Pharmacology: Therapy for Pesticide and Drug Poisoning and Drug Metabolism

Question 1

Properties of chlorinated aromatic hydrocarbons (CAH) (4)

Answer 1

• Lipophilic compounds- stored in body fat and accumulate in food chains
• Cross blood-brain barrier (affects CNS)
• Cross placenta- accumulate in placenta/fetus
• Secreted in milk

Question 2

Mechanism of toxicity for CAH (3)

Answer 2

• Dioxin and other CAH bind to arylhydrocarbon receptor –> enehanced transcription of neighboring genes
• Microsomal enzymes such as arylhydrocarbon hydroxylase are induced

Question 3

Treatment of CAH poisoning (8)

Answer 3

• Antidote: cholestyramine
  - orally administered. Increases fecal excretion of toxins
  - removes bile salts in intestine, blocking enterohepatic recirculation of toxin
  - directly binds to toxin
• Serial activated charcoal
• Supportive therapy and anticonvulsants

Question 4

Paraquat mechanism (6)

Answer 4

• Undergoes cyclic redox and induces generation of superoxide radicals from oxygen
• Superoxide –> more powerful oxidants which induce lipid peroxidation –> damage cell membrane and enzymes –> inflammation and proliferation of fibroblasts –> pulmonary fibrosis

Question 5

Paraquat treatment (7)

Answer 5

• Removal from alimentary tract by gastric lovage and activated charcoal
• Removal by hemodialysis and hemoperfusion
• Serial activated charcoal
  - Removes paraquat subjected to enterohepatic recirculation

Question 6

Anticoagulant rodenticides (types) (2)

Answer 6

Warfarin and Superwarfarin

Question 7

Treatment of warfarin poisoning (8)

Answer 7

• Antidoe: Vitamin K overcomes warfarin’s competition
• Fresh frozen plasma or factor IX replaces clotting factors
• Activated charcoal (removes warfarin from gut)
• Cholestyramine (blocks enterohepatic recirculation)

Question 8

Warfarin is inactivated by

Answer 8

cytochrome P450

Question 9

Methods of removing toxic agents from body (2)

Answer 9

• Hemodialysis

- Activated charcoal

Question 10

Biotransformation

Answer 10

To inactivate and detoxify drugs and other foreign compounds that may cause harm to the body

Question 11

First pass biotransformation (2)

Answer 11

• Drugs absorbed from gut reach liver via hepatic portal vein and enter systemic circulation
• Many drugs are converted to inactive metabolites during first pass through interstinal mucosa and liver
• phase 1 rxns create or unmask a chemical group required for phase 2 rxns

Question 12

Chemical reactions catalyzed by cytochrome P450

(4)

Answer 12

• Oxidation
• Hydroxylation
• Dealkylation
• Deamination

Question 13

Drugs inhibit CYP by two mechanisms:

Answer 13

• Competitive inhibition

- Suicide inactivation

Question 14

Suicide inactivation

Answer 14

• Inhibitor drug is itself metabolized by enzyme to a reactive form that binds covalently to enzyme and irreversibly inactivates enzyme

Question 15

Glucoronidation

Answer 15

Renders new conjugate more water soluble = more easily eliminated

Question 16

Sulfation

Answer 16

Sulfotransferases catalyze transfer of sulfate to hydroxyl group of drugs

Question 17

Acetylation (3)

Answer 17

• N-acetyltransferases catalyze conjugation of moiety from acetyl coenzyme A to drug
• Acetylated metabolites are less water soluble than parent drug –> crystalluria

Question 18

Drug metabolism in neonates and infants (3)

Answer 18

• Overall rate of biotransformation of most drugs is lower in neonates and infants than adults
• Oxidative reactions and glucuronate conjugation occur at lower rate in neonates
• Sulfate conjugation is well developed in neonates

Question 19

Drug metabolism in children (4)

Answer 19

• Phase I enzymes reach adult levels by 6 months of age
• Phase II enzymes reach adult levels between 3-6 months of age
• Drug clearance greatly increases/exceeds adult levels between ages of 2 and 12, so half-lives are shorter in children and dosing requirements are greater than for adults

Question 20

Drug metabolism in elderly patients (2)

Answer 20

• Elderly adults have reduced capacity to metabolize drugs
• Biotransformation via oxidative reactions declines more than biotransformation via drug conjugation, so it is safer to use drugs that are conjugated in elderly patients

Question 21

Drug metabolism in hepatic and renal disease (3)

Answer 21

• Reduce capacity of liver and kidneys to biotransform and excrete drugs = reducing drug clearance
• Oxidative metabolism is impaired in patients with hepatic disease
• Conjugation processes are little affected

Question 22

Drug metabolism and heart failure

Answer 22

• Reduces drug biogransformation

Question 23

CAH: Acute poisoning (organs affected) (5)

Answer 23

• CNS
• Cardiac
• Liver and kidney damage
• Chloracne

Question 24

CAH: Chronic poisoning (3)

Answer 24

• Liver damage

- Hepatic porphyria due to increased activity of aminolevulinate synthase

Question 25

Dioxin

Answer 25

• Example of CAH
• Herbicides used as defoliants in Vietnam War
• Agent Orange

Question 26

Superwarfarin was created due to

Answer 26

A resistance in warfarin that was developed in rats

Question 27

Activated charcoal is effective in removing toxins subject to

Answer 27

Enterohepatic and enteroenteric recirculation

Question 28

Phase I metabolites vs Phase II

Answer 28

Phase I metabolites have parmacologic activity

Question 29

In phase II biotransformation, drug molecules undergo

Answer 29

Conjugation reactions with endogenous substrates

Question 30

Object drug

Answer 30

Action is altered by interaction

Question 31

Phase 1 bio transformation requires

Answer 31

Cytochrome p 450

Question 31

Precipitant drug

Answer 31

Causes the altered action