1. The Cardiovascular Drugs Professor of Medicinal Chemistry
بسم الله الرحمن الرحيم
The Cardiovascular Drugs By
Farghaly A. Omar (Ph.D)
Professor of Medicinal Chemistry

2. I. Antihypertensive Agents II. Antianginal Drugs III. Antiarrhythmics
Major Classes of CVDs
I. Antihypertensive Agents
II. Antianginal Drugs
III. Antiarrhythmics
IV. Cardiotonics
IV. Anticoagulants
V. Antihyperlipidimics 2

3. 1. Identify the mechanism of action of the known
Learning Objectives
Upon completion of this chapter the student should be able to:
1. Identify the mechanism of action of the known
classes of CVDs.
2. List SAR for the different classes of CVDs.
3. Identify clinically significant physicochemical and
pharmcokinetic properties of CVDs.
4. Discuss with chemical structure the clinically
significant metabolism of CVDs and how the
metabolism affect their activity profiles.
5. Discuss Synthesis & analysis of representative
examples of CVDs. 3

4. I. The Antihypertensive agents
Hypertension is one of the most commonly reported
important risk factors, since it is a potential for other
CV-disorders.
Blood Pressure (BP) is commonly expressed as both:
systolic (peak pressure at time of cardiac contraction)
and diastolic (minimum pressure at time of cardiac
relaxation).
WHO specification: systolic Diastolic
Normotensive < < 90
Mild Hypertension 140 – – 105
Moderate Hypertension 160 – – 109
Severe Hypertension 180 – – 119
Very severe Hypertension≥ ≥ 120

5. Classes of Antihypertensive Drugs
Diuretics
Sympathetic (adrenergic) drugs:
- β-blockers; α1-antagonists (azocine group);
centrally acting α2-agonists (Clonidine); methyldopa.
Direct Vasodilators: - Hydralazine; - Sodium
nitroprusside
Calcium channel blockers.
Drugs affecting the renin angiotensin system (RAS):
- Angiotensin converting enzyme inhibitors (ACEIs)
- Angiotensin II-antagonists.

6. 1. Diuretic Drugs
Diuretic: substance that promotes the excretion of urine
Therapeutic Uses
Edematous conditions: Congestive heart failure (CHF), nephrotic syndrome, and chronic liver disease.
Management of hypertension.
Target organ: Kideny (nephron) (Assignment topic 1)
Students are notified to review previously learned knowledge concerning the anatomical structure of the nephron and identify the physiology and functions of its segments.

7. Classes; Sites; & Mechanisms of Action
Site of Action
Mechanism of Action
1. Carbonic anhydrase
Ihibitors
Prox. Convoluted tubules
Inhibit. of renal carbonic anhydrase
2. Loop or high-
ceiling Diuretics
Thick ascend. limb TAL ( loop Henle)
Inhibition of the luminal Na+/K+ /2Cl- transport system
3. Thiazide &
Thiazide-like
Thick ascending limb ( loop Henle) and distal tubules
Inhibition of sodium chloride reabsorption
4. Pot-sparing
Diuretics
Distal tubule and collecting duct
Competit. inhibit. of aldosterone.
5. Osmotics
Proximal tubule
Loop of Henle
Collecting tubule
decrease Na & H2O reabsorption. Decrease medullary hypertonicity elevated urinary flow rate.
Classes; Sites; & Mechanisms of Action

8. 1. carbonic anhydrase inhibitors CAIs
MOA:
Blocking of carbonic acid formation within the proximal
convoluted tubule and distal tubular cells to limit the
number of H-atoms avalailble for exchange with sodium.
This promotes Sodium/water secretion.
Diuretic response is observed when > 99% of CA is inhibited
The acidic SO2NH2 bind strongly to CA (isostere to
carbonic acid).

