3 Medical Mathematics: Drug Metabolism (biotransformation) Flashcards Preview

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Flashcards in 3 Medical Mathematics: Drug Metabolism (biotransformation) Deck (26):

What is drug metabolism?

Is the chemical alteration of the drug molecule by the cells of the animal


What are the Results of biotransformation?

Change in physicochemical properties of the drug
• The metabolite is more water soluble, polar, and ionized
Change in pharmacological activity
• Bioinactivation or detoxification (most drugs)
• Bioactivation or lethal synthesis (few drugs)


What are Examples of biotransformation?

Active drug (aspirin) to active metabolite (salicylic acid)
Inactive drug (chloral hydrate) to active metabolite (trichloroethanol)
Nontoxic drug (parathion) to toxic metabolite (paroxon)


What are Sites of biotransformation?

• Smooth endoplasmic reticulum (microsomes)
• Hepatocyte cytoplasm, mitochondria, lysosomes, nuclear envelope, plasma membrane
Other tissues (the nervous tissue, kidney, GI tract, lungs, and skin)


Hepatic Metabolism

Enzymes lack specificity (e.g., Cytochrome P450, CYP450 “MFO”)
Enzymatic reactions are saturable reactions
Drugs can compete on the same enzyme
Enzymes can be induced or inhibited by drugs
Microsomal enzymes cause oxidation, reduction, hydrolysis and conjugation to glucuronic acid


Types of metabolic reactions

Phase I reactions (Oxidation, Reduction, and Hydrolysis)
Phase II reactions (synthetic) (Conjugation)


Phase I reactions (nonsynthetic)
• Oxidation

Microsomal (hydroxylation, deamination, dealkylation, desulfuration, sulfoxide formation)
Nonmicrosomal (cytosol or mitochondria)
Alcohol and aldehyde dehydrogenase (e.g., ethanol to acetaldehyde)
Xanthine oxidase (e.g., xanthine to uric acid)
Tyrosine hydroxylase (e.g., tyrosine to dopa)
Monoamine oxidase (e.g. metabolism of catecholamines and serotonin)
Oxidation is the most common biotransformation reaction


Phase I reactions (nonsynthetic)
• Reduction

Microsomal (e.g., nitro reduction of chloramphenciol)
Nonmicrosomal (e.g., aldehyde reduction of chloral hydrate)


Phase I reactions (nonsynthetic)
• Hydrolysis

Microsomal hydrolases
Nonmicrosomal hydrolases
» Esterases (e.g., acetylcholine, succinylcholine, procaine) » Amidases (e.g., procainamide)
» Peptidases (e.g., proinsulin)


Metabolites of phase I reactions are...

more or less water soluble, inactive, less active, or more active


Phase II reactions (conjugation)

Combination of a drug or its metabolite with an endogenous substance.
Occur with foreign compounds and endogenous chemicals.
Conjugation is to glucuronic acid, sulfuric acid, acetyl group, methyl group, glycine,
methionine and glutathione.
Conjugation to glucuronic acid is the most common conjugation reaction.
Glucuronidation is microsomal but all other conjugations are nonmicrosomal.
Conjugation is deficient in the neonate.
Metabolite conjugates are usually inactive and water-soluble.
Certain conjugation reactions may lead to formation of metabolites (acyl
glucuronidation of NSAID) that are hepatotoxic.


What Factors alter biotransformation?

Route of administration
Enzyme inducers
Enzyme inhibitors
Liver disease
Hepatic blood flow
Plasma protein binding
Distribution and storage
Diet and nutrition
Body temperature
Environmental factors


Describe Species as a factor affecting biotransformation

Cats are deficient in glucuronyl transferases for phenols and aromatic amines but they may be able to conjugate endogenous substrates such as steroids, thyroxine, and bilirubin.
Cats also are deficient in hydroxylation and dealkylation.
Dogs lack acetylating enzymes.
Ruminants have less plasma pseudocholinesterase than horses, dogs and cats.
Ruminants and horses have high levels of oxidative enzymes.
Pigs are deficient in sulfate conjugating enzymes.
Birds lack oxidative enzymes.
Fish have low levels of drug metabolizing enzymes.


Describe Individual as a factor affecting biotransformation

Certain individuals may by deficient or lack certain enzymes due to genetic differences


Describe Route of administration as a factor affecting biotransformation

First-pass effect for oral and intraperitoneal routes (and drugs administered through the
Lidocaine, propranolol and morphine are examples of extensive first-pass effect


Describe Enzyme inducers as a factor affecting biotransformation

Drugs that stimulate the liver to produce more metabolic enzymes.
Only microsomal enzymes are inducible by drugs.
Examples are phenobarbital, phenylbutazone, griseofulvin, rifampin and chlorinated hydrocarbon insecticides.
Enzyme induction is reversible.
Enzyme induction may lead to tolerance or drug-drug interactions.


Describe Enzyme inhibitors as a factor affecting biotransformation

Drugs that inhibit the liver to produce metabolic enzymes.
Examples are chloramphenicol, cimetidine and ketoconazole.
Enzyme inhibition may lead to drug-drug interactions.


Describe Distribution and storage as a factor affecting biotransformation

Decrease biotransformation


Describe Age as a factor affecting biotransformation

The newborn and geriatric patients may have less biotransformation than adults


Describe Sex as a factor affecting biotransformation

Examples of sex-dependent variations in drug metabolism in humans are ethanol, propranolol, benzodiazepines, and salicylates


Describe Diet and nutrition as a factor affecting biotransformation

Charcoal broiled foods are enzyme inducers (CYP1A) and grape fruit juice is an enzyme inhibitor (CYP3A)
Malnutrition and undernutrition may decrease biotransformation.
Nutrition plays an important role in the regulation of drug conjugates.


Describe Liver disease as a factor affecting biotransformation

May decrease liver enzymes


Describe Hepatic blood flow as a factor affecting biotransformation

May be decreased due to liver disease or drugs resulting in decreased biotransformation


Describe Plasma protein binding as a factor affecting biotransformation

Decreases biotransformation


Describe Body temperature as a factor affecting biotransformation

Hypothermia, shock or anesthesia may decrease biotransformation


Describe Environmental factors as a factor affecting biotransformation

Animals in the tropics may have less biotransformation than animals in temperate climate (e.g., trimethoprim in goats)

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