Exam 1 - Pharmocology Drugs

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Pro-Drugs

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drugs activated by metabolism, parent compound not active
Cyclophosphamide:anticancer drug
Carbamazepine: anticonvulsant
Proton Pump Inhibitors

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Examples of Pro-Drugs

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Cyclophosphamide:anticancer drug
Carbamazepine: anticonvulsant
Proton Pump Inhibitors

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Drug which is both active and has an active metabolite

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Flurazepam: has a half-life of 2-3 hours, benzodiazapam for insomnia dosed once a day (at bedtime) to avoid excessive sedation from drug accumulation

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Drugs that require a different route of administration due to first-pass metabolism

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Nitroglycerin: sublingually
Morphine: IV
Meperidine: IV

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Non-Hepatic First-Pass Metabolism

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Intestinal Metabolism: Chlorpromazine: anti-psychotic, Cyclosporine: immunosuppressant agent

Gastric Acid: Omeprazole, esomerprazole: PPIs

Digestive Enzymes: Insulin

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Non-Hepatic First-Pass Metabolism: Digestive Enzymes

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Insulin

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Non-Hepatic First-Pass Metabolism: Intestinal Metabolism

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Chlorpromazine: anti-psychotic, Cyclosporine: immunosuppressant agent

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Non-Hepatic First-Pass Metabolism: Gastric Acid

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Omeprazole, esomerprazole: PPIs

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Phase I Metabolism

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Usually oxidation, less often reduction or hydrolysis, inactivates parent compound and convert it to more polar compound (if sufficient secreted, if not goes to phase II)
Introduction or unmasking of functional groups
-OH, -COOH, -NH3, -SH, -O-

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Phase I Metabolism: Introduction or unmasking of functional groups

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-OH, -COOH, -NH3, -SH, -O-

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Pro-Drugs

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drugs activated by metabolism, parent compound not active
Cyclophosphamide:anticancer drug
Carbamazepine: anticonvulsant
Proton Pump Inhibitors

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Examples of Pro-Drugs

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Cyclophosphamide:anticancer drug
Carbamazepine: anticonvulsant
Proton Pump Inhibitors

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Drug which is both active and has an active metabolite

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Flurazepam: has a half-life of 2-3 hours, benzodiazapam for insomnia dosed once a day (at bedtime) to avoid excessive sedation from drug accumulation

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Drugs that require a different route of administration due to first-pass metabolism

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Nitroglycerin: sublingually
Morphine: IV
Meperidine: IV

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Non-Hepatic First-Pass Metabolism

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Intestinal Metabolism: Chlorpromazine: anti-psychotic, Cyclosporine: immunosuppressant agent

Gastric Acid: Omeprazole, esomerprazole: PPIs

Digestive Enzymes: Insulin

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Non-Hepatic First-Pass Metabolism: Digestive Enzymes

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Insulin

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Non-Hepatic First-Pass Metabolism: Intestinal Metabolism

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Chlorpromazine: anti-psychotic, Cyclosporine: immunosuppressant agent

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Non-Hepatic First-Pass Metabolism: Gastric Acid

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Omeprazole, esomerprazole: PPIs

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Phase I Metabolism

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Usually oxidation, less often reduction or hydrolysis, inactivates parent compound and convert it to more polar compound (if sufficient secreted, if not goes to phase II)
Introduction or unmasking of functional groups
-OH, -COOH, -NH3, -SH, -O-

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Phase I Metabolism: Introduction or unmasking of functional groups

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-OH, -COOH, -NH3, -SH, -O-

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Major Phase I Enzyme System: Enzyme and Co-Enzyme

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Enzymes: P450 reductase, P450
Co-Enzymes: NADPH, O2

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P450 Enzymes in Human Liver

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2D6, 3A4, CYP2C9, CYP2E1

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CYP2E1

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Metabolized ethanol, acetaminophen

