Michelle Ramsay Flashcards
Define first pass metabolism
All drug doses absorbed from the GI tract are first delivered to the liver via the portal vein. A fraction of the drug is metabolised/filtered and only part of the drug circulates systematically. Therefore oral bioavailability of the drug is reduced.
What is zero order kinetics in relation to drug metabolism?
A constant amount of drug is eliminated per unit time. Rate of elimination is constant and is independent of the total drug concentration in the plasma because the elimination mechanisms are saturable.
What is first order kinetics in relation to drug metabolism?
Constant proportion of drug is eliminated per unit time. Rate of elimination is proportional to the amount of drug in the body i.e. the higher the concentration, the greater the amount of drug eliminated per unit time. Mechanism is not saturable.
Phase I liver metabolism - purpose and types of reactions involved
Makes drugs more polar/water soluble and may create a reactive site for phase II conjugation
Oxidation (cytochrome P450), reduction, hydrolysis (esterases or proteases)
What is the effect of phase I metabolism?
Inactivates the drug, produces an active metabolite (from prodrugs e.g. enalapril, clopidogrel) or produces a toxic metabolite (e.g. paracetamol)
Phase II liver metabolism - purpose and types of reactions involved
Conjugation of drugs with glucuronate (glucuronly transferase), acetate (N-acetyl transferase), sulphate, glutathione, amino acids - making drugs inert and water soluble for excretion
What is the process of normal paracetamol metabolism?
45-55% undergoes conjugation with glucuronide
20-30% undergoes conjugation with sulphate
Remainder undergoes metabolism to intermediate NAPQI (potentially hepatotoxic) then conjugation with glutathione
Resultant products are now water soluble and eliminated via urine
How is liver metabolism of paracetamol affected in overdose?
Phase II glucuronide, sulphate and glutathione pathways become saturated
Increased metabolism of paracetamol to NAPQI and depletion of glutathione means higher concentrations of free NAPQI causing hepatotoxic and nephrotoxic injury
What is the MOA of N-acetyl cysteine in paracetamol metabolism?
NAC acts as a precursor to glutathione production therefore replenishing it’s stores and conjugating free NAPQI to it’s inert and water soluble form for elimination in urine
Give examples of cytochrome P450 inhibitors
Erythromycin Ciproflaxin Sodium valproate Omeprazole Simvastatin Fluconazole/ketoconazole Isoniazid
Give examples of cytochrome P450 inducers
Carbamazepine Rifampicin Alcohol Phenytoin Greseofluvin Phenobarbitone Smoking
How can drugs be eliminated from the body?
Renal tract Faecal tract (via bile) Lungs (volatile gases e.g. inhaled general anaesthetics) Tears Sweat Breast milk
What are the mechanisms of renal drug elimination?
Glomerular filtration of drugs with MW <20,000
Active secretion via anion transporters - acidic drugs e.g. penicillin, salicylic acid, cephalosporins, furosemide
Active secretion via cation transporters - basic drugs e.g. amiloride, morphine, pethidine, quinine
Passive movement (and the reabsorption of lipid-soluble drugs)
How is the liver supplied with blood?
25% of arterial supply is from the hepatic artery
75% of blood supply is from the portal vein containing venous blood returning from the GI tract
How is blood drained from the liver?
Central veins of liver lobules drain into the hepatic vein and back to the inferior vena cava
Which major cells is the liver made up of?
Hepatocytes (60%) - metabolic functions Kupffer cells (30%) - phagocytosis Stellate cells - vitamin A storage and collagen release in response to injury Liver endothelium
Give a brief description of the vascular anatomy of a liver lobule
Hexagonal plates of hepatocytes arranged around a central vein with a triad of branches of the portal vein, hepatic artery and bile duct on each of the 6 corners. Blood enters the lobules via the hepatic artery and portal vein, flows through sinusoids lined be hepatocytes and drained into the central vein. There is also retrograde flow into the bile duct which carries bile to the gallbladder.
Give a brief description of flow of bile through the biliary system
Bile secreted by hepatocytes drains into bile ducts
Left or right hepatic ducts
Common hepatic/bile duct
Cystic duct for entry into gallbladder, duodenum or pancreatic duct (via Ampulla of Vater)
What is bile?
Greenish-yellow liquid consisting of water, electrolytes, bile acids, cholesterol, bilirubin and phospholipids
Where does bile come from?
Bile salts, cholesterol and other organic constituents are secreted by hepatocytes
Large quantities of water, sodium ions and bicarbonate ions are secreted by epithelial cells lining bile ducts (stimulated by hormone secretin)
What controls entry of bile into the duodenum?
Opening of the Sphincter of Odii
Where can gallstones form?
Anywhere along the biliary tract; left and right hepatic bile ducts, common hepatic duct, common bile duct, cystic duct, pancreatic duct, sphincter of Odii
How are bile acids formed?
Bile acids are derivatives of cholesterol and made in hepatocytes. Cholesterol is converted into primary bile acids = cholic acid or chenodeoxycholic acid = conjugated with glycine or taurine to make it more soluble and secreted into canaliculi where they exist as bile salts
Intestinal bacteria convert bile salts into secondary bile acids
