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Transcript
DRUG INTERACTIONS 1. Define what is meant by drug interactions A drug interaction is an event that occurs upon the concomitant administration where the drugs have effects on each others’ action in the body. They may aid (additive) or impair (antagonistic) treatment regimens. They can be described in two different terms: pharmacodynamic or pharmacokinetic PHARMACODYNAMIC Where there is an interaction between the drugs in the effect on the body. So it is the interaction between drugs where an effect of either drug is changed (dynamic = drug effect on the body). For example: Additive: Cyclosporine (an immunosuppressant) having its nephrotoxicity augmented by concomitant administration of an aminoglycoside (antibiotic) Synergistic: Aspirin potentiating the effect of other anti-coagulants (e.g. warfarin) Antagonistic: Bacteriocidal effects of penicillins on growing cells antagonized by bacteroistatic antibiotics (e.g. quinolone) PHARMACOKINETIC Pharmacokinetic drug interactions result where one drug has an effect on the way the body deals with the drug (kinetic = body effect on the drug). See next LO 2. Outline the pharmacokinetic mechanisms of drug interactions Pharmacokinetic drug interactions result where one drug has an effect on the way the body deals with the drug. Interactions of this nature can occur at four different levels: Absorption – where the absorption of a drug into the blood stream is affected by another 1. Complexation reactions: antacids (containing metal ions) and tetracycline antibiotics 2. pH alterations: changing pH can change the ionization of drugs, therefore affecting lipid vs aqueous solubility. Distribution – Where the distribution of a drug through the body is affected by another 1. Displacement from plasma protein binding sites: e.g. NSAIDs (ibuprofen) and highly protein bound drugs. This is rarely clinically significant 2. Alterations in blood flow: proprandolol (beta-blocker) changing liver blood flow (therefore affecting the liver’s ability to metabolise) 3. Induction of binding protein expression: e.g. oestrogens inducing the expression of thyroxine binding protein, therefore affecting thyroid supplementation therapy. Metabolism - Where the metabolism of a drug is affected by another. Therefore affecting blood concentrations, hence the effect of the drug on the body. Remember that metabolism occurs in three stages: Phase I metabolism: The addition of functional groups onto the compound (e.g. addition of hydroxyl groups or hydrolysis of bonds) Phase II metabolism: The conjugation of compounds to functional groups (e.g. glutathione, glucuronic acid and sulfate groups) Phase III metabolism: Active transport out of tissues (e.g. multi-drug resistant transporter) Compounds do not always go through I then II, they can occur at any time. The interactions occur through the interaction between drugs and their metabolizing systems (the enzymes – most commonly the cytochrome P450 mixed function oxidase system). There are two general descriptions of such interactions: 1. Induction of an enzyme system: Some drugs can interact with transcription factors and induce the production of more metabolizing enzymes. This is believed to be an evolutionary defence mechanism to metabolise toxins that the body may be exposed to at high blood concentrations. E.g. dexamethasone inducing the metabolism of phenytoin. Drugs known to be inducers of enzyme systems include: Phenytoin Rifampicin Barbituates Carbamazepine 2. Inhibition of an enzyme system: Some drugs can interact with drug metabolizing enzymes and either disable the binding domain or compete with drugs for access to the binding domain. This can either be: Irriversible – Covalent binding where a new enzyme needs to be synthesized: either to haem or protein at the active site. Reversible – where the drug competes at the active site with normal substrates for the enzyme: covalent binding to the protein, haem or both haem and protein components of the active site. Drugs known to be inhibitors of enzymes include: Erythromycin (macrolide antibiotic) Ketoconazole (and other azole antifungals) Cimetidine (H2 antagonist) Quinidine (anti-cramping agent) Chloramphenicol (antibiotic) Each of the inhibitors/inducers affect specific enzymes in the cytochrome P450 mixed function oxidase. As it is known by what pathways (enzymes) drugs are metabolized by, it is possible to predict what drugs are going to have their metabolism affected by inducers/inhibitors of different enzymes in the CYP450 system Excretion – the excretion of drugs through terminal organs e.g. kidneys and to a much lesser extent lungs, skin, faeces, tears etc. 1. pH alteration: Changing pH can result in different ionization of drugs and hence affect their lipid vs aqueous solubility and hence their renal excretion 2. Competition for renal secretion/reuptake: probenecid reducing the renal tubular excretion of penicillins. 3. Describe the possible consequences of drug interactions on the male urogenital system The consequences of any drug interaction are: Clinically insignificant: The interaction occurs but does not affect the response of the patient to the drug. Clinically significant: where the outcomes of therapy are not expected. This could be when the effect of the drug is too great and causes side effects. This situation could arise with the inhibition of the metabolism of a drug, thus increasing its blood levels resulting in an increased effect. Alternatively, a situation where the effect of a drug is reduced e.g. induction of metabolism or excretory pathways or reduction in the drug absorption. More importantly, undesirable effects of drugs on the male urogenital system in the case of prostatic hypertrophy include: Sympathomimetics: mimicking the effect of the sympathetic system on the internal sphincter causing urinary retention. E.g. pseudoephedrine and phenylephrine in cold and flu tablets and many illicit drugs (all amphetamines, cocaine) Anti-cholinergics: Inhibiting the parasympathetic innervations of the urinary system, thereby relaxing the dertrusor muscle and constricting the internal sphincter. E.g. anti-cholinergic like sedating antihistamines (chlorphineramine), tricyclic antidepressants, phenothiazines etc.