9. Identify the structural features
Examples of CAIs
Acetazolamide
Methazolamide
Identify the structural features
(common & Variable)
Dorzolamide
(Azopt)
Brinzolamide
(Trusopt)

10. 1. carbonic anhydrase inhibitors
Acetazolamide vs. Methazolamide
N-(5-Sulfamoyl-1,3, 4-thiadiazol-2-yl)acetamide
Prototype; Developed from sulfonamides, after it was noticed that sulfanilamide caused metabolic
acidosis.
3. Dorzolamide vs. Brinzolamide
Identify the structural features?
Topically applied in the form of eye drops as an anti-glaucoma agent; used to lower increased intraocular pressure in open-angle glaucoma.
Therapeutic Uses
Urinary alkalinization; Metabolic alkalosis
Glaucoma: acetazolamide, dorzalamide
Acute mountain sickness

11. SAR

12. 2. LOOP DIURETICS High ceiling or Site 2 Diuretics
The organomercurial diuretics.
The 5-Sulfamoyl -2- or -3-aminobenzoic acid derivatives. (furosemide and bumetanide)
Phenoxyacetic acid derivatives as ethacrynic acid
Site 2: The Thick Ascending Limb (TAL) of Henle's loop
MOA:
They inhibit the Na+/K+/2Cl- cotransport system located on the luminal membrane of cells of the thick ascending limb of Henle’s loop.
This leads to significant loss of Na+ and Cl- along with Ca2+ and Mg2+.

13. Furosemide, (Lasix). Bumetanide. (Bumex)
The 5-Sulfamoyl-2- and -3-aminobenzoic acid derivatives
Furosemide, (Lasix).
4-Chloro-N-furfuryl-5-sulfamoyl anthranilic acid
Bumetanide. (Bumex)
Bumetanide is 40 times more
potent than furosemide

14. incompletely absorbed from intestine (60%). Bumetanide:
The main difference between the two substances is in bioavailability and pharmacodynamic potency.
Furosemide:
incompletely absorbed from intestine (60%).
Bumetanide:
Almost completely absorbed (80%) in GIT.
Bumetanide is currently under evaluation as a prospective antiepileptic drug.
In the brain, bumetanide blocks the NKCC1* cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this change makes the action of GABA more hyperpolarizing, which may be useful for treatment of neonatal seizures.
* NKCC1: Na-K-Cl cotransporter 1

15. Synthesis of Furosemide
Cl- or CF3-, phenoxy-, alkoxy-, anilino-, benzyl-, or benzoyl- group.
SAR:
furfuryl-, > benzyl-, > thienylmethyl
essential for optimal activity.
tetrazole,
sulfonamide

16. Phenoxyacetic acids, Ethacrynic Acid, (Edecrin®).
High-Ceiling diuretic for patients hypersensitive to Sulfamoyl containing drugs.
Optimal diuretic activity is achieved when:
1. An oxyacetic acid moiety is placed in the 1-position on the benzene ring.
2. A sulfhydryl-reactive acryloyl moiety is located para to the oxyacetic acid group,
3. Activating groups (Cl- or CH3-) occupy either the 3-position or the 2- and 3-positions.
4. Alkyl substituent of two- to four-carbon atoms in length occupy the position α to the carbonyl on the acryloyl moiety.

17. Thiazide and Thiazide-like Diuretics
Site 3 Diuretics;
Thiazide and Thiazide-like Diuretics
Chlorothiazide
6-Chloro-2H-1, 2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
Hydrochlorothiazide
(10x > Chlorothiazide
Manage excess fluid associated with congestive heart failure. It is also used as antihypertensive
MOA: inhibiting reabsorption of sodium (Na+) and chloride (Cl−) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl− transporter.

