Drug Interactions Lectures 1-3 PDF

DRUG INTERACTIONS LECTURES 1-3 PPM Kelly Lefteri  CONTENT Types of Drug Interactions Pharmacokinetic – ADME Pharmacodynamic Other Interactions Drug-herb Drug-food Practicalities Dealing with Interactions in Practice, includi...

DRUG INTERACTIONS LECTURES 1-3 PPM Kelly Lefteri  CONTENT Types of Drug Interactions Pharmacokinetic – ADME Pharmacodynamic Other Interactions Drug-herb Drug-food Practicalities Dealing with Interactions in Practice, including using BNF Case studies  WHAT IS AN INTERACTION? “....the effects of one drug are changes by the presences of another drug, herbal medicine, food, drink or by some environmental chemical agent” Stockley “when medicines fight each other”  TYPES OF DRUG INTERACTION Pharmacokinetic Absorption What the body does to the drug Distribution Changes in Metabolism plasma Excretion concs Drug Transporter Proteins Pharmacodynamic What the drug does Additive or synergistic to the body Antagonistic or opposing Drug or neurotransmitter uptake Changes in drug response at site  SITES OF PK INTERACTIONS Drug Transport of absorption the drug inside the body Drug displacement (protein-binding) Drug metabolism (biotransformation) Drug CYP3A4, CYP2D6, excretion CYP2C9…  OUTCOMES OF DRUG INTERACTIONS Loss of therapeutic effect Toxicity Unexpected increase in pharmacological activity Beneficial effects e.g additive & potentiation (intended) or antagonism (unintended). Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture  HOW IMPORTANT ARE THEY? ADRs are the 4th most common cause of death Preventable ?? 2/3rds of ADRs are Manageable caused by interactions  DRUG INTERACTIONS Unpredictable Many are harmless Potential harmful only occur in small proportion of pts Severity varied from one patient to another Most often involves: Small therapeutic window Careful control of dose Elderly Impaired renal or liver function Polypharmacy RECAP - THERAPEUTIC WINDOW  What the body does to the drug PHARMACOKINETIC INTERACTIONS Changes in plasma concs  SITES OF PK INTERACTIONS Drug Transport of absorption the drug inside the body Drug displacement (protein-binding) Drug metabolism (biotransformation) Drug CYP3A4, CYP2D6, excretion CYP2C9…  ABSORPTION INTERACTIONS Mechanisms include: Altered pH Formation of drug chelates or complexes Altered GIT motility Induction or inhibition of DTP Malabsorption caused by drugs Drug induced mucosal damage Altered bacterial flora  ABSORPTION INTERACTIONS Changes in gastrointestinal pH Passage of drug though mucous membranes by simple passive diffusion Extent to which they exist in non-ionised lipid soluble form The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form. Absorption governed by pKa, lipid solubility, pH and other formulation parameters Acidic Drug Ketoconazole In acidic Good environment Dissolution Good Non-ionised Absorption  Acidic Drug Ketoconazole Add in antacid Acidic environment In acidic Good Reduced environment becomes more Dissolution Neutral Reduced Good Non-ionised Ionised Absorption  ABSORPTION INTERACTIONS Adsorption, chelation and other complexing mechanisms Antacids – adsorption and other mechanisms Tetracycylines Chelates with divalent and trivalent metallic ions e.g. Calcium, aluminium, bismuth, iron Separate doses by 2-3 hours Activated charcoal in drug overdose Anionic exchange resins (e.g. Colestyramine) Binds to bile acid, but also digoxin, warfarin, levothyroxine etc. 1 hr before or 4-6 hours after other drugs  IMPORTANT POINT!!!! ABSORPTION INTERACTIONS ARE THE ONLY ONES THAT SEPERATING THE DOSES WILL RESOLVE  ABSORPTION INTERACTIONS Changes in GI motility Most drugs largely absorbed in upper part of small intestine Rate of gastric emptying can affect absorption Propantheline delays so ↓ Paracetamol absorption Metoclopramide opposite effect NB. Total amount usually remains unaltered Food affects the rate of gastric emptying Eg1. antibiotics Eg2. Iron  ABSORPTION INTERACTIONS Induction or inhibition of drug transport protein Oral bioavailability is limited Eject drugs that have diffused across lining back into gut (P-glycoprotein – see later) Malabsorption E.g. Neomycin impairs absorption of a number of drugs including: Digoxin MTX  DISTRIBUTION INTERACTIONS