Cardiovascular System [CVS Drugs] [I] Anti-Hypertensive Drugs

Centrally Acting Peripherally Acting

2-agonists Sympathatic Depressants

1-Blockers -Blockers Amine Depletors

Ganglionic Blockers

Direct Vasodilators Angiotensin Antagonists [ACE Inhibitors & AT1Blockers] Ca Channel Blockers

Hypertension: Systolic>140 mm Hg, and/or diastolic > 90 mm Hg. Blood Pressure [B.P] = Cardiac Output [CO] x Peripheral Resistance [PR] Primary (Essential): unknown etiology. Secondary: renal, hormonal, cardiovascular. [i]Centrally acting sympatholytics

[Centrally acting 2 -agonists]

• M.O.A: Stimulation of 2-receptors   sympathetic flow of NE, E from the brain   B.P. • SAR At least one ortho lipophilic substituent: 1. Increase lipophilicity and activity---> increase CNS penetration. 2. Make the two rings non-coplanner.

if become CH2 the drug become alpha-1 agonist ---> Sympathomimetic (Reverse its action) X Guanidine is essential [cyclic or opened] N NH N H2 Hydrophobic Alpha 1 agonists ionic H-bond

N N HN HN 

[a] Cyclic Guanidine Clonidine [Catapress®] Tiamenidine Cl Cl N N NH NH S N N H H Cl Cl

Prototype of this class Isostere to clonidine

 They act on both 2-receptors & Imidazoline receptors [I1].  Imidazoline receptors also mediate the sympatho-inhibitory actions of imidazolines to lower blood pressure. Synthesis of Clonidine:

Moxonidine (Physiotens): Cl

N N

CH3 NH N N H OCH3

•New generation imidazoline I1-receptor agonist

•binds with much greater affinity to the imidazoline I1-receptor than to the α2-receptor. [b] -methyl dopa [Aldomet®]

HO CH3

HO CH2 C COOH

NH2

M.O.A: HO HO CH 3 Aromatic Amino Acid Decarboxylase CH3 HO CH C COOH 2 HO CH2 CH NH2 [ AAAD ] NH2 alpha-methyl dopa alpha-methyl dopamine (bioprecursor) Dopamine-B-Hydroxylase HO

CH3 alpha-methyl NE HO CH CH NH2 OH Alpha-methyl NE: acts as 1- false neurotransmitter with weak adrenergic activity.

2- Acts as 2-agoist   NE and E release. • Uses: • Used orally for moderate hypertension. Safe for pregnant women. • It's sparingly soluble in water [as it is present in zwitter ion form]. So, to be used by injection [if hypertensive crisis], we make -methyl ethyl dopate prodrug which is with free amino to from water soluble HCl salt  which is hydrolyzed in body to give -methyl dopa.

HO HO HO CH CH 3 Et-OH 3 HCl CH3 HO CH C COOH HO CH C COO 2 2 Et HO CH2 C COOH Et

NH2 NH2 NH + alpha-methyl dopa ethyl dopate ester 3 Cl- water soluble HCl salt [ii] Peripherally acting Sympatholytics [1] Ganglionic blockers

• They block nicotinic receptors at postsynaptic membrane of ganglia and prevent Ach induced depolarization  act on sympathetic & para- sympathetic systems. • Was used in neurosurgical operation to maintain low B.P. and in hypertensive crisis. • They are rarely used now as they are non-selective with many side effects.

CH H C 3 3 - N SO3 O S O  The only one used for certain neurosurgical N procedures.  Of short duration [advantage]. Trimetaphan Camsylate [2] Amine depletors

• M.O.A: peripheral 2-agonist & block reuptake & deplete NE stores. • S.E.→ orthostatic hypotension.

