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Pharmacology: Hepatic Metabolism of Drugs - Coggle Diagram
Pharmacology: Hepatic Metabolism of Drugs
Metabolism
Sites
Liver (hepatocytes), kidney (proximal tubule epithelium), Lung (clara cells, type 2 pneumocytes), Intestine (epithelial lining), Skin (epithelial cells), Gut flora (rivals liver in metabolic capacity)
Definition
Results in less pharmacologically active product
Except
Metabolite is more active, more toxic, is carcinogenic
Processes
Enzymes metabolize drugs only since drugs resemble natural compound, and are principally designed for metabolism of endogenous compounds
Enzymes are designed for metabolism of endogenous compounds
Involves many pathways associated with synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids
Phase 1
Convert parent compound into more polar metabolite
Reactions
Oxidation
Oxygen is incorporated into the molecule
Form in vitro after cell homogenization and fractionation
MFO: enzymes require a reducing agent and molecular oxygen
P450
Electron acceptor
Metabolizes certain drugs
Drug target this to inhibit metabolism of certain drugs
Phase 2
Glucuronidation
Most important phase 2 pathway for drugs and endogenous compounds
Products are conjugated then excreted in the bile
Sulfation
Major pathway for alcohols, amines and thiols
Acylation
Acetylation
Requires co-facotr acetyl-CoA, common for aromatic amines and sulfonamides
Fatty acied conjugation
Stearic and palmitic acids are conjugated to drug by esterification reaction
Other Conjugations
Amino Acid
Reacts with drugs by N-acetylation
Glutathione Conjugation
Assists with removal of potentially toxic compounds
Polymorphism
Enzyme differences within populations, variable affinity for substrate, consequences (variable effect and toxicity)
Receptor Theory
Agonists
Drugs or endogenous ligands for the receptor
Increasing concentrations of agonist will produce an increase in biological response
Antagonists
Block or reverse the effects of agonists
Competitive: Compete with agonist for receptor binding
Non-Competitive Antagonists: Bind to receptor at different site to prevent agonist binding
Inverse agonist: Trigger Negative response
Examples
Ethanol
Metabolism into acetate is the dangerous aspect
Provide medication that blunts the effects of alchol dehydrogenase and aldehyde dehydrogenase
Methanol
Metabolism of formate leads to blindness
Provision of ethanol competes with methanol and ethylene glycol
Acetaminophen
Metabolism to NAQPI leads to toxic compounds
Anything that increases NAQPI can lead to increased risk