Mechanisms include: Protein binding Induction or inhibition of DTP Protein – plasma v DTP  PROTEIN BINDING After absorption drugs are distributed around body by circulation In solution in the plasma “water” Bound to plasma proteins Acidic drugs Basic drugs ALBUMIN BINDING SITES Site I (warfarin) Phenytoin Glibenclamide Naproxen Diclofenac Flurorquinolones Site II (benzodiazepine) Ketprofen Ibuprofen Indomethacin  DISPLACEMENT If 2nd drug introduced with  affinity for binding site – DISPLACEMENT occurs, due to competition for binding site Depends on the affinity of the drug to plasma protein. More highly bound drugs capable to displace others. The amount of free drug is increased by displacement by another drug with higher affinity FREE DRUG = ACTION Could lead to overdose in highly bound drugs Warfarin (99%) or Tolbutamide (96%)  IN PRACTICE More theoretical than practical Rapid establishment of new equibilibrium (M & E) Usually overshadowed by other mechansims But can be significant in some cases eg. lithium or digoxin  METABOLISM Mechanisms include: INTERACTIONS Changes in 1st pass metabolism Changes in Enzyme activity Induction Inhibition  METABOLISM - RECAP Chemical reactions changing drugs into metabolites (easier to eliminate via urine and bile) Catalysed by enzymes (mostly in liver) Non polar (fat soluble) into Polar (water soluble) Phase 1 – oxidation (most common), reduction and hydrolysis to give metabolites Pharmacologically inactive Pharmacologically active (but less than original) Prodrug – original not active but metabolite is Phase 2 – change these into conjugates (by conjugation to an ionisable grouping) soluble enough to be excreted unlikely to be active  CHANGES IN 1ST PASS METABOLISM Changes in 1st pass metabolism Blood flow through liver after absorption portal circulation takes drugs directly to liver before distributing to the rest of the body Highly lipid soluble drugs undergo substantial biotransformation Evidence that drugs can affect this by altering blood flow although few clinically relevant examples  ENZYME ACTIVITY Activity affected by environmental conditions Changing these changes rate of reaction of enzyme Temperature pH Concentration Substrate Enzyme Induced biosynthesis of isoenzyme Induction Directly inhibiting activity Inhibition  CYTOCHROME P450 Found in gut wall and in liver  INDUCED BIOSYNTHESIS OF ISOENZYME Homeostatic mechanism for regulating enzyme production in a barrier organ eg. in liver, GIT, kidney Inducer causes alterations in transcription in the nucleus = Increased gene expression = More enzyme = Increased enzyme activity ENZYME ACTIVITY METABOLISM PLASMA CONC ENZYME INDUCTION  ENZYME INDUCTION – KEY POINTS Common interaction not confined to drugs – insecticides & smoking tobacco Most common pathway Phase I oxidation (CYP450) Extent depends on drug and dosage Can take 2-3 weeks to develop/persist Can consider raising dose of affected drugs but requires good monitoring and obvious hazards on stopping (OVERDOSE!!)  ENZYME INDUCERS C R * P G P S  ENZYME INDUCERS Carbamazepine Rifampacin * alcohol Phenytoin Griseofulvin Phenobarbitone Smoking cigarettes  ENZYME INDUCTION EXAMPLES:  anti- Anti-coagulant Rifampacin coagulant e.g. warfarin effect Oral Contraceptive Contraceptives Phenytoin not reliable  INHIBITION OF THE ENZYME Alter the action of the enzyme by slowing down or stopping 4 main mechanisms Competitive Non-competitive Uncompetitive Mechanism  ENZYME ACTIVITY METABOLISM PLASMA CONC ENZYME INHIBITION  ENZYME INHIBITION – KEY POINTS Even more common than induction Unlike induction takes 2-3 days so rapid development of toxicity Most common pathway is still Phase I oxidation (CP450) Significance depends on extent to which serum levels rise – if still within therapeutic range may not be clinically important Can consider reducing dose of affected drugs but requires good monitoring  ENZYME INHIBITORS S I C K F A C E S. C O M  ENZYME INHIBITORS Sodium valproate Isoniazid Cimetidine Ketoconazole Fluconazole Alcohol Chloramphenicol Erythromycin Sulphonamides. Ciprofloxacin "Azole structures" by ZooFari - Citizendium. Omeprazole Metronidazole  ENZYME INHIBITION EXAMPLES:  anti- Anti-coagulant Cimetidine coagulant e.g. warfarin