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
Give a brief description of the enterohepatic circulation of bile acids
Bile acids from liver or gallbladder are secreted into the duodenum (role in fat absorption)
95% is reabsorbed into blood from the terminal ileum and 5% is lost in faeces
Reabsorbed bile acids are carried back to the liver via the portal vein, taken into hepatocytes and secreted again in new bile (6-8 times a day)
List the major functions of bile
Emulsification of fats for digestion and absorption
With pancreatic juice, it neutralises chyme entering the duodenum and aids digestive enzymes
Elimination of waste products e.g. bilirubin and cholesterol, in the blood
What happens to the products of RBC haemolysis?
Globin is broken down into its constituent amino acids which are reused for protein synthesis
Haem is broken down into iron and biliverdin
Iron is returned to bone marrow via transferrin to be recycled into new RBC
Biliverdin is converted into bilirubin and eliminated
How is bilirubin eliminated?
Unconjugated bilirubin is transported by albumin to the liver where it is conjugated with glucuronic acid via uridine glucuronyl transferase making it water soluble
Conjugated bilirubin is secreted into the small intestine where it is converted into urobilinogen or stercobilin (giving faeces its brown colour)
Urobilinogen can be reabsorbed into the blood and excreted in the kidneys as urobilin (giving urine its yellow colour)
What is jaundice?
Yellow discolouration of the skin, eyes (scleral icterus) and mucous membranes due to excess quantities of conjugated and/or unconjugated bilirubin in the ECF
List a few causes of pre-hepatic jaundice
Haemolytic anaemia
Neonatal jaundice
List a few causes of intra-hepatic jaundice
Cirrhosis Hepatitis Hepatocyte damage from drugs Gilberts syndrome Critter-Najjar syndrome
List a few causes of post-hepatic syndrome
Obstruction of bile flow due to gallstones, pancreatic or cholangio-carcinoma
Dublin-Johnson syndrome
What is used to treat neonatal jaundice and how does it work?
Light therapy through the isomerisation of bilirubin, converting it into water-soluble compounds that can be excreted via urine and stools
What are the 4 ways the liver metabolises carbohydrates?
Glycogenesis - storage of glucose in the form of glycogen
Glycogenolysis - breakdown of glycogen into glucose
Glycolysis - conversion of glucose into pyruvic acid
Gluconeogenesis - formation of glucose from non-carbohydrate sources e.g. triglycerides, lactic acid and amino acids
What is glycogenesis stimulated by?
Insulin from pancreatic beta cells
What is the chemical pathway of glycogenesis?
Glucose phosphorylated to G-6-P via hexokinase
Converted to G-1-P
Converted to uridine disphosphate glucose
Converted to glycogen
What is glycogenolysis stimulated by?
Glucagon from pancreatic alpha cells and adrenaline from the adrenal medulla
What is the chemical pathway for glycogenolysis?
Glycogen phosphorylated to G-1-P via phosphorylase
Converted to G-6-P
Converted to glucose via phosphatase
What is gluconeogenesis stimulated by?
Cortisol and glucagon
Give a brief overview of fat metabolism in the liver
Triglycerides converted to acetyl-CoA which enters Krebs cycle to produce ATP via oxidative phosphorylation
Synthesis of lipoproteins
Excess carbohydrates and proteins converted into fatty acids and triglycerides, then stored as adipose tissue
Synthesis of steroid hormones and bile salts from cholesterol
What is the liver’s function in nitrogen metabolism?
Deamination and transamination of amino acids aids conversion of its non-nitrogenous part to glucose and lipids
This results in accumulation of ammonia which is directed to the urea cycle
Urea is then excreted via urine
List a few proteins produced by the liver
Albumin, transferrin, globulins, lipoproteins, alpha-fetoprotein, complement cascade proteins i.e. acute phase proteins
List a few substances that the liver is involved in the detoxification of
Bilirubin
Ammonia
Hormones e.g. all steroid hormones (androgens, oestrogens, cortisol, aldosterone, thyroxine) which are inactivated by conjugation and excretion
Drugs and exogenous toxins e.g. aspirin, paracetamol, ethanol
Outline the two phases of alcohol metabolism
Phase I - ethanol converted to acetaldehyde (hepatotoxic) via alcohol dehydrogenase
Phase II - acetaldehyde converted to acetate via acetaldehyde dehydrogenase (ALDH2)
What are the consequences of chronic ethanol consumption?
Ketosis Hypoglycaemia Hypertriglyceridemia Hyperuricaemia Insulin resistance Mitochondrial inhibition of oxidative phosphorylation
What are the stages of alcohol-induced liver damage?
Fatty liver (steatosis) - deposits of fat cause hepatomegaly Liver fibrosis - acute/chronic hepatitis and formation of scar tissue Cirrhosis - growth of connective tissue and destruction of hepatocytes due to severe liver injury from excessive alcohol intake, chronic hepatitis B/C infection, intake of chemicals or poisons, excessive iron or copper, bile duct obstruction
Which coagulation factors does the liver synthesise?
Vitamin K dependent factors II, VII, IX and X
Which substances does the liver store?
Hepatocytes and stellate cells store vitamin D, K, E and A
Large stores of vitamin B12 (enough for 2-3 years)
Folate
Iron as ferritin
Which part of the liver acinus is most prone to hypoxia?
Zone 3 as its closest to the terminal hepatic venue, this also makes it most likely to be damaged by drug toxicity or back-pressure from the liver. Fatty change also occurs here first.
List the endocrine organs
Pineal, hypothalamus, pituitary, thyroid, parathyroid, thymus, adrenals, pancreas, ovary and testes
Define autocrine signalling
Hormone produced by the cell that has an effect on the cell that secreted it
Define paracrine signalling
Hormone released by a cell which acts upon cells within the gland’s immediate vicinity
Define endocrine signalling
Hormones released by glands have distant target cells and travel to them via the circulation
What are the 3 major types of hormones?
Peptide (act at surface receptors)
Steroid (act at nuclear receptors)
Amino acid derivatives (act at both)
What are the main differences between the nervous and endocrine systems?
Ectodermal vs mesodermal origin
Physical continuity needed to send electrical signals via nerves vs transmission of chemical signals via body fluids
Defined arcades of interaction vs interaction through the generalised circulation
Transmission time is seconds vs minutes to days
What are the two lobes of the pituitary gland called?
Anterior lobe (adenohypophysis) and posterior lobe (neurohypophysis)
Which major hormones are produced by the anterior pituitary lobe?
PRL (prolactin) LH (leutanising hormone) and FSH (follicle stimulating hormone) GH (growth hormone) ACTH (adrenocorticotropic hormone) TSH (thyroid stimulating hormone)
Which major hormones are produced by the posterior pituitary lobe?
ADH (anti-diuretic hormone) and oxytocin
Which hypothalamic hormones are involved in the regulation of pituitary hormones?
Gonadotropin releasing hormone (GRH) regulates LH and FSH
Growth hormone releasing hormone (GHRH) regulates GH
Thyrotropin releasing hormone (TRH) regulates TSH
Corticotrophin releasing hormone (CRH) regulates ACTH
Which tumours of the anterior pituitary can cause syndromes of hormone excess?
GH tumour can cause acromegaly
ACTH tumour can cause Cushing’s disease
TSH tumour can cause secondary thyrotoxicosis
LH/FSH presents as non-functioning pituitary tumour
PRL presents as prolactinoma
