Pharmacodynamic and pharmacokinetic drug interactions

PHARMACOLOGY Pharmacodynamic and pharmacokinetic drug interactions Barbara J Pleuvry The patient’s response to a drug can be modified by individual variation (e.g. age, obesity) and by interactions with other drugs, foods or chemicals ingested at the same time. Any physician administering more than one drug to a patient must be aware of potential interactions. While many are trivial and unimportant some are life threatening. If in doubt, look it up. There are a number of important interactions with herbal supplements, which patients may take without medical advice and may not report at medical consultation. Some examples are shown in Figure 1. Some interactions with herbal supplements Herbal Examples of drugs supplement affected Reason Capsicum ACE inhibitors Antidepressants Absorption increased Echinacea Benzodiazepines Plasma concentrations Calcium channel blockers increased Cyclosporin Immune stimulation Feverfew Anticoagulants Effects increased Garlic Anticoagulants Immunosuppressants Effects increased Effectiveness decreased Ginger Anticoagulants H2-receptor blockers and proton-pump inhibitors Hypoglycaemic drugs Effects increased Increased production of gastric acid Blood sugar reduced Ginko Anticoagulants Antipsychotics Effects increased Seizures may be induced Ginseng Hypoglycaemics Blood sugar reduced St John’s wort Many drugs Antidepressants Increases metabolism May produce serotonin syndrome 1 Barbara J Pleuvry is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK. She is a pharmacist by first degree but has been involved in teaching pharmacology to postgraduates and undergraduates for over 30 years. Her research interests include pain, analgesia and anticonvulsant drugs. ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:4 129 © 2005 The Medicine Publishing Company Ltd PHARMACOLOGY Drugs with different therapeutic indications may have a common pharmacological action that is responsible for sideeffects. Both the tricyclic antidepressants (e.g. amitriptyline) and antipsychotic drugs (e.g. thioridazine) have muscarinic receptor antagonist properties. When combined together or with other antagonists at muscarinic acetylcholine receptors the enhancement of anticholinergic effects can result in heat stroke in hot, humid climates or psychoses, in addition to the more familiar dry mouth and blurred vision. Similarly, drugs with serotoninergic (5-hydroxytryptamine like) activity can produce the ‘serotonin syndrome’ characterized by confusion, hypomania, fever, incoordination, myoclonus and hyperreflexia; examples are combinations of monoamine oxidase inhibitors with tricyclic antidepressants, serotonin selective reuptake inhibitors or pethidine. The syndrome is believed to be overstimulation of 5-HT1A receptors, but why only a small proportion of patients exhibit this response is unknown (see Anaesthesia and Intensive Care Medicine 5:10: 354). Aminoglycoside antibiotics (e.g. streptomycin) chelate with calcium ions to impair its influx into the neuron, thus inhibiting acetylcholine release. This causes an enhancement of competitive neuromuscular blockade. Classification of drug interactions Pharmacodynamic interactions • Interaction at or near the site of action Pharmacokinetic interaction • Interaction at the site of entry • Interaction at or near storage sites • Interaction at or near the site of metabolism • Interaction at or near the site of excretion Pharmaceutical incompatibility 2 The mechanisms of drug, or dietary supplement, interaction are classified in Figure 2. However, many interactions are theoretical or clinically trivial. Drug interactions are usually described as pharmacodynamic (where changes in drug action occur in the area of the target tissue) or pharmacokinetic (when one drug affects the absorption, distribution or excretion of another). Pharmacodynamic changes include the actions of agonists and antagonists at the same or different receptors. Another mechanism of drug interaction is really a pharmaceutical incompatibility when, for example, two drugs are mixed and one complexes with the other. An example is the formation of a complex when thiopental and suxamethonium are mixed in the same syringe. This is simple chemistry and no pharmacological principles are involved. However, pharmaceutical incompatibilities can occur in the body and can be manipulated for the patient’s benefit. An example is the termination of the anticoagulant activity of the strongly acidic heparin by the strongly basic protamine sulphate. Heavy metals can be chelated by chemicals and removed from the circulation or the gastrointestinal tract. A chelate is a complex formed between a metal and a compound that