* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Drug Interactions
Atypical antipsychotic wikipedia , lookup
Discovery and development of tubulin inhibitors wikipedia , lookup
Metalloprotease inhibitor wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Discovery and development of non-nucleoside reverse-transcriptase inhibitors wikipedia , lookup
Orphan drug wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
Discovery and development of integrase inhibitors wikipedia , lookup
Discovery and development of neuraminidase inhibitors wikipedia , lookup
Drug design wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Drug discovery wikipedia , lookup
Discovery and development of ACE inhibitors wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription costs wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Thomas M Penders MD Associate Professor Brody School of Medicine To Err is Human September, 1999 Institute of Medicine issued report on preventable medical errors. Estimated that 50 – 100,000 patients die in hospitals as a result of errors made by medical care providers. Economic loss of $17 to 29 billion in costs of care and lost productivity Drug-Drug Interactions Errors in administration of drugs are a significant portion of this problem. Excessive dosages Failure to monitor results of drug administration Drug-drug interactions – 5% of hospitalizations per year. Multiple Drug Overdose Definition Clinically significant interaction takes place when the therapeutic or toxic effects of a medication are altered by co-administration of another drug. Increasing pharmacopeia and lengthening life span make co-administration of drugs commonplace Particularly notable when drugs have a narrow therapeutic index e.g. Lithium, Digoxin, tricyclics Common Examples CNS depression – additive with multiple sedating agents – antidepressants and antipsychotics Interference with or potentiation of drug metabolism Fluoxetine – Antipsychotics Tobacco tars & several antipsychotics Ciprofloxin & clozaril through P450 Drug metabolism Pharmacokinetics – What the body does to the drug – Absorption, bioavailability, metabolism, excretion Pharmacodynamics – What drug does to the body. Drugs effect on end organ or receptor site Pharmacokinetic Interactions Interactions due to one drugs effect on movement through the body. Absorption – Gut – pH, food administration Distribution – Protein binding – free drug is active e.g. Warfarin Metabolic – result in change in drug concentration Excretion – Change in ability to eliminate – e.g. diuretics and lithium Steady state Pharmacodynamic Interactions Drugs influence on another drugs effects Occurs at end organ or receptor site Most commonly additive effects e.g. SSRIs and MAOIs Purpose of Metabolism Over course of history plants that developed toxins survived. Animal developed enzyme systems to detoxify plant and other toxins Metabolic enzymes are oxidative – render toxins less active and prepare for further degradation and elimination Red Queen P450 system Primary purpose is to metabolize endogenous compound such as steroids and neuropeptides Secondary role for enzymes in GI tract and liver is to detoxify ingested chemicals Including foods, medicines, smokes or other environmental exposures Characteristics of P450 40 enzymes identified in humans Capable of metabolism of multiple substances Six enzymes responsible for 90% of drug oxidation 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. Metabolism Most drugs are lipophilic Lipophilic compounds are difficult to eliminate Biotransformation to more polar and water soluble compounds facilitates elimination Metabolites exit via urine, bile or stool Sites of Drug Metabolism in liver and gut wall. Most drug metabolism occurs First-pass effect – Enzymes in endoplasmic reticulum of gut and liver cells alter most drugs and toxins upon absorption into hepatic circulation CYP 3A4 accounts for 70% of intestinal activity Metabolism proceeds in two phases; phase I oxidation Phase II - glucuronidation Phase I metabolism Addition of small polar groups through oxidative O-dealkylination, mechanisms; N-dealkylination, hydroxylation, N-oxidation, s-oxidation and deamination P450 enzymes contain red-pigmented heme, absorb at wavelength 450 nm. Each enzyme