psychopharmacolgy in organ compromised
DESCRIPTION
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.TRANSCRIPT
Prescribing Dilemmas in Organ Compromised
IPSWZ-2013, Oct 18th, GOA
Dr. Vishwamohan Thakur, MDAHMEDABAD
A
EMD
bsorption
xcretion
etabolism
istribution
PHARMACOKINETICS
Conc. of Drug
Time0
C-max
½ C-max
T-max T-½ (Half-life)
More drug IN than out
More drug OUT than in
Area Under the Curve or Total Exposure to Drug
Half Life
ABSORPTION
Oral i.v. inhaled
Blood conc of drug
Time
C-Maxoral
T-MaxoralT-Maxi.v.
C-Maxi.v.
C-Maxinhaled
T-Maxinhaled
1. C-max, T-max and Area under the curve differs2. Clearance is same3. Half-life is same
3 POINTS about ROUTE of administration
Clinical issues related to oral bioavailability1. In renal failure, there is decreased absorption due to
chelation with co-administered antacids.2. Concurrent administration of food increases the
absorption of ziprasydon, but decreases that of levosulpiride.
3. Buprenorphine has poor oral bioavailability due to hepatic first pass metabolism, but it has good sublingual bioavailability.
DRUG DOSE
metabolitesProtein bound drug
[FREE DRUG]
BLOOD
DISTRIBUTION
CLEARANCELIBERATION
ABSORPTION EXCRETIONKidney
UNWANTED SITE OF ACTION
Bound Free
TISSUE RESERVOIRSBound FreeTHERAPEUTIC SITE
OF ACTIONBound Free
Bile
BIOTRANSFORMATIONLIVER
• 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.
Distribution of psychotropics
• 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
Example of Distribution Issue
• 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.
Rationale
METABOLISM
FIRST PASS METABOLISMintravenous
inj. Systemic Circulation
Oral administration
intestines
Oral Drug
Portal Vein
Metabolism Liver
PHASE-IFUNCTIONALIZATION
POLAR (OH) METABOLITE
PHASE-II
DRUGS, OTHER
XENOBIOTICSWater Insoluble
Urinary excretion
METABOLISMCYP 450 Enzymes
Conjugated METABOLITEHighly water soluble
MW<300
Slightly Water soluble
MW >300
FAECES
CONJUGATION
Phase-IIITransport
-H
-OH
-OH-OH
-OH
-OH-OH
-OH-OH
-OH
• Glucuronidation• Methylation• Sulphation• Acetylation
CYP-450 enzymes on smooth ER Conjugating enzymes in Cytoplasm Transferring enzymes acting on cell membrane
GLYCO-PROTEINS
NUCLEUS
Metabolism of Xenobiotic in Hepatocyte
CELL MEMBRANE OF HEPATOCYTE
CELL MEMBRANE OF HEPATOCYTE
BILE ducts
Portal Vein
Smooth ER
CYP-450• Oxidation• Hydroxylation• Hydrolysis
PHASE - I PHASE - II PHASE - III
Hepatic Vein
BILE ducts
-H
MDR
14
Main Cytochrome P450 enzymes in HumansOnly few of 50 enzymes are involved in the metabolism of
90% xenobiotics and drugs
METABOLISM
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
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)
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.
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
Case of near fatality with VerapamilA 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
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
Inhibits CYP450 3A4, 2C19, 2D6
SAFE
Grapefruit is none of theseGrapes, Oranges or Sweet Lime
• 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 steady-
state levels in blood!
Some other Metabolism Issues (1)
• 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.
Some Metabolism Issues (2)
• Carbamazepine reduces the effectiveness of many psychotropic substances.
• Valproate raises lamotregine levels
Some Metabolism Issues (3)
• 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.
Some Metabolism Issues (4)
USEFUL WEBSITE
WEB site
www.medicine.iupui.edu/clinpharm/ddis/main-table/
USEFUL EXCEL SHEET
Microsoft Excel [email protected]
Interesting Titbits
• The ongoing evolutionary battle between plant and animal
Cytoplasmic Enzymes
Glycoproteins
EXCRETION CLEARANCE
KIDNEY DAMAGE STAGING BASED ON
Normal GFR is 100-130ml/min/1.72m2
• Stage-1 >90 • Stage-2 60-89• Stage-3 30-59• Stage-4 15-29• Stage-5 <15 (or dialysis)
GLOMERULAR FILTRATION RATE
Cp
Cu
Vu
Clearance = Cu x Vu
Cp
Dose
GFR
RENAL CLEARANCEGFR
Speed of drug removal
Calculating GFR using Clearance• Isotope scanning• 24-hour urine collection of creatinine
eCcr = Urine Cr excretion/minS. 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)
Factors affecting GFReCcr = (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
1st order kinetics. Eliminates 50% drug every t-1/2
Zero order kinetics. Eliminates fixed amount of drug every unit time
The Orders of Kinetics of Elimination
TIME
[ DRU
G C
ON
CEN
TRAT
ION
]
Zero order elimination. Fixed amount decreases per unit time. For ex. 10g alcohol per hour
First order kinetics. Fixed % (half, or 50%) of drug eliminated every t1/2
The point at which kinetics of drug elimination changes from zero to 1st order
Clearance Kinetics
Zero-order
Constant AMOUNT cleared
per unit time
Rate does not increase with
drug concentration
Implies drug overdose or
impaired organ
First Order
Constant FRACTIO
N cleared per unit
time
Rate increases with drug
concentration
Implies normal drug
clearance
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!)
THANK
YOU
HOPE TO SEE YOU FOR THE 2ND PART