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CYP2C9

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responsible for 20% of oxidations
Phenytoin and Wafarin (narrow therapeutic window)
NSAIDS (ibuprofen)

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3A4

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most predominant, accounts for 50% of all drug oxidations
Drugs oxidized by P450:
Cyclosporine
Ritonavir: HIV Protease Inhibitors
Nifedipine: Ca2+ channel blockers
Diazepam: benzodiazepines

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2D6

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accounts for 30% of drug oxidations
Examples of Substrates:
Haloperidol: antipsychotic agents
Caryedilol: β-blockers
Codeine: opioid analgesics
Fluorexin: antidepressants

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Phase II Reactions

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Conjugate reactions/synthetic reactions, parent drug or product from phase I combines with an endogenous substance, products of these are usually polar, often inactive and readily excreted, enzymes are called Transferases
Some endogenous substances originate in the diet --> Sulfate

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Phase II Reactions: Endogenous substances that orginate in the body

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sulfate

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Phase II Reactions Enzymes

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Transferases

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Enzyme Inhibition – Competitive

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Two drugs bind to the same active site on an enzyme

Both CYP1A2 substrates: warfarin and Cipofloxin (antibiotic)
One CYP2D6 substrate and inhibitor: Codeine and Quinidine (antiarryhthmic drug)

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Enzyme Inhibition – Competitive: CYP1A2 substrates

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warfarin and Cipofloxin (antibiotic)

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Enzyme Inhibition – Competitive: One CYP2D6 substrate and inhibitor

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Codeine and Quinidine (antiarryhthmic drug)

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Enzyme Inhibition – Irreversible

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This enzyme is permanently inactivated, inhibitor is metabolized to a form that irreversibly binds to and inactivates the enzyme

Erythromycin: irreversibly inhibits CYP3A4, and interacts with many other drugs

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Enzyme Inhibition by Depletion of Cofactors

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Common mechanism for inhibition of Phase II

Conjugation of acetaminophen to sulfate which is reduced by a low sulfate diet

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Inhibitors of Specific CYP Enzyme Isoforms: CYP1A1 & 1A2

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Fluoxetine: Prozac, anti-depressant

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Inhibitors of Specific CYP Enzyme Isoforms: CYP3A4

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Cimetidine: H2 receptor antagonist
Erythromycin
Ketoconazole: anti-fungal
Grapefruit juice

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Inhibitors of Specific CYP Enzyme Isoforms: CYP2D6

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Fluoxetine
Paroxetine: Paxil, anti-depressant
Quinidine

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Inhibitors of Specific CYP Enzyme Isoforms: CYP2C19

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Fluoxetine, Omeprazole

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Inhibitors of Specific CYP Enzyme Isoforms: CYP2C9

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Fluoxetine
Fluconazole: anti-fungal

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Enzyme Induction

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Drug metabolizing enzyme levels may be increased (induced) by prolonged exposure to some drugs, air pollutants, including cigarette smoke, and ingested materials

Increased synthesis of new enzyme:
Dexamethasone: induction of CYP34A, steroid, anti-inflammatory
Rifampin: induction of CYP34A, antibiotic for TB

Decreased Proteolytic degradation of Enzyme:
Ethanol: mediated by induction of CYP2E1

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Enzyme Induction: Increased synthesis of new enzyme

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Dexamethasone: induction of CYP34A, steroid, anti-inflammatory
Rifampin: induction of CYP34A, antibiotic for TB

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Enzyme Induction: Decreased Proteolytic degradation of Enzyme:

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Ethanol: mediated by induction of CYP2E1

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Inducers for Specific CYP Enzyme Isoforms: CYP2A6 & 1A2

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Phenobarbital

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Inducers for Specific CYP Enzyme Isoforms: CYP34A

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Glucocorticoids, Rifampin, Phenobarbital
St John’s Wort: OTC herbal supplement for mild depression