is encoded by one gene Other enzyme systems: Alcohol dehydrogenase, esterase, amidase and flavin monoxygenase Variability of drug response Inhibition Induction Genetic polymorphisms Enzyme Variability Inhibition Drugs metabolized by a common enzyme type will be competing for sites in the liver endoplasmic reticulum A drug’s affinity for an enzyme is “inhibitory potential” Values (Ki) are published from in vitro studies Drugs with little affinity have high Ki and do not bind Drugs with low Ki bind and compete for enzyme Inhibition Drugs with Ki <2 μM are potent inhibitors When two drugs are co-administered, the one with greater affinity (lower Ki) will competetively inhibit Some drugs inhibit without utilizing the enzyme Drugs that inhibit lead to elevated serum levels of the other drug. Inhibition Inhibition Leads to more potent and prolonged pharmacological effect that might result in drug toxicity. Inhibition is rapid in onset and in offset upon discontinuation of blocking agent Effects of inhibition are rapid in developing and disappear quickly. Inhibition P450 greatly affected by competetive inhibition Ketoconazole has low Ki for 3A4 - PROBES When co-administered with terfenadine (metabolic product fexofenadine), leads to elevated levels of terfenidine Toxic cardiac arrhythmias result Terfenidine removed from the market after several deaths Induction Some xenobiotics stimulate synthesis of P450 enzymes. With more sites available metabolic activity increases This may lead to decreases in amount of parent drug and increased amounts of metabolic product Co-administration of a potent inducer may result in decline in serum levels below that required for therapeutic effect. Carbamazepine induces metabolism of many antidepressants Induction Induction Drugs utilizing P450 may have increased side effects or become toxic if active metabolic product increases Hepatotoxicity of Valproic Acid likely due to such a mechanism 3A4, 2D6, 1A2, 2C9 2C19 and 2E1 may all be induced Genetic Polymorphisms Drug metabolism varies between groups and individuals Each individual has two copies of each allele Most common sequence is “wild type” Genetic alterations result in minor changes an sequence affecting enzymatic activity Metabolizer types Poor metabolizers – slower biotransformation Extensive metabolizers – homozygous wild type transform substrate at rate expected for population Ultra-extensive metabolizers – transform at a higher rate than population resulting in reduced levels of drug at site of action Population variation in enzyme activity Phase II metabolism Conjugation reactions provide water soluble products easily excreted In most cases more than one enzyme is involved in metabolism of a particular drug Less likely involved in clinically significant DDI Result in glucuronidation, sulfation, methylation Glucuronidation Most abundant phase II enzymes inlcude uridine 5’diphosphate glucuronyltransferases (UGTs). Major detoxification system. Most activity in liver Most drugs go through phase I Some are directly glucuronidated; lorazepam, oxazapam and temazepam UGTs These benzodiazepines are favored with liver disease Lamotrigine, valporate, NSAIDs, zidovudine, most opiates Methylation S-adenosylmethionine – SAMe Used as treatment for depression Catecol O-Methyltransferase (COMT) One of two ways that catecholamines are metabolized (other is monoamine oxidases) Some CNS drugs are inhibitors of COMT Phase III - transporters Located in intestines and liver as well as blood-brain barrier SLC transporters – importing transporters ABC - effluxing transporters 2D6 N-demethylates fluoxetine to norfluoxetine (half life of up to 16 days with long term use). For many psychotropics 2D6 is considered a low capacity, high affinity enzyme Clears drugs at lower concentrations. When inhibited processing with flow to 3A4 and 1A2, high capacity, low affinity enzymes Drug clearance will be slower and blood levels higher 2D6 Present in brain, bone marrow, gut and liver Only 2% of all enzyme by concentration Most action in liver. Plays a major role in degradation of fluoxatine, tricyclics, most antipsychotics, methadone, codeine, benztropine, amphetamines, donepazil 25% of all psychotropics 2D6 Strong Inhibitors: Fluoxetine, Paroxetine, Quinidine Moderate