effect  cytotoxic Azathioprine Allopurinol effect Terfenadine Erythromycin Arrhythmias  WHICH LIST IS WHICH?? Only ONE list has R and P in it (Inducers) Enzyme Inducers = Reduce Plasma Conc  ALCOHOL INDUCER OR INHIBITOR? How can it be in both?? Metabolised by CYP450 enzymes, mainly CYP2E1 Can be either an inducer or an inhibitor of CYP2E1 Differs not only with AMOUNT but also the PATTERN of alcohol intake Acute intake – inhibition of the enzymes Chronic alcohol intake – enzyme induction (changed environment)  OTHER ENZYMES Induction and inhibition can happen to any enzyme Antabuse = Disulfram Inhibition of acetaldehyde dehydrogenase Interaction with alcohol  THE ANTABUSE REACTION Acetaldehyde dehydrogenase Alcohol Acetaldehyde Acetate Acetaldehyde Effects include: Flushing of face, head, shoulders, arms & hands Tachycardia Breathlessness Giddiness & hypotension Nausea, vomiting & headache  ANTABUSE  Clinically used to treat alcoholism Reaction can occur with; Any alcoholic drink Alcohol containing medicines Topical applications in v. sensitive patients E.g. aftershave, perfumes etc. Other relevant substances which can cause a similar reaction: Metronidazole (100%) Chlorpropamide (up to 33%)  METABOLISM – GENETIC FACTORS Increased understanding shows isoenzymes subject to genetic polymorphism Primarily in research stages not used clinically (watch this space!!) More research being carried out to see if this can increase ability to predict drug interactions  EXCRETION INTERACTIONS Mechanisms include: Changes in active renal tubular secretion (incl. DTP) Effects on tubular re-absorption Co-transportation Changes in urinary pH Changes in renal blood flow Biliary excretion RECAP URINE FORMATION CHANGES IN ACTIVE RENAL TUBULAR SECRETION Drugs that use the same active transport systems can compete with one another for excretion Separate for WOAs and WOBs E.g. probenecid and penicillin P-glyocoprotein (DTP)  CHANGES IN TUBULAR REABSORPTION Effects of some drugs eg. diuretics can change re-absorption of sodium Drugs e.g. Lithium re-absorbed by the same mechanism Promoted sodium excretion Activation of compensatory mechanism which increases Na + and Li+ tubular re-absorption Differs due to class and site of action Thiazides – proximal convoluted tubule (more relevant) Loop – loop of Henle (more marginal)  CHANGES IN URINARY PH Drugs return to the blood from the tubular filtrate in unionised form through lipid membrane Simple passive diffusion Follows concentration gradient E.g. weakly acidic drugs (HX) In acidified tubular filtrate the drug will be unionised so will be able to diffuse back into blood If alkalised tubular filtrate drug will be in ionised form (X) so unable to diffuse freely and are excreted in urine  DRUG EXCRETION Acidic drug Tubule Tubular Filtrate Plasma Wall + − 𝑯 + 𝐗 ⇌ 𝐇𝐗 Drug returned by diffusion into plasma Drug excreted in urine  ACIDIFIED TUBULAR FILTRATE Acidic drug Tubule Tubular Filtrate Plasma Wall + − Most Drug 𝑯 + 𝐗 ⇌ 𝐇𝐗 returned by diffusion into plasma Small amount excreted in urine  ALKALISED TUBULAR FILTRATE Acidic drug Tubule Tubular Filtrate Plasma Wall Less drug + − returned by 𝑯 + 𝐗 ⇌ 𝐇𝐗 diffusion into plasma Most Drug lost in urine  CHANGES IN URINARY PH IN PRACTICE Small significance as drugs weak acids/bases Almost all metabolised by liver to inactive compounds so few reach urine unchanged Can be used in overdose e.g. alkalising urine with antacids with OD of salicylates (e.g.aspirin) and in MTX overdose  CHANGES IN RENAL BLOOD FLOW Flow partially regulated by production of renal vasodilatory Pg Synthesis inhibited Decrease Pg Vasoconstriction Decrease blood flow Decrease filtration Excretion of drugs reduced E.g. Lithium and NSAIDs  DRUG TRANSPORTER PROTEINS This is NOT the same as distribution interactions! - Different proteins!!!  DRUG TRANSPORTER PROTEINS Drugs cross membranes by both passive diffusion and DTPs P-glycoprotein in luminal membrane Efflux pump Actively transport drugs out of cells when they have passively diffused in Can be inhibited and Induced Effects most PK processes (A, D and E)  ABSORPTION AND DTP P-glycoprotein is in entire intestinal wall from small intestine to rectum Inhibition or induction can alter bioavailability  DISTRIBUTION AND DTP Induction or inhibition of drug transport protein (DTP) Distribution of drugs to brain and some organs (e.g. testes) limited by DTP e.g. P-glycoprotein Important for the BBB as a defence against the penetration of toxins and drugs into the CNS Drugs that are inhibitors of DTPs could therefore  uptake of drug into brain  adverse CNS effects OR be beneficial?  