Drug Interactions

1. Drug Interactions Thomas M Penders MD Associate Professor Brody School of Medicine

2. 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

3. 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.

5. Multiple Drug Overdose

6. 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

7. 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

8. 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

9. 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

10. Steady state

11. Pharmacodynamic Interactions Drugs influence on another drugs effects Occurs at end organ or receptor site Most commonly additive effects e.g. SSRIs and MAOIs

12. 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

13. Red Queen

14. 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

15. 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.

16. 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

17. Sites of Drug Metabolism Most drug metabolism occurs in liver and gut wall. 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

18. Phase I metabolism Addition of small polar groups through oxidative mechanisms; N-dealkylination, O-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

19. Variability of drug response Inhibition Induction Genetic polymorphisms

20. Enzyme Variability

21. 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

22. 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.

23. Inhibition

24. 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.

25. 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

26. 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

27. Induction

28. 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

29. 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

30. 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

31. Population variation in enzyme activity

32. 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

33. 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

34. UGTs These benzodiazepines are favored with liver disease Lamotrigine, valporate, NSAIDs, zidovudine, most opiates

35. 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

36. Phase III - transporters Located in intestines and liver as well as blood-brain barrier SLC transporters – importing transporters ABC - effluxing transporters

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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%.

44. Tamoxifen

45. 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.

46. 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, demethylationand dealkylation Metabolism of endogenous steroids, cholesterol and lipids Including oral contraceptives

47. 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

48. 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

49. 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

50. 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