Pharmacology

Front 1

Describe Phase 1 Detoxification

Back 1

– add or expose functional groups on parent molecules (-OH, -NH2, -SH)
– loss of pharmacologic activity
• sometimes increase activity, eg. prodrugs
– Located on smooth ER
– Mixed function oxidases monooxygenases, or microsomal oxidases, etc.
• Cytochrome P450 family (CYP)
– Drug interactions
» Inhibited
» Induction (gene expression)

Front 2

Describe Phase 2 Detoxification

Back 2

– Biosynthetic reactions
– covalent linkage (conjugations) with various molecules
• glucuronic acid, sulfate, glutathione, amino acids, acetate
– Mostly cytosolic localization
May precede phase1 reactions with some drugs

Front 3

Enzymes of Phase 1

Back 3

CYP1; CYP2A6; CYP2B6; CYP2C8; CYP2C9; CYP2C18; CYP2C19; CYP2D6; CYP2E1; CYP3A4; CYP3A5
Flavin monooxygenase; amine oxidases; dehydrogenations; reductions; hydrolyses

Front 4

Enzymes of Phase 2

Back 4

Glucuroniddation: UDP glucoronosyltransferase
2. Acetylation: N-acetyltransferase
3. Glutatione conjugation: GSH-S-tranderase
4. Glycine conjugation: Acyl-CoA glycine transferase
5. Sulfation: Sulfotransferase
6. Methylation: Transmethylases
7. Water conjugation: epoxide hydrolas

Front 5

Where does biotransformation occur?

Back 5

– Major:
• Liver - First Pass Metabolism for some oral drugs (via portal system)
– Minor:
• Kidneys
• GI tract
– GI first pass effect: clonazepam, chlorpromazine, lidocaine
– gastric acids: penicillin (pen G injected in Gluteus)
– digestive enzymes: insulin
– microorganisms
• Lungs
• Skin

Front 6

CYP1A2; CYP2A6; CYP2C9; CYP2E1; CYP3A4; Cofactors; modifications

Back 6

• Functional requirements:
– NADPH-cytochrome p450 reductase (Flavoprotein)
• NADPH (electron donor)
• flavin adenine dinucleotide (FAD)
• flavin mononucleotide (FMN)
– Cytochrome p450 hemoprotein
• must bind heme + iron for activity
molecular oxygen

Front 7

CYP3A4

Back 7

50% of drugs in PDR; general inducers (Barbiturates, Phenytoid, Rifampin, Griseofulvin, Carbamazepine); general inhibitors (grapefruit juice)

Front 8

CYP2C9

Back 8

Warfarin; General inducers (Barbiturates, Phenytoid, Rifampin, Griseofulvin, Carbamazepine)

Front 9

CYP2E1

Back 9

Acetaminophen; induced by ethanol

Front 10

Describe drug-drug interaction in CYP’s

Back 10

• Reversible inhibition of cyps:
– Cimetidine, ketoconazole, macrolides,
• Permanent inhibition (suicide inhibitors) drugs that when metabolized by enzyme form reactive intermediates that form covalent bonds with enzyme, inactivating it.
– Hormones: spironolactone, Grapefruit furanocoumarins, Clopidogrel, Ritonavir, Glitzone antidiabetic drugs
– Drug-drug interaction: less enzymes = ↑toxicity
*inducers promote tolerance/cross-tolerance
*inhibitors increase toxicity

Front 11

What determines drug tolerance?

Back 11

– range from 2 fold to 30 fold variation in drug disposition and effects
• Genetic Factors (Pharmacogenomics)
• Diet & Environment
• Age and Sex; Drugs metabolized at reduced rate during prepubertal period; Very young and elderly metabolize less; Males may metabolize faster (animal models)
• Drug-Drug Interactions
• Diseases: liver, cardiac, renal

Front 12

Examples of drug transport polymorphisms

Back 12

1. P-glycoprotein
2. Neurotransmitter transport
3. AA transport

Front 13

Polymorphisms of Phase 1 Reactions

Back 13

1. Decreased CYP2D6: (a) autosomal recessive; increases toxicity; (b) mephenytoin; truncation o fCYP2C19; poor metabolizers; autosomal recessive
2. Increased CYP2D6: autosomal recessive; reduced drug effects

Front 14

Polymorphisms of Phase 2 Reactions

Back 14

• ê n- acetylation
– Drugs: Isoniazid & Hydralazine
– slow metabolizers
= lupus erythematosus-like syndrome with hydralazine
= peripheral neuropathy with Isoniazid
– autosomal recessive trait

Front 15

Describe FDA approval

Back 15

In vitro studies
2. Human Clinical Trials
Phase 1: non-blind small study
Phase 2: single-blind small study
Phase 3: double-blind large multicenter study
3. Post Marketing Surveillance (Phase 4)

Front 16

Major types of gene mutations in liver enzymes

Back 16

1. insertions/deletions
2. single nucleotide changes

Front 17

Describe Pharmacogenetics

Back 17

Mutations in genes involved in drug metabolism and transport (pharmacokinetic) and drug action (pharmacodynamic) can produce individual variability in drug response and toxicity.
Pharmacodynamic – difference in target receptors or enzymes