EXCRETION AND DTP Modest role P-glycoprotein in proximal tubule cells in kidneys Pumps drugs into the urine  P-GLYCOPROTEIN Inducers Inhibitors Rifampacin Macrolides e.g. erythromycin Dexamethasone Amiodarone St John’s wort Antifungals Verapamil  NOTABLE DRUGS EFFECTED Calcium channel blockers (CCBs) e.g. amlodipine Calcineurin inhibitors e.g. cyclosporin, Digoxin Macrolide antibiotics e.g. clarithromycin Protease inhibitors Loperamide (OTC!) See article  What the drug does to the body PHARMACODYNAMIC Changes INTERACTIONS in drug response at site NOT due to changes in plasma concentration from pharmacokinetics  PHARMACODYNAMIC INTERACTIONS Between drugs which have similar or antagonistic pharmacological effects or side-effects. Competition at receptor sites Drugs acting on the same physiological system. Predictable from pharmacology Likely to occur with related drugs.  RECEPTOR SITES Drug forms complex at receptor The intended or unintended effect produced may lead to; 1. Changes in the number of available receptors or their ability to respond 2. Pharmacological interactions 3. Physiological interactions 4. Chemical drug interactions At times may also be used to therapeutic advantage  RECEPTOR ALTERATION Drug A, when administered chronically INCREASES or DECREASES the number of its own receptors or alters the adaptability of receptors to physiological events Same effect when plasma levels increased through an interaction  PHARMACOLOGICAL INTERACTION Drug A (an antagonist) and drug B (an agonist) compete for the same receptor site and as a function of their respective concentrations either prevent (antagonist) or produce (agonist) an altered effect  PHYSIOLOGICAL INTERACTION Drug A and drug B interact with different receptors and ENHANCE or OPPOSE each other’s action via different cellular mechanisms  CHEMICAL INTERACTION Drug A interacts with drug B and prevents drug B from interacting with its intended receptor  ADDITIVE OR SYNERGISTIC INTERACTIONS Same pharmacological effect Not always from same drug class Prescribed effect Side effect Mechanism of action Sometimes response can be more than 1+1 (synergy)* Can be used as clinical intention (not always bad!) * Synergy - The effect of two or more drugs taken together is greater than the sum of their individual effects at the same doses  ADDITIVE OR SYNERGISTIC EXAMPLES: CNS depressant CNS depressant  CNS depression e.g.sedatives e.g.alcohol K+ supplements K+ sparing drugs Hyperkalaemia  Anticholinergic Anticholinergic Anticholinergic effects ( incl. e.g. Amitriptyline e.g. Benzhexol heat stroke) Antihypertensive Antihypertensive  hypotensive β blocker loop diuretic effect e.g. Atenolol e.g. furosemide PD INTERACTIONS AND THE BNF Drugs: That cause hepatotoxicity/ nephrotoxicity That cause thromboembolism With anticoagulant or antiplatelet effects That cause bradycardia That cause hypotension or first dose hypotension That prolong the QT interval With antimuscarinic effects Reduce/increase serum potassium That cause ototoxicity  ANTAGONISTIC OR OPPOSING INTERACTIONS Activities opposed to each other Direct effect at receptor or opposing physiologicial actions As before: Not always from same drug class Prescribed effect Side effect Mechanism of effect  OPPOSING INTERACTION EXAMPLES Agonists/antagonists NSAIDs and antihypertensive agents NSAIDs inhibit Pg synthesis Increases vascular tone Decreases the efficacy of antihypertensive drugs.  