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Jam.customer.netspace.net.auB. 20 Endocrine pharmacology
a. Describe the pharmacology of insulin preparations and their use.
51 amino-acid polypeptide composed of two chains linked by disulfide bonds synthesized by ß cells of the pancreas as proinsulin proinsulin is cleaved into insulin and C-protein before secretion endogenous production 1 unit/h plus 10-20 units/day after food synthetic preparations were formerly bovine or porcine, now recombinant controlled release preparations by complexing with zinc or protamine administered by subcutaneous injection for fast or slow-release preparations non-complexed preparations also administered IV by infusion metabolized by hydrolysis of the disulfide bonds in the liver and kidney 2α and 2ß subunits, binds to α unit, ß unit is a tyrosine kinase causes a cascade of protein phosphorylations activates GLUT 4 glucose uptake transporter in muscle and fat↑ synthesis of fat, proteins, glycogen (↓ breakdown)↑ K+ uptake↓ ketone production↑ growth hypersensitivity to components of insulin for type I diabetes as replacement therapy commonly basal long-acting plus short-acting boluses before meals perioperatively stabilized with infusion IV plus glucose and K+ type II diabetes with resistance to oral therapy generally normal glucose while fasting perioperatively without therapy b. Describe the pharmacodynamics and pharmacokinetics of the oral
hypoglycaemic agents with their clinical implications and side effects.
James Mitchell (December 24, 2003) uncertain mechanism of actionreduce fasting and post-prandial blood glucose bind receptors on ß cells ↓ K+ conductance, ↑ insulin release this effect is opposed by thiazide diuretics (↓ glucose tolerance) ↓ glucagon secretion (mechanism uncertain) sulfonamide allergy (rash, type I)flushing with alcohol use chlorpropamide: ↑ ADH release and effect c. Describe the mode of action and adverse effects of thyroid hormones and
T , thyroxine, 3,5,3´,5´-tetraiodothyronine synthesized in the colloid of the thyroid follicles reaction with tyrosine residues of thyroglobulin to form MIT and DITcondensation of MIT and DIT to form T and T (bound to thyroglobulin) hydrolysis of thyroglobulin to liberate MIT, DIT, T and T release of T (17%) and T (83%), deiodination of MIT and DIT activation of T to T in the periphery (1/ ) inactivation of T by conversion to rT 3,3´,5´-triiodothyronine (1/ ) highly protein-bound to TBG, TBPA and albumin (T 0.04% free, T 0.4% free) autoregulated by negative feedback of free concentration on TSH, TRH
binds to intracellular receptors (similar to steroid, vitamin A and D receptors)↑ RNA polymerase James Mitchell (December 24, 2003) ↑ Na+,K+ ATPase activity↑ mitochondrial activity ↑ metabolic rate↑ catecholamine responsiveness relevant only as toxic metabolites (e.g. nitroprusside), not used clinically contain -N-C=S moietyhigh oral bioavailability concentrated in thyroid, prolonging effect inhibit I organification, tyrosine coupling and peripheral deiodination can cause autoimmune syndromes and agranulocytosis iodideshigh dose I- cause inhibition of T release and deiodination non-selective ß-blockers reduce symptoms of hyperthyroidism (e.g. propranolol) d. Describe the glucocorticoid and mineralocorticoid activities of steroid drugs
and their adverse effects.
synthesized in the adrenal cortex from cholesterol in response to ACTH diurnal variation in levelscirculates 75% bound to CBG (an α -globulin) synthetic glucocorticoids are albumin-bound metabolism to cortisone in kidney (20%) which has 80% potency inactivation in liver to multiple metabolites some effects are too fast to be gene-mediated ↑ gluconeogenesis, glycogen synthesis↑ muscle catabolism, bone reabsorption↑ insulin synthesis, lipogenesis adrenal suppression by exogenous steroids James Mitchell (December 24, 2003) inhibit cyclooxygenase II, phospholipase A , IL-1 & 2 synthesis ↑ circulating neutrophils, ↓ other leukocytes↑ susceptibility to infection ↑ ICP (minor)↓ ACTH, TSH, FSHpsychosis, cataracts ↑ acid, pepsin secretion↑ fat absorption↓ Ca2+ absorption (oppose vitamin D) fetus speed maturation and surfactant production mineralocorticoid synthesized in the zona glomerulosa of the adrenal cortex details in Renal Physiology (1.D)exogenous analogue: fludrocortisone e. Describe the pharmacology of glucagon.
1 mg (100 U) glass ampoule with water for reconstitution synthesized by the α cells of the pancreas rapid hydrolysis in plasma and in the liver and kidney similar proteins synthesized by the gut including GLP which stimulates insulin release N-terminal binds specific cell-surface receptors↑ cAMP initiates cascade of protein dephosphorylation ↑ glycogenolysis, ketogenesis, gluconeogenesis ↑ insulin, catecholamine, calcitonin release James Mitchell (December 24, 2003) effect limited by hepatic glycogen stores ß-blocker poisoning with cardiac failure f. Describe the pharmacology of vasopressin and its analogues.
ADH nonapeptide hormone synthesized in supraoptic and paraventricular nuclei released from posterior pituitary neurones in response to hypotension (7-10% volume change → low pressure baroreceptors)↑ osmolarity (change of 1-2%) angiotensin IIsympathetic activity, stress drugs (chlorpropamide, barbiturates, carbamazepine, clofibrate) exogenous analogue DDVAP (1-desamino-8-D-arginine vasopressin) selective V agonist used for bleeding and anti-diuretic effect administered nasally, sc, IM and IVt1/ 20 min renal and hepatic hydrolysis of peptide and disulfide bonds ↓ collecting duct permeability to water (via ↑ cAMP) results in insertion of aquaporin 2 in membrane ↑ release of VIII and vWF (V -like receptors on endothelium) James Mitchell (December 24, 2003)
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