Guanethidine

NH

N CH2 CH2 NH C NH2 [3] Selective 1-blockers

Quinazolines Prazosin [Minipress®] Terazosin [Itrin®]

O O H3CO N H3CO N N N C N N C O O N N H CO H3CO 3 NH NH2 2

Contain tetrahydrofuran moiety   lipid solubility improve bioavailability and duration [taken once daily]. Doxazosin [Cardura®] O O H3CO N N N C O N H3CO

NH2

Contain 1,4-benzodioxan moiety   lipid solubility  improve bioavailability and duration [taken once daily] Used for BPH [Benign Prostatic Hypertrophy]& hypertension Side effects: SYNCOPE [postural hypotension as they inhibit vasoconstriction normally initiated by the baroreceptors upon postural change and the subsequent drop in pressure] especially after 1st dose [used at bed time], palpitation, dizziness.. Acyl moeity has great activity &greatly affect pharmacokinetic of the drug

O H3CO N N N C R N H3CO

NH2 Piperazine may be replaced by another heterocyclic ring 4-amino is Essential for alpha-1 affinity [4] Direct vasodilators • Drugs that act directly on arterial smooth muscles [without interference with autonomic innervation] • They are potent drugs used in emergency but with side effects as: – Reflex tachycardia: so, used with -blocker [as anti- arrhythmic agent]. – Na+ and water retention [stimulate renin release from kidney]: so used with diuretics. 1- Arterial Vasodilators: [acts by opening of K+ channels] Diazoxide Hydralazine [ Apresoline® ]

N CH3 NH NH2 fr ee hydrazino gp is Essential N + N Cl S Na N O O Used as Na salt [soluble] injection 1-hydrazinyl phthalazine Used in hypertension [emergency] Orally active drug It  insulin secretion, so : Diazoxide is administered orally in the management of hypoglycemia caused by hyperinsulinism associated with pancreatic or extrapancreatic malignancy in adults.

Assay of Hydralazine:

Depending on its reducing properties  titration with oxidizing agent as KIO3 [Andrew's method]

R-NH-NH2 + KIO3 + 2 HCl  R-OH + ICl + KCl + 2 H2O + N2

Minoxidil [ Hairback® Hair lotion& Regain®]

N

N

H2N N NH2

O

 Used in hypertension in patients unresponsive to other drugs. Orally active & long acting.  Cause hirsutism  used in Alopecia. Activation: [PRODRUG]

N N N N Sulftransferase H2N N NH2 H2N N NH2 inactive prodrug active form in man O O SO3 N-oxide is essential 2. Arterial and Venous Vasodilators: Na Nitroprusside • M.O.A: by metabolism  release NO  vasodilatation. [so, NO is essential for activity]. • Uses: in emergency I.V. infusion [inactive orally]  with rapid onset and short duration [most powerful vasodilator] • Side effects: • Release CN-  methemoglobinemia. • Metabolized to SCN-  hypothyroidism. -2 CN + CN [Na ]2 NC Fe CN .2 H2O ON CN [5] Angiotensin Antagonists

Renin Angiotensin Converting Enzyme Angiotensinogen Ang I Ang II [10 peptides] [ ACE ] [8 peptides ]

1. Vasopressor. 2. Stimulate Renin secretion, thus increase B.P. increase Na+ and water retention. [a] ACE inhibitors [Prils] • Major side effects: dry cough [due to  bradykinins]  so, contraindicated in asmatic patients. • This class is effective for diabetic patients [with nephropathy] • (-blocker   insulin release)

Glutamate [protonated]

Zn++ ACE [ metallo protein enzyme ] H (+)

binding to Zn++ Drug H-bond hydrophobic bond (-) ionic

So, the requirements for the ACE inhibitor drug is: Contain anionic site [ COO- ] Contain H-bond forming group [ C=O ] Contain SH, COO- or phosphinate group to react with Zn++. Contain hydrophobic moiety [if methyl as in captopril  S isomer is more active > R ] 1st Generation Captopril [Capoten®]

• The prototype of ACE I  used for severe essential & reno- vascular hypertension. • Disadvantages: Due to SH group  Rash and loss of taste. • It's rapidly inactivated by formation of disulfide bridge  short acting.

