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 Worksheetdocvmt@gmail.com

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