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Theoretic Clinical Examples of CYP Interactions: Ketoconazole and Zolpidem

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Ketoconazole: inhibits CYP34A but is not a substrate

Zolpidem: is a substrate for CYP3A4 but does not inhibit or induce it

Result of Co-administration: the patient may be heavily sedated in the morning

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Theoretic Clinical Examples of CYP Interactions: Quinidine and Codeine

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Quinidine: inhibits CYP2D6 but is not a substrate

Codeine: is metabolized to active metabolite by CYP2D6 but does not inhibit or induce it (adverse effects include constipation and respiratory depression)

Result of Co-administration: codeine may not produce an analgesic effect

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Influence of Gender on Drug Metabolism: Gender-dependent differences in metabolism may exist for

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Ethanol, Propranolol, Benzodiazepines, Estrogens, and Salicylates

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Influence of Gender on Drug Metabolism: Pregnancy

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During the 2nd and 3rd trimester of pregnancy induction of metabolism occurs and drug doses may need to be increased for certain drugs


Phenytoin: may need to be increased for seizures

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CYP450 Polymorphism: CYP2C9 variants

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show reduced activity
Warfarin: lower doses needed for anticoagulation

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CYP450 Polymorphism: CYP2C19 deficiency

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leads to improved healing rates from ulcers
Omeprazole: increased toxicity

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Conjugating Enzyme Variants

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NAT (N-acetyltransferase) drug conjugating enzymes:

Acetylates, (Slow acetylators have less of the enzyme)
Isoniazid, procainamide, caffeine, etc.

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Cyclophosphamide

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anticancer drug, pro-drug

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Esomerprazole

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PPI, Non-Hepatic First-Pass Metabolism (gastric acid)

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Omeprazole

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PPI, Non-Hepatic First-Pass Metabolism (gastric acid), Inhibitor of CYP2C19, CYP2C19 deficiency can caused increased toxicity

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Cyclosporine

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immunosuppressant agent, CYP3A4 accounts for its drug oxidation, Non-Hepatic First-Pass Metabolism (Intestinal Metabolism)

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Chlorpromazine

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anti-psychotic, Non-Hepatic First-Pass Metabolism (Intestinal Metabolism)

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Meperidine

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IV to avoid first pass metabolism

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Morphine

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IV to avoid first pass metabolism

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Carbamazepine

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anticonvulsant, pro-drug

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Nitroglycerin

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sublingually to avoid first pass metabolism

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Flurazepam

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has a half-life of 2-3 hours, benzodiazapam for insomnia dosed once a day (at bedtime) to avoid excessive sedation from drug accumulation, Drug which is both active and has an active metabolite

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Insulin

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Non-Hepatic First-Pass (Digestive Enzymes)

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Wafarin

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narrow therapeutic window, CYP2C9 responsible its oxidation, CYP1A2 substrate (competitive inhibitor with Cipofloxin), CYP2C9 variantsshow reduced activity (lower doses needed for anticoagulation)

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Phenytoin

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CYP2C9 responsible its oxidation, may need to be increased for seizures, During the 2nd and 3rd trimester of pregnancy induction of metabolism occurs and drug doses may need to be increased

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Diazepam

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benzodiazepines, CYP3A4 accounts for its drug oxidation

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Nifedipine

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Ca2+ channel blockers, CYP3A4 accounts for its drug oxidation

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Ritonavir

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HIV Protease Inhibitors, CYP3A4 accounts for its drug oxidation

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Fluorexin

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antidepressants, CYP2D6 accounts for its drug oxidation

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Haloperidol

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antipsychotic agents, CYP2D6 accounts for its drug oxidation

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Codeine

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opioid analgesics, CYP2D6 accounts for its drug oxidation (CYP2D6 substrate), but does not inhibit or induce it (adverse effects include constipation and respiratory depression)

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Caryedilol

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β-blockers, CYP2D6 accounts for its drug oxidation