COOH N

O SH

CH3

1'-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]-L-proline 2nd Generation [with COOH 3rd Generation group]  Dicarboxylate] [with phsophinate] Enalapril [ Ezapril® ] Fosinopril [Monopril®]

HO O

Enalaprilate [active form] Phosphinate prodrug

HOOC O O H3C O O P C N N N O O H O COOH H3C CH3 O PRODRUG CH3

Advantages over captopril:  It binds to Zn++ by phosphinate 1. No SH group. group. 2. Phenethyl group is highly lipophilic,   It's a prodrug  Fosinoprilate binding to receptor and  activity. [it’s [active] taken ONCE daily].  Less active than dicarboxylate 3. Containing Alanine as second amino drugs. acid  Dipeptide  [better fitting to  Contain only one amino acid [as the enzyme]. captopril] [b] AT1 blockers [Sartans]: No dry cough

® Losartan [Cozaar ]

Losartan is a selective, competitive Angiotensin II receptor type 1 (AT1) receptor antagonist Irbesartan [Aprovel®]

like losartan, possesses the acidic tetrazole system, which most likely plays a role, similar to the acidic groups of angiotensin II, in binding to the angiotensin II receptor. RENIN INHIBITORS • Renin is a circulating enzyme that is secreted by the kidneys that participates in the renin–angiotensin system. It is responsible for cleaving angiotensinogen, which is produced in the liver, to angiotensin I. Angiontensin I is converted to angiotensin II, which plays an important role in regulating blood pressure. • Inhibitors of renin have usefulness in managing cardiovascular diseases such as hypertension and heart failure because of their ability in reducing the influence on the renin–angiotensin system through reduced biosynthesis of angiotensin II. • Aliskiren (Tekturna) is the first renin inhibitor approved by the FDA in 2007 for the management of hypertension. [6] β-Blockers

• Uses: antihypertensive, anti-arrythmic and anti-anginal & for glaucoma, pheochromocytoma, migraine prophylaxis. • Side effects: Some of these drugs exhibit intrinsic sympathomimetic activity [ISA], due to structural similarity to -agonists.

-agonists -blockers [without catechol moiety]

HO OH N.B: Non-selective -blockers: act on both 1 [in heart] & 2 [in bronchi] HO CH CH NH 2 2  not used for asmatic patients. Selective 1 –blockers: can be used for asmatic patients.

Norepinephrine aromatic system + ethanolamine moeity is Essential (act on  > ) * 2ry amino ---> protonated ---> ionic bond with receptor. * OH make H-bonding. * Aromatic system make hydrophobic bonding.

OH HO CH3 OH X CH CH2 NH R HO CH CH2 NH CH3 Y CH3

increase bulkiness, no X Epinephrine will increase (act on B>) OCH2 aryl ethanolamine afffintiy and activity aryl oxypropanolamine [R] HO [S] OH CH3 may be another ring or substituent : HO CH CH2 NH CH 1. ortho show no selectivity CH3 2. para increase selectivity.

Isoproterenol (act on ) [i] Aryl ethanolamine derivatives [ non-selective ] Labetalol Beta activity

O H2N OH H N CH3 HO

Alpha activity

It's non-selective -blocker + 1-bloker [due to bulky group on N]  3:1 With no reflex tachycardia. Used as racemic mixture of 4 isomers. Two of these isomers, the (S,S)- and (R,S)- are inactive. The third, the (S,R)-isomer, is a powerful α1 blocker. The fourth isomer, the (R,R)-isomer, is a mixed nonselective β blocker and selective β2 agonist. Sotalol OH CH 3 CH CH 2 NH CH CH3

H3C O2S HN

Non-selective -blocker, has additional antiarrhythmic properties and prolongs action potential duration through K channels blockade. [ii] Aryloxypropanolamine derivatives Non–selective drugs Propranolol [Inderal®] Nadolol

O N O N H H HO OH OH

HO

 With no ISA.  With membrane stabilizing (MS) effect  No ISA. in  doses [used as anti-arrhythmic  With 2 OH groups   lipophilicity  agent]. not pass BBB  no CNS side effects.  With  lipophilicity  dizziness and  Taken once daily [with affinity to the hallucination. receptor].  Metabolized to 4-hydroxy metabolite [active] Synthesis of propranolol Timolol Oxyprenolol O OH OH H H N O N CH3 O N CH N N 2 CH3 S O

 It's thiadiazole derivative used for glaucoma [ I.O.P].  It's an open chain analogue of  It's with  affinity due to t-butyl propranolol. group.  With ISA & MS properties.  S-configuration is more active. Selective drugs

