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Metabolism and Elimination
Drug Metabolism and Elimination
34
Pharmacology
Graduate
06/23/2010

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Term
First-order Kinetics
Definition
Rate of drug metabolism is directly proportional to free drug concentration

A FRACTION of the drug is metabolized per unit time
Term
Zero-order kinetics
Definition
the rate of drug metabolism remains constant

A CONSTANT amount of drug is metabolized per unit time

Ex: alcohol. only a shot metabolized per hour
Term
Phase I of P450
Definition
changes the parent drug by adding O, N, or S to make it more water soluble.

These drugs are then usually excreted by the kidney
Term
Phase II of P450
Definition
Takes water soluble chemical and links it to the parent drug to make it more water soluble

Does NOT use cytochrome system
Term
Drugs that stimulate the MFO system do so via..
Definition
Induction, which means an increase in enzyme synthesis

Include sedatives, tranquilizers, analgesics, some antihistamines
Term
Drugs that inhibit the MFO system do so via..
Definition
a decrease in the activity of existing enzyme

Include: the antihistamine cimetidine (tagamet); secobarbital (seconal; suicide inactivator)
Term
Name the 6 Conjugation Reactionsin Phase II of drug metabolism
Definition
Glucouronidation, Glutathione, Amino Acid, Sulfate, Acetylation, and Methylation
Term
What four steps are involved in acetaminophen metabolism?
Definition
1. oxidation
2. reactive intermediate
3. Glutathione Conjugation
4. Hepatic Cell Death
Term
Reactive Intermediate
Definition
Term
The First-Pass Effect occurs when there is a ....
Definition
High Extraction Ratio
Term
First-Pass Effect
Definition
Elimination of a large fraction of drug during first passage through the gut wall and then through the liver

Examples: nitroglycerin, propranolol, imipramine, acetylsalicylic acid
Term
What two steps are involved in the elimination of drugs and what organ(s) are included in each step?
Definition
1. Metabolism: liver
2. Excretion: kidney, liver (bile), lungs
Term
What are the three parts of renal excretion of drugs?
Definition
filtration, reabsorption, and secretion

reabsorption is through passive transport (tubule)

secretion involves active transport and is also in the tubule
Term
Glomerular Filtration Rate (GFR)
Definition
the percentage of blood cleared per unit of time (always labeled as something per minute)

Represents a clearance (Cl) of plasma
Term
What prevents drug filtration in the kidneys?
Definition
plasma protein binding and large molecular size

Ex: thyroxine is 99% bound
Term
Protein binding has no effect on what process that takes place in the kidneys?
Definition
Proximal Tubular Secretion (this involves active transport)
Term
In order to prevent the excretion of a weak acid (aka want to reabsorb it in the distal tubule) what should you do to the urine?
Definition
Make it more acidic
Term
In order to excrete a weak base, what should you do to the urine?
Definition
make the urine more acidic.

This will cause ionization of the weak base, it will not be passively reabsorbed, and will be secreted.
Term
What 5 things affect the transport of a drug in distal tubular reabsorption?
Definition
pH, concentration, size, lipid solubility, and ionization.

Distal Tubular Reabsorption involves passive transport
Term
Equation to determine the amount of blood cleared of a drug per minute?
Definition
GFR = 125 ml/min = clearance
Term
What is the normal renal blood flow?
Definition
650-700 ml/min

rate of urinary excretion depends on the renal blood flow
Term
What is the equation to determine clearance?
Definition
Cl (ml/min) = (drug in urine x Urinary Blood flow) / plasma drug concentration
Term
4 steps in the enterohepatic cycle
Definition
portal vein, liver, common bile duct, and small intestine
Term
What factors affect pulmonary excretion?
Definition
plasma solubility, cardiac output, respiration

The more cardiac output, the more blood is going through the lungs at a time
Term
Factors that affect increased toxicity and/or decreased effectiveness of a normal dose
Definition
age (renal and hepatic metabolism), renal disease, liver disease, drug interactions

liver makes the drugs more water soluble when it metabolizes them. The older you get, the less efficient your liver is at metabolizing.
Term
factors that indicate renal disease
Definition
1. excretion of an active drug is less than or equal to 50%
2. renal function drops below 50% normal adult value
3. drug has low therapeutic value
Term
clinical importance of liver disease
Definition
parenchymal liver disease, heptatic perfusion (cardiac failure, cirrhosis)

affects mainly those drugs with high extraction ratio
Term
Drugs that enhance liver metabolism via induction
Definition
*pheobarbital, phenytoin, phenylbutazone
Term
drugs that directly inhibit liver metabolism
Definition
*Cimetidine, carbidopa, MAOI, disulfiram
Term
Drugs that inhibit the renal tubular secretion of weak acids
Definition
*penicillin, salicylates
Term
Drugs that inhibit the renal tubular secretion of weak bases
Definition
*Cimetidine
Term
What affect does grapefruit juice have on certain drugs?
Definition
it inhibits first-pass elimination of drugs metabolized by certain CYP P450s
It inhibits cytochromes which causes drug potency to be accentuated
include CYP 34A, 1A2, and 2A6
Term
Drugs that have interactions with grapefruit juice
Definition
Dihydropyridine Ca2+ channel blockers, cyclosporine, midazolam, estrogens, and caffeine
Term
Plavix is metabolized by which cytochrome in the P450 cycle
Definition
CYP2C9
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