Inhibitors: Duloxetine, Fluphenazine, Risperidone, Buproprion Weak Inhibitors: Venlafaxine, Sertaline, Citalopram Substrates: Most antidepressants, Most Antipsychotics, Benztropine, Diphenhydramine, Metprolol Pro drugs - Codeine Analgesic effect depends on conversion to morphine. Depends on 2D6. Inhibition can result in poorer pain control. Fluoxetine and Paroxetine are strong inhibitors Fluoxetine is oxidized to norfluoxetine Fluoxetine (Ki .22) and norfluoxetine (Ki 1.48) – may require a 4-8 week washout period before introduction of other 2D6 Metabolized agents Paroxetine Potent 2D6 inhibitor (Ki 2.0) Half life 21 hours, no active metabolites Fluoxetine and Paroxetine are relative contraindicated together with drugs that increase QT interval i.e. tricyclics, phenothiazines, some second generation antipsychotics Other Drugs Ritanovir – potent 2D6 inhibitor (Ki .16) Also inhibits most other enzymes 2D6 is induced in pregnancy Not a lot of evidence of drug induction of 2D6 Tamoxifen Used to treat estrogen receptor positive beast cancer. Active metabolite, endoxefen, has 10 to 100X the affinity to estrogen receptor. Breast cancer survivors suffer depression and hot flashes frequently treated with SSRIs Woman on Tamoxifen plus fluoxetine, paroxetine and sertriline have relapse rate of 16% compared to usual rate of 7.5%. Tamoxifen 2D6 genetics Wild type exists in 90%, PMs in about 8% of caucasians Asians have 1% PMs. Northern African populations have high prevalence of UEMs (29% Ethiopians) Over 100 SNPs for 2D6 gene identified. Those with greater potency as enzymes has side effects To codeine (nausea), Tamoxifen (hot flashes) and other agents. Star D suggested ultra rapid metabolizers may fail to respond to some SSRIs. 3A4 Accounts for 30% of P450 activity in liver and 70% in gut Performs the bulk of oxidative metabolism of drugs Phase I metabolism of endogenous and exogenous compounds including hydroxylation, demethylation and dealkylation Metabolism of endogenous steroids, cholesterol and lipids Including oral contraceptives Genetic variability 50 variations identified High activity variants seen require increased doses of drugs metabolized by 3A4 Poor metabolism alleles are likely incompatible with life Inhibitors Strong inhibitors increase plasma levels of substrate 3 to 5 times. Nefazodone, ketoconazole, grapefruit juice Some drugs affected by 3A4 inhibition; fentanyl, quinidine, pimozide Deaths prompted contraindication of pimozide with any azole antifungals, macrolide antibiotic or protease inhibitor Benzodiazepines Alprazolam, midazolam, triazolam depend on 3A4 50% dose reduction recommended for alprazolam 75% reduction of triazolam when administered with nefazodone. Buspirone levels enhanced with 3A4 blockers i.e. Erythromycin, efaverenze Grapefruit juice Furanocoumarins inhibit 3A4 6-8 ounces of Grapefruit juice taken with a 3A4 substrate will significantly increase blood levels Drug sparing and augmentation – cimetidine and Clozaril Inducers Carbamazepine – induces its own metabolism Also Topiramate, Methylprednisone, modafanil, prednisone and St. John’s Wort May lead to lower levels of oral contraceptives 2C9 A main metabolic pathway for oral hypoglycemics and NSAIDS. Substrates include Phentoin, Warfarin, modafanil 10 % of caucasians are 2C9 poor metabolizers (these polymorphs rare in African Americans or Asians Valproate is an inhibitor of 2C9 and may lead to increased levels of substrates 2C19 Polymorphs common; Asians have high prevalence of poor metabolizers Most proton pump inhibitors metabolized by this pathway Citalopram, Escitaloprem, Sertaline, diazepam levels are increased in populations who have poor metabolism Fluoxetine is a potent inhibitor 2C19 Overall 14% of population are PMs Clopidogrel (Plavix) is a pro-drug metabolized by 2C19 Inhibitors (proton pump inhibitors, antidepressants) Reduce effectiveness i.e. reinfarction rate with concomiant use Ampli-Chip Several services now available to provide a profile of P450 activity Roche’s Amplichip Gene Test approved by FDA to confirm genotypes for 2D6 and 2C19. Cost $600.00 This test only provides genotyping, an approximation of the phenotype 1A2 Enzyme important in the metabolism of many xenobiotics including polycyclic hydrocarbons found in cigarette