Atenolol [Tenormin®] Esmolol

CH3 CH3 O N CH3 O N CH3 H H OH OH

O

NH2 O

O Amide [Para substitution] Ester prodrug Short acting drug [9 min.]  substituted  selective used in minor operations to  cardiac (without ISA) excitability. [7] Calcium Channel Blockers [CCBs]

• They may act on: • B.V.  anti-hypertensive. • Heart  anti-anginal or anti-arrhythmia [a] 1,4-Dihydropyridine derivatives SAR

o > m > p [as steric hinderance make two rings non-coplanar]

e-withdrawing gp [as Cl , NO2] X

ary group in no. 4 is essential [ should be non-coplanar ]

R -OOC COO-R R3 & R5 must be bulky 5 3 two ortho COO are essential to ensure non-coplanarity

R6 N R2 H if aromatized ; inactive R2 & R6 are small groups NOT essential but increase activity [so, keep away from light to avoid photodecomposition]

must be 2ry amine not 3ry

N.B : if R3 isn't like R5 ; the compound will be chiral [S>R]

Uses: Used for hypertension [act on B.V. not on heart due to their lipophilicity]. Nifedipine [Epilat®] Amlodipine [ Norvasc® ]

NO2 Cl H3C - OOC COO - CH3 H3COOC COO - C2H5

H3C N CH3 H3C N CH2 O CH2 CH2 NH2 H H

 Cl instead of NO2  NO photodecomposition.  The PROTOTYPE.  Ethyl ester instead of methyl    The main disadvantage is lipophilicity and  steric hindrance. photodecomposition  Amino ethoxy methyl group  (aromatization & reduction) lipophilicity [taken once daily] &  absorption. NO

H3C - OOC COO - CH3

H3C N CH3 Felodipine (Plendil)

Cl

Cl

H3COOC COOC2H5

H3C N CH3 H •A second-generation dihydropyridine channel blocker. •The drug is used in the treatment of angina and mild-to-moderate essential hypertension. •Felodipine, like most of the dihydropyridines, exhibits a high degree of protein binding and has a half-life ranging from 10 to 18 hours. Cardio-Selective CCBs

[b] Phenyl alkyl amines [c] Benzothiazepines Verapamil [Isoptin®] Deltiazem [Altiazem®]

d is the active form 3ry amino is fully ionized at physio logical pH [polar to act on heart] MeO H3C [trans is inactive] CH3 H MeO N OMe S H NC CH3 O CH3 OMe C N OH O O 3ry amino [50% as active metabolite] N H3C CH3  With central 3ry amine separated by 2-3 C from aryl moiety. Benzothiazepine derivative  With chiral C  2 isomers [levo more potent > dextro]. Selective to cardiac muscles  used mainly Long acting drug with high affinity to cardiac as anti-arrythmic agent. myocardial cells. [II] Anti-Anginal Drugs

• [i] Organic Nitrates & Nitrites [NO- releasers] • M.O.A:

• RONO2 + R'-SH [nitrate receptor in coronaries]  RSNO [thionitroso gp]  NO  activation of guanyl cyclase   cGMP  dephosphorylation of Myosin-P converting it to Myosin light chain which can't interact with actin  relaxation of smooth muscles  vasodilatation. • Side effects of Nitrates: • Rapid tolerance: due to consumption of tissue thiols. • Headache, reflex tachycardia & explosive properties.

[a] Rapid acting drugs : [Rapid onset, short duration and rapid 1st pass metabolism]  used in acute cases. Amyl nitrite [Isopentyl Glyceryl trinitrate nitrite]

H3C CH2 ONO2 CH CH2 CH2 ONO CH ONO2 H3C CH2 ONO2 Taken as sublingual tablets or transdermal patches Taken by inhalation in emergency [onset in 2 minutes] [onset in seconds] Redistribute coronary blood flow to

ischemic regions and  myocardial O2 demand. Synthesis of glyceryl trinitrate:

CH2 OH CH2 ONO2 3 HNO3 CH OH CH ONO2 o H2SO4 / 10 CH2 OH CH2 ONO2 [b] Slow acting drugs: [Used in chronic cases for prophylaxis and treatment]

Erythritol tetranitrate Isosorbide dinitrate [Dinitra®]