18. Saturation increases potency
SAR
Lipophilic substituent: potency and duration.
EWG: Cl-, Br-, CF3-, & NO2-
Small alkyl
as CH3.
Essential for activity
substitution of the 4-, 5-, or 8- position with an alkyl diminished diuretic activity,

19. Site 4: Diuretics, Potassium-sparing diuretics
Diuretics that increase sodium and chloride excretion,
without a concomitant increase in the urinary excretion
rate of potassium.
Classification:
1) Aldosterone antagonists (e.g. Spironolactone)
2) Direct-acting diuretics (e.g. Triamterene ; amiloride)
Properties and uses:
These agents are not potent diuretics when used alone
but, when combined with a thiazide - eg, Aldactizide
They reduce potassium loss, minimize alkalosis.
The onset of diuresis with combination therapy is much
more rapid than with spironolactone alone. 

20. 1) Aldosterone antagonists Spironolactone,(Aldactone).
Antidiuretic Hormone
Sod. & water retention
Binding to Mineralocorticoid
receptor in the late DCT & CD.
Spironolactone is metabolized to Canrenone which is an active aldosterone antagonist.
Q: Identify the similarities and difference between
the aldosterone agonists & antagonists?

21. Spironolactone Metabolites:
Active aldosterone antagonists
Canrenone
Q: Assign the medicinal chemistry relationship between
Spironolactone & Canrenone?

22. 2) Direct acting potasium-sparing diuretics
Triametrene(pKa = 6.2)
Amiloride (pKa = 8.7)
Aminopteridine derivative
Pyrazinolylguanidines Derivative
MOA:
Blocking Na+ channel in the late DCT & CD, through
binding negaticely charged regions within the channel.
The two drugs are weak organic bases.
The binding is pKa dependent:
Amiloride strong base is 100x> more potent than
Triameterene

23. R Generic Name 2. Antihypertensive Sympatholytic Drugs
2.1 Peripheral acting sympatholytics:
Mainly α1 –antagonists & β-blockers
Such drugs bind to adrenoreceptors blocking the
binding of epinephrine and hence preventing its
vasoconstricting effects .
R Generic Name
a) α1-Selective adrenergic blockers
Prazocin
Terazocin
Doxazocin

24. b) 1st Generation Nonselective β-blockers
Propranolol
Nadolol
Pindolol
c) 2nd Generation Selective β1-blockers
Atenolol
Acebutolol
d) 3rd Generation Nonselective α1/β1-blockers
Labetalol
Carvedilol

25. 2.2 Central acting Sympatholytics
Centrally acting sympatholytics block sympathetic
activity by binding to and activating centrally inhibitory
α2-adrenoreceptors (in the brain stem).
This binding reduces sympathetic output to the
Vasculature leading to vasodilatation.
Methyldopa
(Prodrug)
Clonidine
Review Q. How polar compds. Penetrate the BBB?
α-Methylnorepinephrine
False neurotransmitter

26. 3. CALCIUM CHANNEL BLOCKERS
Composite actions on cardiovascular system resulting in negative inotropic effect; vasodilatation.
Selective blockade of the slow inward in Ca2+ channel. This leads to electrochemical uncoupling in the contraction process of the heart.
Calcium channel blockers have been approved for management of hypertension, angina pectoris, and specific types of arrhythmias
Chemical classes:
These compounds have diverse chemical structures and can be grouped into four chemical classes, each of which produces a distinct pharmacologic profile:

27. MOA:
Binding to specific receptor sites located within the
Central α1 subunit of L-type slow channels (e.g. potential –
Dependent channels).
Potential dependent channels can exist in one of three
Conformations:
- Resting state (open): allows Ca2+ to enter.
- Inactive state : refractory to further depolarization.
Ca2+ channel blockers preferentially bind in either the
open or inactive state reducing Ca2+ flux.
Classes of Ca2+ channel Blockers:
1)1,4-dihydropyridines
2) phenylalkylamines
3) benzothiazepines
4) diaminopropanol ethers:

28. 1)1,4-dihydropyridines:
Nifedipine
2) phenylalkylamines:
Verapamil
3) benzothiazepines:
Diltiazem
4) diaminopropanol ethers: Bepridil

29. 1,4-Dihydropyridines (1,4-DHPs) Nifedipine:
The prototype of 1,4-DHPs
Antianginal & antihypertensive.
Chemically are secondary amines exist in equilibrium between ionized and unionized form at physiological pH.
3,5-Dimethyl 2,6-dimethyl-4-(2-chlorophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate.
Nifedipine
Amlodipine
Nimodipine

30. Synthesis of Nifedipine+
Assay of 1,4-Dihydropyridines (BP93):
Redox titration with cerric ammonium sulfate using ferroin as indicator untill the pink color is discharged.

