug interactions with antibiotics :Visit Davidson s Page 17 ( 21th edition 2010)
Prescribing for the elderly
Old people, especially the very old, require special care and consideration from prescribers. Elderly patients often receive multiple drugs for their multiple diseases.This greatly increases the risk of drug interactions as well as adverse reactions, and may affect compliance. The balance of benefit and harm of some medicines may be altered in the elderly . Frail elderly patients may have difficulty swallowing tablets; if left in the mouth, ulceration may develop. They should always be encouraged to take their tablets or capsules with enough fluid, and whilst in an upright position to avoid the possibility of oesophageal ulceration. It may be helpful to discuss with the patient the possibility of taking the drug as a liquid if available.
Manifestations of ageing:In the very old, manifestations of normal ageing may be mistaken for disease and lead to inappropriate prescribing. In addition, age-related muscle weakness and difficulty in maintaining balance should not be confused with neurological disease
Disorders such as lightheadedness not associated with postural or postprandial hypotension are unlikely to be helped by drugs.
Sensitivity: The nervous system of elderly patients is more sensitive to many commonly used drugs, such as opioid analgesics, benzodiazepines, antipsychotics, and antiparkinsonian drugs, all of which must be used with caution. Similarly, other organs may also be more susceptible to the effects of drugs such as antihypertensives and NSAIDs.
Pharmacokinetics : The most important effect of age is reduction in renal clearance. Many aged patients thus excrete drugs slowly, and are highly susceptible to nephrotoxic drugs. Acute illness may lead to rapid reduction in renal clearance, especially if accompanied by dehydration.
Hence, a patient stabilised on a drug with a narrow margin between the therapeutic and the toxic dose (e.g. digoxin) may rapidly develop adverse effects in the aftermath of a myocardial infarction or a respiratory-tract infection.
The metabolism of some drugs may be reduced in the elderly.
Pharmacokinetic changes may markedly increase the tissue concentration of a drug in the elderly, especially in debilitated patients.
Adverse reactions : Adverse reactions often present in the elderly in a vague and non-specific fashion.
Confusion is often the presenting symptom (caused by almost any of the commonly used drugs). Other common manifestations are constipation (with antimuscarinics and many tranquillisers) and postural hypotension and falls (with diuretics and many psychotropics). Bleeding associated with aspirin and other NSAIDs is more common in the elderly
Other drugs which commonly cause adverse reactions are antiparkinsonian drugs, antihypertensives, psychotropics, and digoxin.
Guidelines for prescription in elderly :
Always consider whether a drug is indicated at all.?
Limit range
Reduce dose
Review repeat prescriptions regularly
Elderly patients benefit from simple treatment regimens. Only drugs with a clear indication should be prescribed and whenever possible given once or twice daily.
Explain clearly
Repeats and disposal : Instruct patients what to do when drugs run out, and also how to dispose of any that are no longer necessary.