ONO2 ONO2 O 4 5 O2NO 1 6 ONO2 O O2NO 2 3

O2NO

By metabolism it gives Isosrobide-2- mononitrate & Isosorbide-5-mononitrate With 15 min. onset and 3 hrs duration [which is active] [ 5-nitro is used as a drug (Monomack®)] [ii] Miscellaneous Vasodilators Nicorandil Dipyridamole [Persantin®]

N OH H N N N N O NO2 HO N N OH O N N N

OH Used for prophylaxis from angina attack Dual M.O.A: [cause V.D.] & from cerebral ischemic  Nitrate compound  vasodilator. attacks [anti-platelets, as it inhibits  Act as K-channel activator  hyper- phosphodiestrase]. polarization  muscle relaxation  level of adenosine  coronary vasodilatation Synthesis of Nicorandil:

N N H2N N + H C OH OH NaNO / H 3 H 3 Nicorandil OH H SO O N 2 4 CH3 OH O O O Nicotinic acid Anti-Arrhythmic Drugs

There are 4 classes of anti-arrhythmic drugs:

Class I Na+ channel blockers -Blockers [indirect  in Ca++ influx]  E.g. Class II Propranolol Class III K+ channel blockers Class IV Ca++ channel blockers [I] Class I [Na+ channel blockers ] [Membrane stabilizing drugs] • M.O.A: • By blocking sodium channels   depolarization   duration of action potential  anti-arrhythmic action. • With membrane stabilizing effect  may be used as L.A.

Class Ia [moderate dissociation  moderate activity] Quinidine Procainamide Disopyramide

N O Et H N C NH CH CH N H3CO 2 2 2 NH2 * Et N HO CH2 O N  It’s the amide of procaine [local anesthetic].  The prototype drug.  By metabolism : N-  Used orally or I.V.  Present as d(+) isomer , if acetylation giving N-  It’s structurally similar to l(-) it’s called quinine [anti- acetyl procainamide anti-muscarinic drugs [ ] which is malarial]. Acecainide [with anti-muscarinic class III anti-arrhythmic agnet [K+ channel blocker] side effects as dry mouth, blurred

O O Et vision….]. H3C C HN C NH CH2 CH2 N  With –ve inotropic Et effect [used with caution if there’s congestive heart failure]. Class Ib [with rapid dissociation  least potent] Lidocaine [Xylocaine] Mexiletine [3] CH3 CH3 O Et CH3 [2] NH C CH2 N Prototype of class Ib O CH2 CH NH2 Et [1] CH3 CH3

 Used I.V. [NOT orally] due to first pass effect; see below] It can be taken orally due to:  Used as L.A [as procainamide]. 1. Ether linkage is more stable than  2-ortho methyl gps : essential that they amide linkage to hydrolysis. make steric hindrance to  hydrolysis of 2. Presence of 1ry amine  no N-de- amide. By metabolism : alkylation  no toxic metabolites.

CH3 3. Presence of -methyl group which O Et H make steric hindrance that  hydrolysis NH C CH2 N CH2 N Et Et of 1ry amine by MAO & also  CH3 N-deethyl derivative lipophilicity. Mono Ethyl Glycine Xylidide [MEGX] [weakly active ; causes Constipation & convulsion]

Class Ic [Benzamide derive.] [with very slow dissociation  most potent]: Encainide with bulky gp around amide [w?]

O

H3CO C NH

HC CH2 N

CH3 Class III Class III drugs : Potassium-channel blockers   duration of action potential.

Amiodarone [ Cordarone® ]

O

O C

I I Et

O CH2 CH2 N Et M.O.A : with class I [membrane stabilizing] , II [-blocking] & IV [CCB]. Side effects : 1. Very slow onset & very long duration [Hard drug]. It’s long acting drug due to protein binding. 2. Abnormal thyroid functions. Anti-Hyperlipidemic Drugs

• Lipids transported in blood stream as lipoproteins; VLDL, LDL, IDL, HDL. • Plasma cholesterol & its transporter LDL  Atherogenic potential. • IpCa [specific lipoprotein]   fibrinolytic activity  thrombosis.

