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Antihypertensive Agents

Antihypertensive Agents

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Published by: anaeshkl on Apr 07, 2012
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According to site of action
According to mechanism of action
According to usage during anaesthesiaDIURETIC AGENTS
hypertension control with diuretic-based pharmacotherapy results in better prevention of heartfailure than pressure reduction with other drugs
through depletion of body sodium stored, reduction of  blood volume +vasodilatation
depletion of body sodium stores and reduction in bloodvolume
sodium contributes to vascular resistance by increasingvessel stiffness and neural reactivity, possibly related toincreased sodium-calcium exchange with a resultantincrease in intracellular calcium
initially, reduced blood volume, reduced cardiac output,increased peripheral vascular resistance
after 6-8 weeks, cardiac output returns to normal, peripheral resistance declines
direct vasodilating effects
with vasodilatation, cardiac output is maintained or increased
indapamide, a non-thiazide sulfonamide diuretic has both diuretic and vasodilator activities
amiloride, inhibits smooth muscle responses tocontractile stimuli, probably though effects ontransmembrane and intracellular calcium movement thatare independent of its action on sodium excretion
selection of diuretics
mild to moderate hypertension
loop diuretics (frusemide)
severe hypertension, when multiple drugs with sodium-retaining properties are used
in renal insufficiency, when GFR is < 30-40ml/min
 blood pressure response continues to increase as doseincreases
Antihypertensive agents
 NC Hwang 2008
emerged from synthesis of more potent carbonicanhydrase, prototype is hydrochlorothiazide
all have an unsubstituted sulphonamide group
main site of effect is at distal convoluted tubules where10% of filtered NaCl is reabsorbed
mechanism of action
main effect
inhibition of NaCl transport predominantly inthe distal convoluted tubules by inhibition of  Na
symport (or transporter)
other effects
retention of carbonic anhydrase inhibitoryactivity -increased excretion of HCO
due to increased delivery of NaHCO
tocollecting tubule, increased luminal negativeelectrical potential -enhanced secretion of K 
and titratable acid (regulated by aldosterone)
competition with the secretion of uric acid -initial hyperuricaemia
reduction of the normal lumen-positive potential derived from K 
recycling across theapical membrane of the DCT, Ca
and Mg
are not driven out of the lumen by electricalforces hypomagnesaemia
lower intracellular Na
enhances basolateralmembrane Na
exchange increasingoverall reabsorption of Ca
in additon to activereabsorption of through apical membrane Ca
channel at DCT (regulated by parathyroidhormone)
rarely cause hypercalcemia but can unmask hypercalcemia due to other causes, e.g.hyperparathyroidism, carcinoma, sarcoidosis)
facilitation of the opening of Ca
channels in the pancreatic beta cells, causinghyperpolarization of these cells reducingglucose-evoked insulin secretion – hyperglycaemia
may be related to hypokalaemia ashyperglycaemia is partially reversible withcorrection of hypokalaemia
short-term thiazide usage raises cholesterol,triglycerides, and LDL, long-term usage is notnecessarily associated with significantalterations in lipid levels
degree of protein binding determines the contributionthat filtration makes to tubular delivery of thiazides
sulphonamides are organic acids and are secreted by theorganic acid secretory system
secretion inhibited by indomethacin and probenecid
compete with the secretion of uric acid, uricacid secretory rate may be reduced with initialhyperuricaemia
adverse effects
hyponatraemia, hypochloraemia, reduced extracellular fluid
hypokalaemia*, metabolic alkalosis, arrhythmia*,weakness, fatigability, parasthesia
hyperuricaemia*, gout
hypertriglyceridaemia*, hypercholesterolaemia
* associated with hydrochlorothiaxide > 25mg/day
drug interactions
quinidine (prolongation of QT interval leading to polymorphic ventricular tachycardia or torsade de pointes, due to hypokalaemia)
thiazides diminish the effects of 
anticoagulants, uricosuric agents,sulphonylureas, insulin
thiazides increase the effects of 
anaesthetics, diazoxides, digoxin, lithium, loopdiuretics, vitamin D
effect of thiazide diuretics decreased by
as action depends partly on production of  prostaglandin, effect can be inhibited by NSAIDs
 bile acid sequestrants (reduce reabsorption of thiazides), methanamines (alkalinization of urine)
risk of hypokalaemia increased by
amphotericin B and corticosteroids
Antihypertensive agents
 NC Hwang 2008
Loop diuretics
sulphonamide derivatives –frusemide, bumetanide,torsemide
 phenoxyacetic acid derivative –ethacrynic acid
main site of effect is at ascending loop of Henle where35% of filtered NaCl is reabsorbed
mechanism of action
main effect
selective inhibition of Na
transportsystem in the luminal membrane of the thick ascending limb of loop of Henle
other effects
inhibition of Na
uptake inhibits cotransport of  phosphate and other vital metabolites -hypophosphataemia
inhibition of Na
cotransporter,reduction of the normal lumen-positive potentialderived from K 
recycling, increase in Mg
excretion –hypomagnesaemia,hypocalcaemia
weak inhibitor of carbonic anhydrase activity -increased excretion of HCO
hypovolaemia associated enhanced uric acidreabsorption in proximal tubule – hyperuricaemia
increase urinary excretion of K 
and titratableacid due to increase delivery of Na
to distaltubule
inhibition of Cl
and Ca
influx in pancreatic beta cells reduces insulin release; and inhibitionof glucose transport in adipocytes –glucoseintolerance
alterations in the electrolyte composition of endolymph occurs most frequently with rapidintravenous administration, less frequently withoral administration -ototoxicity
higher incidence with ethacrynic acid
lowers HDL
sensitization to sulphonamide can result inautoimmune reaction –thrombocytopenia
adverse effects
hyponatraemia, hypochloraemia, reduced extracellular fluid, hypercalcaemia may occur with severe dehydration
hyperuricaemia, gout
hypokalaemia, metabolic alkalosis, arrhythmia(especially with digoxin), weakness, fatigability, parasthesia
increase plasma concentration of LDL cholesterol andtriglycerides, while decreasing HDL cholesterol
autoimmune reaction, bone marrow depression
gastrointestinal disturbances
severe Na
and volume depletion
sensitive to other sulphonamides for sulphonamide- based diuretics
hepatic cirrhosis
decreased secretion of the drug, in part becauseof the high serum aldosterone concentrationsleading to enhanced salt reabsorption at thecollecting ducts
drug interactions
aminoglycosides (augmentation of ototoxicity)
oral anticoagulant (increase activity)
digoxin (potentiate digoxin-induced arrhythmias)
increase plasma concentrations of lithium, propranolol
sulphonylureas (hyperglycaemia)
cisplatin (increased risk of diuretic-induced ototoxicity)
 NSAIDs (reduce diuretic response)
 probenecid (reduce transport into tubular lumen andhence diuretic response)
thiazide diuretics (synergism of diuretic activity)
Antihypertensive agents
 NC Hwang 2008

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