smoke Linked to carcinogenesis Major enzyme in oxidation of melatonin and methylxanthines: caffeine and theophylline Expressed in liver, codon on chromosome 15 1A2 About 20 variations known, mostly rare. SNPs involved with inducibility of enzyme One SNP associated with susceptibility to Tardive Dyskinesia. Same SNIP (1a2*F) associated with increased QT with antipsychotics Relationship between caffeine metabolism and plasma concentrations of olanzapine and clozapine 1A2 Fluvoxamine is a potent inhibitor and may increase clozapine levels tenfold Ciprofloxin increases clozapine levels threefold Estrogen containing oral contraceptives or replacement hormones moderately inhibit 1A2 leading to toxicities with use of caffeine, clozapine and haldol. 1A2 1A2 induced by hydrocarbons in cigarette smoke. 1A2 induction increases clearance of many antipsychotic drugs: clozapine and olanzapine Smoking cessation in schizophrenic patients leads to elevated blood levels of substrate Alternately stabilization of schizophrenic symptoms on a smoke free inpatient unit leads to increased clearance, declining blood levels and relapse upon resumption of smoking 1A2 Other inducers of 1A2 include brussel sprouts, broccoli and cabbage, charcoal grilling Heavy exercise will induce as potently as heavy cigarette smoking. 2E1 Unique enzyme with limited but important substrates. Inactivation of industrial solvents, acetaminophen hepatotoxicity, activator of chemical carcinogenesis and producer of free radicals causing cytotoxicity and tissue damage Role in metabolism of alcohol Anesthetics 2E1 Inhibitors include acute alcohol, isoniazid, disulfram, watercress Chronic alcohol use increases enzyme activity 10 fold Uncontrolled diabetes, obesity, smoking (including marijuana) may result in induction Organic compounds are metabolized to compounds which are carcinogenic. Increase 2E1 associated with increased cancer risk 2E1 Acetaminophen is metabolized by glucuronadation. When glucuronide is overwhelmed (i.e. overdose) it is metabolized by 2E1. The metabolic product of this interaction (NAPQI) is hepatotoxic. Situations where glutathione levels are reduced or 2E1 (smoking, opiate consumption, HIV, Hepatitis C) carry Higher risk for acetaminophen hapatotoxicity Renal Clearance Drugs or active metabolites cleared primarily by renal excretion: Lithium Carbonate – thiazides increase levels Excretion enhanced by xanthines (Caffeine, theobromine) Gabapentin – Excreted unchanged in urine with no known interactions involving elimination Board Questions 1 is true in regard to Which of the following statements venlafaxine? A. B. C. D. It is highly protein bound It is unlikely to inhibit cytochrome P450 enzymes It has a flat dose-response curve It is not FDA approved for generalized anxiety disorder (GAD) E. It has a high risk of inducing hypertension at low doses B. Board Questions 2 A 68 year old man with bipolar I disorder has done well on lithium. His most recent blood level was 0.8 mEq/L. He has a variety of medical problems. He now presents with pressured speech, racing thoughts and insomnia. Serum lithium level is now 0.3 mEq/L. Wife noted changes about two weeks after addition of a new medication. You are confident of adherence to lithium regimen. What class of drug was added to his regimen? Board Questions 2 A. B. C. D. E. E ACE inhibitor Beta blocker NSAID Thiazide diuretic Xanthine bronchodilator Board Question 3 A 27 year old patient announces she is pregnant despite having taken an oral contraceptive for 4 years. Which of the following four medications might account for failure of oral contraceptives? A. Lithium B. Divalproex C. Carbamazepine D. Lamotrigine E. Gabapentin C Board Question 4 Which of the following will double blood levels of lamotrigine? A. B. C. D. B Carbamazepine Divalproex Phentoin Phenobarbital Board Question 5 A 38 year-old woman with a history of estrogen receptor positive breast cancer is currently taking tamoxifen. She has recently become tearful, withdrawn and anergic. She notes difficulty with sleep and hot flashes since initiation of tamoxifen. Which of the following is the most appropriate agent to use to treat her depressive symptoms? Board Question 5 A. B. C. D. E. B Venlafaxine Paroxetine Gabapentin Fluoxetine Duloxetine