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Psychopharmacolgy in organ compromised

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This is the first part of two talks entitled, "Prescribing dilemmas in organ compromised patients" at the annual conference of Indian Psychiatric Society West Zone, delivered on 13th October, 2013 at Goa, India.

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Psychopharmacolgy in organ compromised

  1. 1. bsorption istribution Conc. of Drug etabolism C-max xcretion Area Under the Curve or Total Exposure to Drug ½ C-max 0 Half Life T-max T-½ (Half-life) More drug IN than out More drug OUT than in Time
  2. 2. Oral i.v. inhaled C-Maxinhaled C-Maxi.v. Blood conc of drug C-Maxoral T-Maxinhaled i.v. T-Max Time T-Maxoral
  3. 3. 3 POINTS about ROUTE of administration 1. 2. 3. C-max, T-max and Area under the curve differs Clearance is same Half-life is same Clinical issues related to oral bioavailability 1. 2. 3. In renal failure, there is decreased absorption due to chelation with co-administered antacids. Concurrent administration of food increases the absorption of ziprasydon, but decreases that of levosulpiride. Buprenorphine has poor oral bioavailability due to hepatic first pass metabolism, but it has good sublingual bioavailability.
  4. 4. TISSUE RESERVOIRS Bound  Free THERAPEUTIC SITE OF ACTION Bound  Free UNWANTED SITE OF ACTION Bound  Free BLOOD LIBERATION ABSORPTION DRUG DOSE CLEARANCE [FREE DRUG] EXCRETION Protein bound drug LIVER Kidney metabolites BIOTRANSFORMATION Bile
  5. 5. Distribution of psychotropics • Distribution issues are somewhat uncommon with psychotropic medications. Most psychotropics are protein bound. (Lithium is exception). • So hypo-proteinemias can cause increase in free drug and so might require reduction in dosage. • Serum Blood levels of drugs include both protein bound and free drug. So this can be misleading.
  6. 6. Example of Distribution Issue • 48 year old male with history of bipolar disorder was treated with sodium valproate 1250mg and Quetiapine 500mg • Sensation of tingling in arm for more than 20 minutes – Concern about a transient ischemic attack (TIA) given untreated hypertention (155/95) and family hx – Started on enalapril 5mg bid and aspirin 325mg/day • Within 3 days, onset of fatigue, terrible fatigue and sedation and incoordination – Presention is consistent with valproic acid toxicity – Valproic acid level is unchanged – 95ug/ml • Recommendation; d/c aspirin
  7. 7. Rationale • Divalproic acid tightly bound to plasma proteins • Aspirin is also tightly bound to proteins – Displace valproic acid – Only changed ratio of bound to unbound valproic acid – Total amount of divalproic acid unchanged • Discontinuing Aspirin solved the problem.
  8. 8. intravenous inj. Systemic Circulation Oral administration Metabolism Liver Portal Vein intestines Oral Drug
  9. 9. CYP 450 Enzymes Slightly Water soluble DRUGS, OTHER XENOBIOTICS Water Insoluble PHASE-I FUNCTIONALIZATION POLAR (OH) METABOLITE PHASE-II CONJUGATION Phase-III Transport Urinary excretion FAECES MW >300 Conjugated METABOLITE Highly water soluble MW<300
  10. 10. Portal Vein CELL MEMBRANE OF HEPATOCYTE -H -H MDR CYP-450 NUCLEUS • Oxidation • Hydroxylation • Hydrolysis • • • • Glucuronidation Methylation Sulphation Acetylation -OH BILE ducts Smooth ER CYP-450 enzymes on smooth ER PHASE - I GLYCOPROTEINS Hepatic Vein -OH -OH -OH -OH -OH -OH -OH -OH Conjugating enzymes in Cytoplasm PHASE - II CELL MEMBRANE OF HEPATOCYTE Transferring enzymes acting on cell membrane PHASE - III BILE ducts
  11. 11. Main Cytochrome P450 enzymes in Humans Only few of 50 enzymes are involved in the metabolism of 90% xenobiotics and drugs 14
  12. 12. FACTORS AFFECTING CYP450 (1) • Age (Young metabolize faster) • Sex (Males metabolize faster) • Habits (Smokers and Chronic Alcoholics metabolize faster) • Genetic Polymorphism – Fast and Slow metabolizers • Drugs (CYP inhibitors and CYP inducers) – Inhibition occurs immediately – Induction takes time and is lasting
  13. 13. METABOLISM AND CYP450 (2) • Almost all psychotropics are metabolized by CYP450 Enzyme system – Except Lithium, Lorazepam, Gabapentin etc • CYP450 have – Substrates (drugs metabolized by CYP enzymes) – Inhibitors (drugs that inhibit CYP enzymes) – Inducers (drugs that increase CYP enzymes)
  14. 14. METABOLISM AND CYP450 (3) • Substrates – Almost all psychotropics. Thus they are susceptible to activity of inhibitors and inducers • Inhibitors – Many drugs including many psychotropics • Examples: Fluvoxamine, Paroxetine, Clomipramine, CPZ, Bupropion, Duloxetine, Moclobemide, Grapefuit juice • They increase the toxicity of substrates, reduce activity of prodrugs like aspirin, tramadol, codeine • Inducers – Examples: Carbamazepine, Phenobarbitone, Modafinil, Phenytoin, St. John’s Wort, Tobacco, Chronic Alcoholism – They reduce effectiveness of substrates after some time.