SIGNAL TRANSDUCTION MECHANISMS e.g. Hypoglycaemia produces a release of catecholamines Compensation mechanisms triggered = Increased blood glucose levels Also trigger symptoms for preventative action (eating sugars) Caution with patients taking insulin and -blockers -blockers block reaction triggered by the catecholamines Corrective mechanisms not adopted Increased risk of a serious reaction  DRUG OR NEUROTRANSMITTER UPTAKE INTERACTIONS Drug actions at adrenergic neurones Receptor blocking Re-uptake mechanisms Stockley “interactions at adrenergic neurones” – sep handout 5 1 Hypertensive 2 Crisis 3 4 Interactions at adrenergic neurones – Stockley’s Drug Interactions  HYPERTENSIVE CRISIS Increased amounts of NAdr available for release Massive stimulation in bd vessels Vasoconstriction Marked rise in BP (200+/150+) Symptoms: Severe headaches Intracranial haemorrhage Death DRUG INTERACTIONS WITH FOOD AND HERBS  DRUG-HERB INTERACTIONS Stockley only includes published reports St John’s Wort Enzyme inducer CP450 (CYP3A4) Also p-glycoprotein inducer Affects the clearance of numerous drugs, including cyclosporin, SSRIs, digoxin Major active constituents Hyperforin Hypercin (std but only some preps)  OTHER HERBS EFFECTING DRUGS Ginkgo biloba inhibits platelet aggregation factor. Use with warfarin, aspirin, NSAIDs and clopidogrel increases the risk of bleeding. Ginseng can also cause problems with bleeding with same drugs (unknown mechanisms) Chamomile – potential problems with benzodiazepines, barbituates and opioids (mechanism unknown)  DRUG-FOOD INTERACTIONS We have already considered: Drug absorption (chelation) Calcium, aluminium, bismuth, iron GI motility (empty or not) Others include: Lithium and Sodium intake Levodopa and protein-rich meals Tyramine in MAOIs (cheese reaction) Warfarin and various foods/drinks  LITHIUM AND SODIUM Salt consumption can cause fluctuations in serum lithium see PK excretion lecture Co-transportations of both Na+ and Li+ Patients advised to keep salt intake constant as possible  LEVODOPA AND PROTEIN RICH MEALS Protein can decrease absorption of levodpa into plasma High levels can also interfere with transport across BBB Protein is broken down into Large Neutral Amino Acids (LNAAs) (e.g. phenylalanine, tyrosine, and tryptophan) Shown to compete with levodopa as same transport system used to cross GI wall and BBB Protein still important in diet BUT avoid major changes in consumption  “CHEESE” REACTION Release of NAdr Causing vasoconstriction Absorption of tyramine MAOI Hypertensive Transport of Crisis tyramine to circulation via liver  TYRAMINE-RICH FOODS Cheese Yeast extract (marmite) Foods where bacterial degradation has occurred Pickled herrings Caviar Chianti Liver Bacterial decarboxylation Amino acids Proteins Tyramine (incl. tyrosine)  WARFARIN:FOOD INTERACTIONS Decreased warfarin effect (Vitamin K – Not Potassium!!)) Green leafy vegetables Decreased warfarin effect (CYP450 inducers) Cruciferous veg (sprouts, cabbage, broccoli) Char grilled meats Avocado Increased warfarin effect (CYP450 inhibitors) Cranberry juice Grapefruit juice Soya  GRAPEFRUIT JUICE Inhibits intestinal CYP3A4 Only slightly affects hepatic (IV) Also inhibits p-glycoprotein (DTP) Mechanism?? Assumed naringin → naringenin (processing) So not whole fruit (but some new reports implicating this) Can affect many other drugs including CCBs, cyclosporin, terfenadine, carbamazepine, alprazolam  VITAMIN C Large doses of vitamin C Acidification of the urine Excretion of weak acids inhibited Effects NSAIDs, acetaminophen, and tetracyclines (e.g., doxycycline) Increase the plasma levels  OTHER FOODS EFFECTING DRUGS Soya - enzyme inhibition – clozapine, haloperidol, NSAIDs, phenytoin Garlic – increased platelet activity – anticoagulants, NSAIDs Ginger – inhibition of thromboxane synthetase (in vitro) – anticoagulants Hawthorn – unknown mechanism – -blockers, digoxin  KEY POINTS Key differences between PK and PD interactions Absorption interactions dealt with differently Enzyme inducers/inhibitors Basic pharmacology – receptors Side effects not just pharmacological intention of drug Be alert with narrow therapeutic window drugs or where necessary to keep serum levels at or above a suitable level Reduced liver or renal function (e.g. In elderly) are high risk  SUMMARY: DRUGS TO WATCH OUT FOR Antihypertensives Theophylline Anticoagulants Digoxin Anticonvulsants Antidepressants Cytotoxics Hypoglycaemics  CONTENT OF UNIT Types of Drug Interactions Pharmacokinetic – ADME Pharmacodynamic Other Interactions Drug-herb Drug-food Practicalities Dealing with Interactions in Practice, including using BNF Case studies