contains two or more potential ligands. The stability of the chelate varies with the metal and the ligand. Calcium has a higher affinity for oxygen ligands than for sulphur and nitrogen ligands, while mercury and lead have the opposite affinity. This enables drugs to be designed that chelate only with a specific metal. Some chelating agents used in medicine are listed in Figure 3. Some chelating agents used in medicine Chelating drug Desferrioxamine Therapeutic use Iron poisoning Comments Has low affinity for iron in haemoglobin and cytochrome enzymes but high affinity for iron stored as ferritin and haemosiderin Dicobalt edetate Cyanide poisoning. May be used after large doses of sodium nitroprusside Toxic Penicillamine Heavy metal poisoning Wilson’s disease (copper is deposited in the body) Also used in rheumatoid arthritis, but mechanism does not involve chelation Pharmacodynamic interactions occur because of the presence of another drug at the site of drug action. Sodium calcium edetate Lead poisoning The calcium in the molecule prevents hypocalcaemia Additive or synergistic interactions Additive or synergistic interactions occur when two drugs with similar pharmacological properties are given together. A common example is ethanol combined with other sedative drugs such as benzodiazepine anxiolytics or histamine H1-receptor antagonists used for travel sickness. Benzodiazepines alone have a high therapeutic index and while overdoses may cause prolonged sedation they are seldom fatal. In contrast, a combination of benzodiazepine overdose with ethanol is often fatal. Tetracycline Antibiotic May chelate with ions in the intestine (e.g. calcium or iron) reducing absorption of the drug because the chelate is highly insoluble Pharmacodynamic interactions ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:4 3 130 © 2005 The Medicine Publishing Company Ltd PHARMACOLOGY Synergy or potentiation is seen when sulphonamide antibiotics are combined with trimethoprim. Both drugs are bacteriostatic when given alone, while the combination is bactericidal. The mechanism of this interaction is shown in Figure 4. Drugs with similar adverse effects may also be additive particularly with respect to ototoxicity (e.g. ethacrynic acid and streptomycin) or nephrotoxicity (e.g. tobramycin and cephalothin). However, not all combinations of similar drugs cause clinical problems. For example furosemide and streptomycin combinations do not appear to result in enhanced ototoxicity in practice. The noradrenergic neuron Monoamine oxidase Synthesis Storage site Opposing or antagonistic interactions Receptor agonist and antagonist interactions come into this classification. Many of these are useful, such as naloxone reversal of an opioid overdose and flumazenil reversal of benzodiazepineinduced sedation. It also includes functional antagonisms in which two drugs exert opposite effects on different receptor systems and thus physiologically oppose one another. Glucocorticoids cause hyperglycaemia and oppose the actions of hypoglycaemic agents. The opposing effects of the two drugs are well known and the combination is seldom prescribed. Release Reuptake by carrier molecule Alteration in drug transport mechanisms Many drugs compete with each other for uptake at the site of action. The noradrenergic neuron is a prime site for this type of action (Figure 5). Indirectly acting sympathomimetic drugs (e.g. amphetamine derivatives) need to be taken up into the neuron in order to release noradrenaline. Adrenergic neuron blocking agents Catechol-O-methyl transferase Receptor Key Noradrenaline (norepinephrine) Bacterial DNA pathway: site of action of antibiotics 5 Para-aminobutyric acid (PABA) + pteridine and glutamic acid Folic acid synthetase Absorbed from diet in mammals Sulphonamides inhibit (e.g. guanethidine) which were formerly used as antihypertensive drugs, required uptake into the neuron to produce their effects. All these drugs use the noradrenaline reuptake mechanism. The tricyclic antidepressants inhibit this reuptake process and diminish the action of drugs requiring it. Amphetamine-like drugs and adrenergic neuron blocking agents are not widely used. Folic acid Dihydrofolate Dihydrofolate reductase Changes in fluid and electrolyte balance Digitalis glycosides are the prime example of drugs that alter the electrolyte balance. Increased cardiac contractility is brought about by inhibition of Na+/K+-ATPase, causing a build-up of Na+ in the cardiac cell. This results in an increase in Na+/Ca2+ exchange and a build-up of intracellular calcium and enhancement of contraction. In high doses this can lead to disturbances of cardiac rhythm. Plasma K+ normally competes with digitalis for the binding site on