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Pharmacology:

 the science that deals with interactions of chemical substances with living cells, tissues, and organisms.

2 main subdivisions:

1) Pharmacokinetics
2) Pharmacodynamics
Pharmacokinetics

Concerned with the processes that determine the concentration of drugs in the body fluids and tissues over time.
Drug absorption, distribution, biotransformation
Pharmacodynamics
The actiosn of drugs on target tissues
Concerned with biochemical mechanisms of drug's effects and the dose-response relationship

Drug metabolism and excretion

Metabolism and excretion contribute to ELIMINATION of drug from body
LIVER is the site for most major drug metabolism
Drug metabolism renders the drug more water soluble and allows it to be excreted from the body
Drug metabolites are eliminated through urine and bile. Urine is primary.
2 groups of enzymes that allows for drug metabolism:
Phase I oxidative and reductive enzymes (most enzymes are oxidative)
Phase II conjugative enzymes
Drug Biotransformation:
Drug --> Phase I Metabolism --> Phase I Metabolite --> Phase II Metabolism --> Phase II Metabolite
Phase I may increase, decrease, or unchange the drug's pharmacologic activity. Phase II usually causes a drug to be inactive, and some drugs may skip PI and go straight to PII.
Phase I oxidative and reductive enzymes:
Most cause drugs to undergo oxidation. Reduction is very rare.
Enzyme-substrate interaction unique
Cytochrome P450 superfamily consists of mixed fx oxidases. This accounts for most of the primary PHASE I enzyme involved in drug OXIDATION.
Cytochrome P450 Reaction: 
BASIC REACTION:
Drug +O2 + NADPH + H(+) --> Drug + (OH(-)) + H2O + NADP(+)

Cytochrome P450 Properties

-Found within Smooth ER
-Co-localized with NADPH-cytochrome p450 reductase
-Activity dependent on NADPH and O2
-Reactions catalyzed by CYP450 are ALIPHATIC HYDROXYLATION, N-DEALKYLATION, AND O-DEALKYLATION
-Has several different ISOFORMS
-Some drugs can be metabolized by a single isoform and some are metabolized by multiple isoforms

CYP3A4

the most common isoform (50%) involved with human drug metabolism. 

CYP2D6

is second most common isoform(30%)

Inhibition of CYP450 enzymes:

Inhibition mechanics:
-Simple competitive inhibition (reversible)
-Can involve 2 diff drugs competing for same catalytic binding site
-Can be tight but reversible binding of a drug to the iron of CYP450 (imidazole drugs like  ketoconazole and cimetidine)
-The irreversibility comes in the formation between the drug metabolite and CYP450 iron or the covalent modification of the enzyme itself.
Induction of CYP450:
Induction of enzymes also represents important cause of drug interaction
Induction caused by increased synthesis of new enzymes which increases transcription/translation or is due to the decreased proteolytic breakdown of the enzyme.
Phase II Conjugative Enzymes:
-These enzymes attach polar molecule to increase water solubility.
-Conjugation occurs after PI reactions (but not always, think INH)
-Several isoforms of enzymes exist
-There are 3 classes:
  1. Glucoronosyl transferases
  2. N-acetyltransferases
  3. Sulfotransferases and methyltransferases
Glucuronosyl transferases
- Enzymes that conjugate drugs with a molecule of glucuronic acid.
- New conjugate is more water soluble and is easily eliminated from body.
N-acetyltransferases
-Cytosilic enzymes catalyze addition of acetyl group to drug substrates (from Ac-CoA)
- Results in increase in H2O solubility and enhanced elimination of conjugate
- Sulfonamides (sulfa drugs)
Sulfotransferases 
-Metabolize drugs and endogenous compounds by adding sulfate groups. 
- 3'-phosphoadenosine 5'-phosphosulfate (PAPS)
-PAPS provides sulfate
Methyltransferases
- Catalyze the addition of methyl groups to drug substrates and other small endogenous molecules. 
- S-adenosyl-L-methionine (SAM)
Drug Excretion:
- Metabolism + Excretion = Elimination
- metabolized as well as unmetabolized can be subject to excretion.
Drug Excretion takes place where?
Major routes of excretion are renal and biliary.
Renal Excretion
Primary organ for removal of drugs from body. Renal function thus influences duration of action and pharm effects of drugs.
Three processes for Renal Excretion:
1) Glomerular filtration
2) tubular secretion
3) Tubular reabsorption
Glomerular Filtration
- about 130mL of plasma water filtered each minute (190L/day) across glomerular.
- Selective filtration occurs such that small molecules <5000MW is filtered. Larger ones are stuck.
Active Tubular Secretion
-there are two energy requiring secretory systems that are present in the proximal tubular cells of the renal nephron.
- one is for anions
- one is for cations
- active tubular secretion is a rapid mode of drug excretion.
- drugs are largely secreted renally by this mechanism have half life of <2 hours.
- active secretion not well developed in infants and the elderly.
Passive Diffusion
Represents important factor in urinary excretion. If not excreted, it can be reabsorbed by the body and reenters the bloodstream.
- tubular reabsorption of water increases the drug concentration in renal filtrate, leading to concentration gradient and passive reabsorption.
Passive Diffusion affected by 2 major factors:
-Lipophilicity:
lipo drugs undergo passive diffusion at higher rate due to lipid-lipid interaction of membranes.

-Charge:
uncharged drugs pass through lipid membrane much easier than those that have charge.
- drug metabolism minimizes reabsorption by making drugs more hydrophilic (polar)
Biliary Excretion
-1L of bile per day secreted by liver.
-un-ionizable compounds, cations, and anions are transported from the liver into the bile by 3 independent carrier mediated active transport systems
- the cation and anion transport systems are similar to the renal ones.
Biliary Excretion and Conjugation:
- favors compounds with >300MW.
- conjugation of Phase II leads to increased MW.
- Phase 2 conjugated drug metabolites are good for Biliary Excretion.
- conjugated drugs can be passively reabsorbed by the GI tract if hydrolized by bacterial enzymes. Process is called enterohepatic cycling.
Enterohepatic Cycling:
- when conjugated drugs passively reabsorbed by the GI tract via bacterial enzymes.
-occurs with drugs with adequate lipid solubility.
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