[I] Drugs affecting lipoprotein catabolism Bile acid sequestrants [Anion Exchange Resin]

• M.O.A: • They exchange their anion with bile acid  binding with bile acid forming insoluble resin that is rapidly eliminated   bile acid in body. • To compensate  body stimulate cholesterol catabolism in liver [ uptake of cholesterol in blood by  LDL receptors]. * NOT absorbed  safe drugs. • Disadvantages: can’t be taken in patients with Homozygous Familial Lipoproteinemia [HFL]  -ve LDL receptor patients.

 Polymer of divinyl benzene + styrene + quaternary ammonium CH3

H2C CH2 CH 2 N CH3 compound. CH Cl- 3 n  The safest drug for hyperlipidemia. Cholestyramine [Questran®] [II] Drugs affect lipoprotein synthesis [i] Nicotinic acid & its derivatives • M.O.A: Inhibit lipolysis   release of free fatty acids & triglycerides from fatty tissues   synthesis of VLDL & LDL.

Nicotinic acid [Niacin] Acipimox

COOH N COOH

H C N N 3 O

 Taken in  dose [4 gm / day]   Nicotinic acid analogue [isosteric with short duration. replacement of pyridine ring with  If taken in small doses  act as pyrazine]. Of lower potency vit.B3.  With higher duration, less side effects. [ii] Fibrates [-aryl oxy isobutyric acid derivatives] [Clofibric acid derivatives]

• M.O.A: • [1]  VLDL catabolism [ hepatic lipase activity]   plasma triglycerides. [ main effect]. • [2] Inhibit incorporation of acetyl CoA into early step of cholesterol synthesis   cholesterol.

Phenoxy moeity is Essential

O COOH C alpha-aryl oxy isobutyric acid is Essential Y CH3 H3C

Bulky gp to increase lipophilicity & bioavailability acid is the active form ; but with low bioavailability ; so,

Ester prodrug separation from phenyl by 3C Clofibrate Etofibrate [Lipo-Merz®]

N O O

Cl O C COO - Et O C O C Cl C O H3C CH3 H3C CH3

 The Prototype of fibrates.  Di-ester prodrug; by hydrolysis it  Prodrug of clofibric acid to  gives Clofibric acid [ VLDL & LDL] + bioavailability. Nicotinic acid [ VLDL]  Disadvantage: viscous liquid.  Used ≠ all types of hyperlipidemia. Bezafibrate [Bezalip®] Gemfibrozil [Lopid®]

Cl 3 C spacer H CH3 N H3C C COOH O C COOH O O H3C CH3 CH3 H3C (3rd Generation)  NOT a Prodrug.  Atypical fibrate [3 C spacer].  With bulky lipophilic gp to   Not a prodrug. potency &  duration > clofibric   HDL also [advantage]. acid. [III] Statins [HMG CoA Reductase Inhibitors] • M.O.A.: By inhibition of synthesis of cholesterol   uptake of cholesterol from blood by  LDL receptors [so, statin inactive in HFL]. • Statins should contain 3,5-dihydroxy acid moiety to be active which is present either as; lactone ring [prodrug] or free.

Statins

H C 2 H C 3 1 3 HO COOH HMG CoA reductase HO COOH Acetyl CoA 3 Cholesterol O OH 4 3-Hydroxy-3-Methyl-Glutaryl CoA 5 Mevalonic acid S CoA [HMG CoA] [3,5-dihydroxy acid] 1st Generation Pravastatin Lovastatin Simvastatin [Zocor®] [Lipostat®]

O OH O OH methyl gp incrase activity OH Prototype HOOC O O HO O O CH3 O C CH CH CH O 2 3 O C C CH2 CH3 H H C CH 3 3 H3C CH3 O C C CH2 CH3 H3C CH3 decrease toxicity CH 3 CH3 Decalin nucleus OH

 Natural drug isolated  Semi-synthetic drug.  Semi-synthetic drug. from Asperigillus  Prodrug.  NOT a prodrug. fungi.  3 times more potent  OH:  hydrophilicity &  Prodrug. Homolog of Lovastatin.  toxicity. 2nd Generation ® ® Fluvastatin [Lescol XL ] Atorvastatin [Lipitor ]

HO COOH OH F

F N

N COOH OH OH NH O

Synthetic, with heterocycle + F + Isopropyl gp; they are not prodrugs. Rosuvastatin (Crestor)

• is one of the more recently introduced statins (3rd generation). • As with all statins, there is a concern of rhabdomyolysis and as such, the FDA has mandated that a warning about this side effect, as well as a kidney toxicity warning, be added to the product label.