Na+/K+-ATPase and thus the sensitivity of the enzyme to digitalis is increased if plasma K+ is low. Digitalis may be used to treat heart failure and the oedema associated with the disease is often treated with diuretics. Both the loop diuretics and, to a lesser extent, the thiazide diuretics lower plasma K+ and may thus increase digitalis toxicity. Lithium can take the place of sodium in a number of cellular processes, thus lithium toxicity is enhanced by low dietary salt. Trimethoprim inhibits Tetrahydrofolate DNA Inhibition of a single enzyme by either sulphonamides or trimethoprim results in a bacteriostatic effect but inhibition of both enzymes is bactericidal 4 ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:4 Inactive metabolite 131 © 2005 The Medicine Publishing Company Ltd PHARMACOLOGY Metabolism The pharmacological actions of many drugs are terminated by metabolism that produces more water-soluble compounds that can be more readily excreted by the kidney. Most drug metabolism occurs in the liver (see Anaesthesia and Intensive Care Medicine 2:8: 322). Oxidation, reduction or hydrolysis of drugs (phase 1 reactions) occurs in the endoplasmic reticulum often using cytochrome P450, a nonspecific enzyme system. A number of drugs and environmental pollutants can induce the P450 system (see page 139) increasing drug metabolism, though the effect may take several days or weeks to develop. Enzyme induction has been responsible for failure of oral contraception and ineffectiveness of corticosteroid or anticoagulant therapy. All the enzyme-inducing agents can also increase the metabolism of each other. Some drugs have some selectivity for different isoforms of cytochrome P450 and they are responsible for more selective drug interactions. Grapefruit juice inhibits the activity of the CYP 3A3/4 isoform of cytochrome P450 that is responsible for the metabolism of a number of calciumchannel blockers including felodipine, nifedipine, nimodipine and nitrendipine. An over two-fold increase in plasma concentrations of these drugs has been reported in patients drinking grapefruit juice with a consequent decrease in blood pressure and increase in side-effects, at least with felodipine. Other drugs (e.g. chloramphenicol) inhibit cytochome P450 enzymes causing reduced metabolism and prolongation of drug activity. This may lead to toxicity if the drug affected has a low therapeutic index, such as phenytoin. Ketoconazole selectively inhibits the P450IIIA4 isoenzyme, which also metabolizes cyclosporin. This interaction is well known and transplant patients may need less than 25% of the dose of cyclosporin if ketoconazole is co-prescribed. Ketoconazole also appears to stop the metabolism of cyclosporin by the gut wall. Some other drugs that inhibit cytochrome P450 enzymes are given in Figure 6. Not all drugs are metabolized by the cytochrome P450 enzymes. Concurrent drug therapy can inhibit other drug-metabolizing enzymes and result in toxicity. Monoamine oxidase inhibitors can cause a number of interactions at the noradrenergic nerve terminal (Figure 5). They prevent the breakdown of noradrenaline that is taken up into the nerve so that more is accumulated in the store. Indirectly acting sympathomimetic drugs (e.g tyramine) cause enhanced release of noradrenaline, over-stimulation of the α1-adrenoceptors and a potential hypertensive crisis. Pharmacokinetic interactions Absorption, distribution, metabolism and excretion of drugs can all be modified by interaction with other drugs. There are many examples of this type of interaction, but only some of the more important ones are mentioned here. Absorption Most interactions occur due to changes, usually reduction, in the absorption of orally administered drugs. If a drug is given acutely for a single dose effect (e.g. analgesics, anxiolytics, hypnotics) changes in the rate of absorption may alter the peak plasma concentration and the maximum therapeutic effect obtained. In contrast, when drugs are given chronically, it is usually the total amount of drug absorbed that is important rather than the rate of absorption. The largest absorptive site in the gastrointestinal tract is the small intestine, therefore drugs that enhance gastric emptying (e.g. the prokinetic agent, metoclopramide) hasten drug absorption, while drugs that inhibit gastric emptying (e.g. muscarinic acetylcholine receptor antagonists) slow absorption. This interaction is exploited in anaesthesia when metoclopramide is used to increase the rate of onset of oral morphine administered as MST-Continus tablets. The combined administration of paracetamol and metoclopramide has also been used to enhance the rate of drug absorption in the treatment of migraine. The formation of