31. SAR Phenyl ring nocoplanar Pharmacophore X: ortho; meta. EWG
C3; C5 Esters
Eseential
Identical or nonidentical
R3 & R4: alkyl amino alkyl.
Identical or non identical

32. 2) phenylalkylamines
Verapamil (Isoptin)
5-[(3,4-Dimethoxyphenylethyl)methylamino]-2-(3,4-dimethoxphenyl)-2-isopropylpentanenitrile
Tertiary amine that is almost ionized at physiological pH; water soluble; hence utilize the aqueous phase in the opened channel to reach their site of action.
It is more cardioselective than being vasoselective (coronary vasodilator and antiarrhythmic)
Marketed as racemic mixture; The levo form (-) is the most potent.

33. 3) benzothiazepines
Diltiazim
Antianginal and as antiarrhytmic.
It is highly lipid soluble.
it is absorbed rapidly and extensively
subjected to first-pass metabolism.
its bioavailability is only about 40%.
4) diaminopropanol ethers
Bepridil
It is a basic compound (pKa ~ 10) and is
primarily protonated at physiologic pH (7.4).
Its actions are not solely based on its
ability to block Ca2+ channels. Bepridil also blocks fast Na channels (good antiarrhythmic activity)

34. 1) Angiotensin-Converting Enzyme Inhibitors (ACEIs)
DRUG THERAPY AFFECTING THE RAS
Medicinal agents which can block either the synthesis of angiotensin II (ACEIs) or the binding of angiotensin II to its receptor (AT II antagonists) should attenuate the actions of this pathway.
Captopril is the firstly ACE Inhibitor approved 1981.
Fourteen years later, losartan was approved as the first angiotensin II receptor antagonist.
1) Angiotensin-Converting Enzyme Inhibitors (ACEIs)
Classified into three groups based on their chemical composition:
1.1) Sulfhydryl-containing inhibitors. Captopril
1.2) Dicarboxylate-containing inhibitors. Enalapril
1.3) Phosphonate-containing inhibitors. Fosinopril

35. THE RENIN-ANGIOTENSIN PATHWAY
The renin-angiotensin system is a complex, highly regulated pathway that is integral in the regulation of blood volume, electrolyte balance, and arterial blood pressure.
Renin
Angiotensinogen
(α1-globulin)
Angiotensin I (decapeptide)
ACE
Angiotensin II (octapeptide)
Vasoconstrictor
Aldosterone synthesis
Degrade bradykinin
Inactive Fragments
Angiotensinase

36. A model of ACE inhibitor binding.
Identify the possible types of binding of the illustrated Ligand with the biological target?
Suggest the essential
structural features for ACEIs?
ACE:
Contains anionic site.
two hydrophobic sites.
Hydrogen bonding site.
A zinc pocket.

