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