insoluble chelates between tetracycline and a variety of divalent and trivalent ions has already been described (Figure 3). Fluoroquinolone antibiotics (e.g. ciprofloxacin, norfloxacin), which inhibit DNA topoisomerase II and prevent the supercoiling of DNA, also form poorly soluble chelates with these ions. The effect of pH changes on drug absorption are discussed on page 135. A rise in gastric pH due to H2-receptor antagonists and antacids can markedly reduce the absorption of the antifungal agent ketoconazole but, in general, the effects of these drugs on absorption are small and variable because most drugs are absorbed in the small intestine rather than in the stomach. The simultaneous presence of two anaesthetic gases in the lung may cause the ‘second gas effect’ in which the rapid absorption of one gas causes more gas to be delivered to the alveoli, leading to the enhanced absorption of the second anaesthetic. This phenomenon has been seen with 75% nitrous oxide and 1% enflurane, when the plasma concentration of enflurane rises much faster in the presence of nitrous oxide. Excretion Inhalational anaesthetics are excreted in the expired air and this can be increased by the addition of carbon dioxide to the inhaled gas to stimulate ventilation. Most other drugs are excreted in the bile or the kidney. Renal excretion can be altered by changes in protein binding (discussed above), inhibition of tubular secretion, alteration in kidney blood flow or urinary pH. Probenecid is the classical example of a drug that was designed to compete with the active transport mechanism that secretes acids (e.g. the penicillins) into the renal tubule. Prolongation of the action of penicillin was essential in the early days when availability of the antibiotic was low and the price high. Several other acidic drugs share this property (e.g. aspirin, indometacin, sulphonamides) and all can cause increases in the plasma concentrations of each other. Prostaglandins cause renal capillary vasodilatation, and prostaglandin production is inhibited by NSAIDs, causing a Distribution Many theoretical drug interactions involve competition for plasma protein and tissue protein binding sites (see page 136). While displacement of a drug from its binding site causes a transient increase in free (active) drug concentration, this is followed by increased elimination until a new steady state is reached. Few of these cause clinical problems, but there are some well-documented exceptions. Aspirin and the sulphonamides are given in large enough doses to cause displacement of other substances bound to albumin, including bilirubin. This can be catastrophic in a jaundiced newborn baby because unbound bilirubin can penetrate the brain causing basal ganglia disorders. Aspirin and sulphonamides can also change the ratio of free to bound phenytoin in the plasma making dose adjustment more difficult and narrowing the therapeutic window. ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:4 132 © 2005 The Medicine Publishing Company Ltd PHARMACOLOGY Enzyme inhibitors involved in drug interactions Drug Enzyme inhibited Comment Allopurinol Xanthine oxidase Increases mercaptopurine toxicity Ecothiopate and Cholinesterase organophosphorus pesticides Prolongation of suxamethonium neuromuscular blockade Disulphiram and metronidazole1 Aldehyde dehydrogenase Increase in blood aldehyde concentrations after alcohol (Antabuse reaction) Erythromycin Cytochrome P450IIIA Inhibition of benzodiazepine metabolism Phenelzine and tranylcypromine Monoamine oxidase Reduced destruction of tyramine from dietary sources causing hypertensive crisis Metronidazole also inhibits the enzyme responsible for the oxidation of the S(-) isomer of warfarin leaving the more potent anticoagulant in the body causing a prolongation of bleeding time 1 6 reduction in renal blood flow. This is an important interaction for renally excreted drugs with a low therapeutic index, such as lithium. Changes in urinary pH affect the elimination of weak acids and weak bases. While this is not an important interaction for most drugs, it can be used to enhance excretion of overdoses of susceptible drugs.  FURTHER READING Mayo Clinic Staff. Herb and drug interaction: ‘Natural’ products not always safe. 2004. http:www.mayoclinic.com/invoke. cfm?id=SA00039 Peng C C, Glassman P A, Trilli L E, Hayes-Hunter J, Good C B. Incidence and severity of potential drug–dietary supplement interactions in primary care patients: an exploratory study of outpatient practices. Arch Intern Med 2004; 164: 630–6. Stockley I H. Drug interactions. 5th ed. London: The Pharmaceutical Press, 2000. ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:4 133 © 2005 The Medicine Publishing Company Ltd