37. 1.1) sulfhydryl-containing inhibitors:
CAPTOPRIL (Prototype of ACEIs)
(2S)-1-[(2S)-2-Methyl-3-sulphanylpropanoyl]pyrrolidine-2-carboxylic acid.
Identify the essential FGs and
Their binding types with ACE?
Orally active ACE inhibitors.
Solubility in water?,
in methylene chloride and in methanol.
Chemical class? Peptide type
It is short acting?
Several side effects:
- dry irritating cough and Skin rashes, due to
accumulation of bradykinin.
- It may also cause abnormal metallic taste

38. Synthesis of captopril:
ASSAY
Dissolve g in 30 ml of water. Titrate with 0.05 M iodine , determining the end-point potentiometrically.
1 ml of 0.05 M iodine is equivalent to mg of C9H15NO3S.
2RSH I2
R-S-S-H

39. 1.2) dicarboxylate-containing inhibitors:
Enalapril maleate:
Non-thiol ACEIs: maintains the ability to chelate zinc.
The free acid (enalaprilat) shows excellent intravenous activity, but it has very poor oral bioavailability.
Esterification of enalaprilat produced enalapril (prodrug), a compound with superior oral bioavailability.
Approximately 10-fold more potent than captopril. (Why?)
The enhanced binding was proposed to be due to a mimicking transition state of angiotensin I hydrolysis. The extra binding groups (COOH and NH) accommodate for the loss of potency by replacing the SH group for chelation with zinc.

40. 1.3) phosphonate-containing inhibitors:
fosinopril.
The phosphinic acid is capable of binding to ACE in
a manner similar to enalapril.
A model of ACE inhibitor binding.
ACE:
Contains anionic site.
two hydrophobic sites.
Hydrogen bonding site.
A zinc pocket.

41. Structure-activity Relationships
Essential features for ACE inhibitory activity:
The N-ring must contain a carboxylic acid (anionic/ cationic binding site) .
b. Large hydrophobic heterocyclic rings in the N-ring increase potency and alter pharmacokinetic parameters.
c. Groups A, B, or C serve as zinc binding groups.
d. The sulfhydryl group: Superior binding to zinc.
Can form disulfides which may shorten duration of action.
e. Esterification of the carboxylate or phosphinate produces an orally bioavailable prodrugs.

42. 2) ANGIOTENSIN II RECEPTOR ANTAGONISTS
Losartan:
Non-peptide angiotensin II receptor
antagonist. Orally active.
Substituted imidazole moiety; Biphenyl system; Tetrazole nucleus (acidic group).
2) Valsartan:
Named for the valine portion of the compound. The first non-imidazole Ag-II antagonist. Slightly more potent than losartan.
The amide carbonyl is isosteric with the imidazole nitrogen of losartan and can serve as a hydrogen bond acceptor similar to the imidazole nitrogen.

43. SAR: Essential structural features:
The “acidic group”: COOH; Tetrazole; Sulfonamide.
The tetrazole and carboxylate groups must be in the o- position for optimal activity (the tetrazole group is superior in terms of metabolic stability, lipophilicity, and oral bioavailability).
3) The n-butyl group of the model compound provides hydrophobic binding.
4) The imidazole ring, or an isosteric equivalent, is required..
5) Substitution with a variety of R groups including COOH, methyl alcohol, an ether, or an alkyl.

44. The Direct vasodilator
1) Hydralazine:
1-hydrazinophthalazine hydrochloride
has been used to treat mild to sever hypertension.
The exact mechanism is not completely clear, it is
supposed to interfere with Ca2+ stores or activate guanyl
cyclase.
2) Sodium nitroprusside:
Na2[Fe(CN)5NO]
Disodium pentacyanonitrosylferrate
mainly used as IV infusion in
hypertensive crisis.
Act by releasing NO.

45. Antianginal Drugs
Angina is the principle symptom of ischemic heart disease which may lead to myocardial infarction.
The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels.
The goal of antianginal drug therapy is to restore the balance between myocardial oxygen demand and supply.
Therapeutic Classes
Organic nitrates
Calcium channel blockers
3) β-blockers
4) Platelets aggregation inhibitors

46. Sites and action of antianginal drugs
Coronary
Blood flow
Heart Rate
2,3
1,2,4
2,3
O2 Supply
O2 Demand
Cardiac
Contractility =
1,2,3
Regional flow Distribution
Myocardial
Wall Tension
1,2,4

