2
Nephron sites of action of diuretics
Osmotic DiureticsMannitol, urea, glycerine, isosorbideProperties of osmotic diuretics:
Freely filtrated by glomerulus Negligible tubular reabsorptionChemically inertUsually non metabolized
4
HO-C-H
HO-C-H
CH2OH
CH2OHH-C-OH
H-C-OH
--
--
-
Mannitol
Mechanism of ActionOD is filtrated and increases osmotic
pressure in tubular lumenHence, increases excretion of water
and electrolytes Almost all of electrolyte are
excreted: Na+, K+, Ca++, Mg++, HCO3-,
phosphate
5
Carbonic Anhydrase Inhibitor Acetazolamide, Dichlorphenamide, Metazolamide Mechanism of ActionsKidney:
Inhibition of Bicarbonate (HCO3-) reabsorption Reduces Na-H-exchange NaHCO3 is
excreted along w/ H2O Eye:
Inhibits formation of aqueous humor decreases intra ocular pressure
CNS: anti convulsive effects due to pH decrease direct effect
6
Synthesis of acetazolamide
Methazolamide
Dichlorphenamide
ThiazidesHydrochlorothiazide (HCT), Chlorothiazide,
Bendroflumethiazide, Chlorthalidone, Metolazone, Indapamide)
Mechanism of ActionsThiazides are secreted by proximal tubules but
works in distal convoluted tubulesInhibit Na+-Cl- symporter from the lumen to
tubular cells increase Na+, Cl- excretion (and water)
Some thiazides have weak CA-I effect
8
Effects on Electrolytes Increases Na+ and Cl- excretion K+ excretion also increase associated with
increased Na+ in distal tubules. Inhibits uric acid secretion hyper
uricemia and gout Decreases Ca2+ excretion (unknown
mechanism) tends to increase plasma Ca++ Delays osteoporotic process
Increases Mg2+ excretion
9
Loop DiureticsFurosemide, torasemide, bumetanide, ethacrynic
acidSite of action: thick ascending limb of
Henle.Mechanism:
Loop diuretics should be excreted into the lumen
Inhibits Na+, K+, 2Cl- symporter significantly increases the excretion of Na+, K+, Cl-
Osmotic gradient for water reabsorption is also decreased increasing water excretion
Ca2+ and Mg2+ are excreted as well.
10Furosemide
Bumetanide
Potassium Sparing Diuretics
1. Na+ channel inhibitor (Amiloride, triamterene)
Inhibit Na+ reabsorption Na+ excretion
Reduced K+ secretion K+ retention
2. Aldosterone antagonist (Spironolactone, eplerenone)
Aldosterone induces the expression of Na/K- ATPase and Na+ channel
Spironolactone and eplerenone blocks aldosterone receptor reduces Na+ reabsorption and K+ secretion
11
Cardiovascular Drugs
MAJOR CLASSIFICATION :-
1. ANTI-HYPERTENSIVES2. CARDIAC GLYCOSIDES3. ANTI-ARRHYTHMIC DRUGS4. ANTI-ANGINAL
ANTI-HYPERTENSIVES:Classificationcentrally acting - -agonists, othersganglionic blocking agents-adrenergic blocking agents & -adrenergic blocking agentsangiotensin converting enzyme inhibitorsangiotensin antagonistspotassium channel "openers"calcium channel blockersnitrovasodilators & direct agentsinodilatorsdiuretics
survey
Direct Acting Agents (Vasodilators)Nitric OxideNitroprussideNitroglycerine & Organic Nitrates
Purines / Adenosine
Hydralazine
STRUCTURE OF VASODILATORS
Sodium Nitroprusside
Hydralazine Purine
ACE InhibitorsAngiotensinogen
renin
Angiotensin I Bradykinin
ACE
Angiotensin II inactive fragments
Angiotensin III
ACE InhibitorsCaptopril – active with active metabolites
Enalapril – prodrug via hepatic metabolism
Linisopril – active , renal excretion
Ramipril – prodrug via hepatic metabolism
to diacid moiety
Captopril Enalapril
Lisinopril Ramipril
STRUCTURE OF ACE INHIBITORS
Potassium Channel OpenersMinoxidilDiazoxidePinacidil
ATP dependent K+ channelmembrane hyperpolarisation and relaxation
Minoxidil DiazoxidePinacidil
-Adrenergic BlockersPhenyoxybenzaminePhentolaminePrazosinTrimazosin, Doxazosin
dual & -adrenergic blocking agentsLabetalolCarvedilol
Calcium Channel BlockersVerapamil
Nimodipine, Nifedipine, Nicardipine
Amlodipine
Felodipine
Diltiazem
Verapamil Nimodipine
Nicardipine
Amlodipine
Diltiazem
STRUCTURES
Chemical classes & Actions of calcium channel blockers
phenylalkylamines - verapamil