Anti-Coagulants [i] Heparin [injectable anti-coagulants]

COO- CH2OSO3- O O O OH O OH O

OSO3- NHSO3- D-glucoronic acid D-glucosamine with sulfate ester bisulfite ester n

• Natural anti-coagulant; composed of mucopolysaccharide polysulfonic acid esters. • Not used orally [highly ionic + it’s sugar] & not taken I.M. [irritant make edema & hematoma]. • Only used I.V. or S.C. [rapid onset drug].

M.O.A. very slow rate Prothrombin + AT III Degraded Prothrombin [inactive] [natural anti-coagulant]

Rapid Prothrombin + AT III + Heparin Degraded Prothrombin

Antidote for Heparin [acidic] is Protamine Sulphate [which is basic in nature due to its basic arginine amino acid].

Heparinoids  Low-Molecular-Weight Heparins e.g. Enoxaparin (Clexane) which is derived from the intestinal mucosa of pigs. [ii] Oral anti-coagulants [Indirect acting Vit. K antagonists] M.O.A.: Role of vitamin K

O O COOH Carboxylase COOH C HC CH2 CH2 C HC CH2 CH COOH NH Vitamin K NH Thrombin Prothrombin [active] [inactive]

• By inhibition of activation of vitamin K  anti-coagulant effect. • They inhibit epoxide reductase & naphthaquinone reductase  making vitamin K always in inactive form: O OH O CH3 CH CH 3 reductase 3 NAD O R R NADH R O OH O vit K reduced vit K 2,3-epoxide (Naphthaquinone) (active coagulation factor) oxidized metabolite • N.B: • They are with slow onset due to presence of preformed coagulation factors  not used in emergency. • Their effect last for > one weak after stopping till liver can resynthesize active prothrombin. • In emergency start treatment with heparin + oral anti-coagulant; when effect of oral drug starts to appear  stop heparin.

[a] 4-Hydroxy coumarins SAR: 4-Hydorxy coumarin is essential +

Substitution on C3 [not essential but  lipid solubility   bioavailability] Dicoumarol Warfarin [Marevan®]

O OH OH C OH H2C CH3 CH

O O O O O O Slow onset – long duration – toxic Rapid onset – intermediate [obselet now] duration + non-toxic [b] 1,3-Indanediones Phenindione [Dindivan®] Anisindione [Miradone®]

increase lipophilicity O OCH3 O

H ionizable H must be present H ion izable H [must be present] O WHY? O

2-phenyl indan-1,3-dione 2-(4-methoxy phenyl) indan-1,3- dione More active + less toxic. With slower action than coumarins & more toxic Platelet Aggregation Inhibitors [PAIs]

• [i] COX- inhibitors: Aspirin [ TX synthesis] • [ii] Substances affect cAMP: Dipyridamole • [iii] Platelet Specific Receptor Antagonists • [Adenosine DiPhosphate Receptor  ADP- Antagonists] • M.O.A: • By inhibition of this receptor  which form fibrinogen bridges between platelets  anti- platelet effect.

Tetrahydro Thieno-Pyridine derivatives Ticlopidine [Ticlid ®] Clopidogrel [Plavix®]

Cl S Cl S N N

COO CH3

Both are prodrugs [should give active SH gp] : S S SH O N N N COOH R R R [active form]

Haemostatics [Anti-Fibrinolytics]

• Tranexamic acid [Kapron®]: • Used orally & I.V. COOH

H2N H2C COOH

CH2 NH2

Tranxemaic acid

Plasminogne activator Plasminogen Plasmin fibrin degradation [with Lysine amino acid] Cardiotonic Drugs

• They are drugs that  contractile forces of the heart [INOTROPIC] •  used in CHF [Congestive Heart Failure].

Steroidal drugs Non-steroidal drugs  1-agonists[as Dopamine & Dobutamine]  Cardiac glycosides [e.g.  PDEIs [Phospho Diesterase Digoxin] Inhibitors].  Ca channel opener. THANK YOU