  15. 15. METABOLISM BEGINS IN THE GUT • The metabolism of many drugs starts in the gut itself. • The gut cells contain CYP-450 as well as the efflux pumps of MDR and p-glycoproteins which render much of the drug inactive. • Grapefruit juice inhibits these enzymes leading to large amount of drugs to enter portal system. • The felodepine trials using grapefuit juice to mask the taste of alcohol
  16. 16. Case of near fatality with Verapamil A 42-year-old lady brought in emergency. Doctors had to insert a breathing tube, and then a pacemaker, to revive her. She was taking a Verapamil to help prevent the headaches. Toxic level of verapamil in blood ? Attempted suicide by taking overdose ??? H/o grapefruit juice with verapamil
  17. 17. The mysterious Case of Fluvoxamine • • • • 75-year-old lady on Fluvoxamine-150 since 2 years. Sudden palpitations while vacationing. Grapefruit juice was served everyday by daughter. Naringin and Bergamottin in grapefruit inhibit the gut (but not hepatic) CYP-450 enzymes which metabolize Fluvoxamine. • People who have mutant genes for 2D6 CYP-450 develop severe anxiety reactions when given SSRIs in usual dose as they lack efficient 2D6 CYP
  18. 18. Grapefruit is none of these Grapes, Oranges or Sweet Lime Inhibits CYP450 3A4, 2C19, 2D6 SAFE
  19. 19. Some other Metabolism Issues (1) • Valproate should be avoided in liver disease. • Olanzapine dose needs to be reduced in liver disease. • Injectable Olanzapine is rapidly sedating when given i.m. • Injected psychotropics have higher steadystate levels in blood!
  20. 20. Some Metabolism Issues (2) • Risperidone has high effectiveness despite first-pass metabolism. • Clozapine becomes hematotoxic when carbamazepine is added. • Clozapine and Olanzapine lose effectiveness in smokers. • Ziprasidon is not affected by smoking.
  21. 21. Some Metabolism Issues (3) • Carbamazepine reduces the effectiveness of many psychotropic substances. • Valproate raises lamotregine levels
  22. 22. Some Metabolism Issues (4) • Lorazepam, Oxazepam and Temazepam are safe in liver disease but not other benzos. • Tramadol can cause serious interaction with SSRIs like peroxetine, fluvoxamine and sertraline.
  23. 23. WEB site www.medicine.iupui.edu/clinpharm/ddis/main-table/
  24. 24. docvmt@gmail.com
  25. 25. Interesting Titbits • The ongoing evolutionary battle between plant and animal
  26. 26. Cytoplasmic Enzymes Glycoproteins
  27. 27. KIDNEY DAMAGE STAGING BASED ON GLOMERULAR FILTRATION RATE Normal GFR is 100-130ml/min/1.72m2 • • • • • Stage-1 Stage-2 Stage-3 Stage-4 Stage-5 >90 60-89 30-59 15-29 <15 (or dialysis)
  28. 28. Dose Cp Speed of drug removal C x Vu Clearance = u Cp Vu GFR Cu
  29. 29. Calculating GFR using Clearance • Isotope scanning • 24-hour urine collection of creatinine eCcr = Urine Cr excretion/min S. Creatinine • Inulin clearance (not insulin) – It is more ideal than creatinine as it is neither absorbed nor secreted by renal tubules, so it reflects GFR • Using GFR calculators using S. Creatinine value – CG (Cockroft and Gault Equation) eCcr = (140-age) x Weight in Kg x (0.85 if female) 72 x S. Creatinine in mg% – MDRD (Modification of Diet in Renal Disease)
  30. 30. Factors affecting GFR eCcr = (140-age) x Weight in Kg x (0.85 if female) 72 x S. Creatinine in mg% • Age – GFR declines with age (note how the GFR becomes half in an 80 yr old compared to the 20 yr old according to CG formula) • Sex – Female have lower GFR (note how females are assumed to have 15% lower GFR in the CG formula) • Weight – Note the CG formula • Race – This is not part of CG formula, but other GFR formulas do take it into account
  31. 31. Zero order kinetics. Eliminates fixed amount of drug every unit time 1st order kinetics. Eliminates 50% drug every t-1/2
  32. 32. [ DRUG CONCENTRATION] Zero order elimination. Fixed amount decreases per unit time. For ex. 10g alcohol per hour The point at which kinetics of drug elimination changes from zero to 1st order First order kinetics. Fixed % (half, or 50%) of drug eliminated every t1/2 TIME
  33. 33. Renal vs Hepatic Clearance Renally Cleared • Lithium • Gabapentine • Pregabalin • Topiramate • Amisulpride • Duloxetin • Milnacipran • Venlafexine Non-Renally Cleared • Divalproex • Quetiapine • Carbamazepine • Lamotregine • Haloperidol • Aripiprazole • Moclobemide • Reboxetin • Tianeptine • Buspirone • Zaleplon • Zolpidem • Zopiclone (excreted by lungs!)

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