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NSAIDS (ibuprofen)

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CYP2C9 responsible its oxidation

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Cimetidine

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H2 receptor antagonist, Inhibitor of Specific CYP Enzyme Isoform CYP3A4

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Ethanol

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mediated by induction of CYP2E1 (Metabolizes it), Decreased Proteolytic degradation of Enzyme, Gender-dependent differences in metabolism may exist

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Acetaminophen

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Metabolizes CYP2E1

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Cipofloxin

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antibiotic, CYP1A2 substrate (competitive inhibitor with Wafarin)

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Quinidine

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antiarryhthmic drug, inhibits CYP2D6 but is not a substrate

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Erythromycin

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irreversibly inhibits CYP3A4, and interacts with many other drugs, Inhibitor of Specific CYP Enzyme Isoform CYP3A4

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Fluoxetine

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Prozac, anti-depressant, Inhibitor CYP1A1 & 1A2, CYP2C9, CYP2C19, CYP2D6

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Paroxetine

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Paxil, anti-depressant, Inhibitor of Specific CYP Enzyme Isoform CYP2D6

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Fluconazole

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anti-fungal, Inhibitor of CYP2C9

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NSAIDS (ibuprofen)

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CYP2C9 responsible its oxidation

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Cimetidine

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H2 receptor antagonist, Inhibitor of Specific CYP Enzyme Isoform CYP3A4

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Ethanol

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mediated by induction of CYP2E1 (Metabolizes it), Decreased Proteolytic degradation of Enzyme, Gender-dependent differences in metabolism may exist

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Acetaminophen

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Metabolizes CYP2E1

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Cipofloxin

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antibiotic, CYP1A2 substrate (competitive inhibitor with Wafarin)

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Quinidine

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antiarryhthmic drug, inhibits CYP2D6 but is not a substrate

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Erythromycin

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irreversibly inhibits CYP3A4, and interacts with many other drugs, Inhibitor of Specific CYP Enzyme Isoform CYP3A4

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Fluoxetine

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Prozac, anti-depressant, Inhibitor CYP1A1 & 1A2, CYP2C9, CYP2C19, CYP2D6

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Paroxetine

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Paxil, anti-depressant, Inhibitor of Specific CYP Enzyme Isoform CYP2D6

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Fluconazole

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anti-fungal, Inhibitor of CYP2C9

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Ketoconazole

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anti-fungal, Inhibitor of Specific CYP Enzyme Isoform CYP3A4

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Benzodiazepines

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Gender-dependent differences in metabolism may exist

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Propranolol

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Gender-dependent differences in metabolism may exist

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Zolpidem

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is a substrate for CYP3A4 but does not inhibit or induce it

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St John’s Wort

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OTC herbal supplement for mild depression, Inducer for Isoform CYP34A

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Glucocorticoids

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Inducer for Isoform CYP34A

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Grapefruit juice

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Inhibitor of CYP3A4

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Phenobarbital

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Inducer for CYP2A6 & 1A2, CYP34A

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Rifampin

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induction of CYP34A, antibiotic for TB, Increased synthesis of new enzyme, Inducer for CYP34A

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Dexamethasone

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induction of CYP34A, steroid, anti-inflammatory, Increased synthesis of new enzyme

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Estrogens

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Gender-dependent differences in metabolism may exist

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Caffeine

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Conjugating Enzyme Variant, NAT (N-acetyltransferase) drug conjugating enzyme, Acetylate (Slow acetylators have less of the enzyme)

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Procainamide

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Conjugating Enzyme Variant, NAT (N-acetyltransferase) drug conjugating enzyme, Acetylate (Slow acetylators have less of the enzyme)

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Isoniazid

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Conjugating Enzyme Variant, NAT (N-acetyltransferase) drug conjugating enzyme, Acetylate (Slow acetylators have less of the enzyme)

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Salicylates

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Gender-dependent differences in metabolism may exist