act on inner phosphorylation gate of Ca channel
benzothiazepines - diltiazem
Mechanism unclear
dihydropyridines - nifedipine
act on outer gate of calcium channel
-adrenergic agonistsInclude:
AdrenalineNoradrenalineIsoprenalineDopamineDobutamineDopexamine
Structure of Beta- adrenergic agonists
AdrenalineIsoprenaline
Dopamine Dobutamine
Dopexamine
Cardiac Glycosidescombination of an aglycone, or genin,
with 1-4 sugar moleculespharmacological activity resides in the geninattached sugars modify the water/lipid solubility
and potency of the glycosidegenins are related to the bile acids, steroids,
sex & adrenocortical hormones,cyclopentanoperhydrophenanthrene nucleusto which is attached an unsaturated lactone ring
at C17
all naturally occurring genins possessing a C14-OH
• Digitoxin• Gitoxin• Digoxin• Ouabain(strphanthin-G)• Thevetin
Cyclopentanoperhydro ring
ANTI-ARRHYTHMIC AGENTS:Arrhythmia
an arrhythmia is,an abnormality of the rate, regularity, or site
of origin of the cardiac impulse, or a disturbance in conduction that causes an
alteration of the normal sequence of activation of the atria and ventricles
these may arise from abnormal impulse generation, altered conduction, or both
Class-1 : quinidine,lignocaine, flecainide
Class-2 : propranolol,sotalol.Class-3 : amiodarone Class-4 : verapamil
Amiodaroneclass III antiarrhythmic agent effective
orally & IV in the treatment of ventricular and atrial arrhythmias
analogue of thyroid hormone200 mg tablet containing 75 mg of organic
iodineprolongs APD and ERP, of atrial, nodal and
ventricular tissuesexplains its broad spectrum of activity
decreases automaticity in the SA node by reducing the slow phase 4 depolarisation
Amiodarone
Flecainide
ANTICOAGULANT
AND
ANTIPLATELET DRUGS
Haemostasis is the arrest of blood loss from a
damaged vessel. This usually involves:
a. localized vasoconstriction
b. platelet adhesion and activation
c. blood coagulation.
Intrinsic pathway Extrinsic pathwayXII XIIa
XIaXI
IXCa2+
IXaPF-3Ca2+
VIII
XaCa2+
PF-3V
X X
IIICa2+
VIIa VII
Commonpathway
Prothrombin(factor II) Thrombin
XIII
XIIIaFibrinogen Fibrin
Stable fibrinpolymer
ANTICOAGULANTS
Two types of drugs are employed in
preventing blood coagulation, heparin and
the vitamin K antagonists.
Their mechanisms of action
differ, as do their clinical uses.
Heparin
Heparin is a rapidly- acting anticoagulant.
Heparin occurs normally complexed to
histamine in mast cells.
It is strongly acidic.
Mechanism of Action
Heparin increases activity of antithrombin III
which inhibits activated serine proteases
such as IIa (thrombin) IXa, Xa, XIa, XIIa
and XIIIa, in the clotting cascade.
Therapeutic uses preoperative prophylaxis against deep
vein thrombosis
in acute myocardial infarction
to prevent pulmonary embolism in patients
with established thrombosis
to prevent clotting in extracorporeal
circulation devices.
Warfarin
Warfarin is a coumarin derivative.
Another example is dicoumarol.
These anticoagulants act by antagonizing
Vit K which is essential for the synthesis
of a number of clotting factors including
Factors II, VII, IX.
Adverse effects
bleeding
hemorrhagic infarction in the
breast, intestine and fatty tissues
crosses placenta.
ANTIPLATELET DRUGSThese include:
1. Cyclooxygenase inhibitors – aspirin etc
They are used in unstable angina and
myocardial infarction
2. Inhibitors of ADP receptor activity – eg
ticlopidine, clopidogrel.
3. Ticlopidine
4. Dextran
Clopidogrel
Ticlopidine
BIBLIOGRAPHY:-
HKS & V.K.Kapoor – Medical & pharmaceutical chemistry 2nd edition reprint.
Ashutoshkar- Medicinal Chemistry- 4th edition.
Wilson & Gisvold.Google.comWikipedia.comScience Direct
SOUMYAKANTA MISHRA0281961106 (Roll no.)8 th semesterM.S.I.P
SYNTHESIS
SYNTHESIS OF ACETAZOLAMIDE
CONVERSION OF L-MANNITOL
SYNTHESIS OF UREA
2NH3 + CO2 NH2COONH4 ammonium carbamate
NH2COONH4 NH2CONH2 + H2O urea
Survey
SURVEY
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