47. 1) The Organic nitrates:
The organic nitrates are simple nitrous or nitric acid esters of polyhydroxy alcohols.
- rapidly absorped.
- Sensitive to moisture.
- explosive. O
R-O-N=O R-O-N=O R-N=O
Nitrite Nitrate Nitro
Esters
MOA:
R’-S-N=O
R-S-N=O2
R’-SH
Esters
Nitric oxide
Free radical
NO
Glutathione
Interferes with phosphorylation of several proteins (Myocin)
Relaxation of smooth muscles

48. Mechanism of action
1- Release of Nitric oxide by hepatic organic nitrate reductase 48

49. General method for synthesis
Analysis:
RONO
Phenol-2,4-disulfonic acid
Yellow colored product

50. Classes:
Raipdly acting: for acute anginal attacks
1) Amyl nitrite (isopentyl nitrite); (Inhal. for emergency)
2) Glyceryl Trinitrate GTN (sublingual administration)
3) Isosorbide dinitrate (IDN) (sublingual administration).
Slowly acting compounds (prophylactic):
1) Pentaerythrytol tetranitrate
2) Isosorbide dinitrate (IDN);
3) Isosorbide mononitrate
Amyl nitrite
Glyceryl Trinitrate
Isosorbide Dinitrate
Pentaerythritol tetranitrate

51. Nicorandil Nicotinamide derivative Nitrate ester Dual mechanism:
- Nitrate compound (Vasodilator?
- Pot. Channel activator (Vascular SM relaxing effect

52. SAR:
1- The vasodilating effect is due to the released nitric oxide (NO). (Prodrugs?)
2- Conversion of nitrites and nitroso requires one electron. (nonenzymatic; rapid onset) R-O-N=O N=O [(CN)5Fe-N=O]2- (nitroprusside; vasodilator)
3- Nitrates conversion to N=O is enzymatic (mainly in the vascular wall).
4- Polynitrates e.g. GTN; IDN; IMN and PTN release only one N=O molecule.
5- Sublingual administration and duration of action!!

53. ANTIARRHYTHMIC DRUGS Classification: (mode of action)
1) Class I: membrane stabilizing agents. (IA; IB; IC); Fast Na+ channel blockers (quinidine; lidocaine; disopyramide; mexiletine; phenytoin; propaphenone)
2) Class II: -Adrenergic blocking agents (propranolol; atenolol).
3) Class III: Drugs that prolong the action potential: amiodarone; bretylium; sotalol
4) Class IV: Calcium channel blockers: Verapamil; diltiazem; Bepiridil

54. 1) Membrane stabilizing drugs:
1) Lidocaine hydrochloride
2-(Diethylamino)-2,6-acetoxylidide
For treatment of ventricular arrhythmia.
Its action based on membrane stabilization through blockade of fast Na+ channel.
Rapid onset after IV injection (Emergency). Short half-life:15–30min.
Not effective orally.
2) Tocainide:
α-methyl analogue
similar activity to lidocaine
but it is orally active.
T1/2 = 12 hours.

55. 3) Drugs that prolong the action potential
Amiodarone hydrochloride:
Structural features:
Benzofurane nucleus; Diiodophenyl moiety
Very slow onset; Long duration
Identity test: Dry heat test violet vapours (Iodine)
Sulfuric aid orange yellow color (benzofuran)

56. Cardiotonics
Drugs Used for treatment of congestive heart failure (CHF).
1.1) Cardiac Glycosides (cardiac steroids)
Important class of naturally occurring drugs.
Their action is cardiotonic that increase the contractile force and rate of the myocardial contraction (positive inotropic effect).
Mode of action
The enhancement of myocardial force of contraction resulted primarily from increased intracellular Ca2+.
How the calcium ions level increased in myocardial cells?

57. Chemistry of cardiac glycosides:
The molecule consists of two main parts:
A Steroidal Nucleus (non sugar part) - Aglycone
A sugar part 1 C B D A
cardinolide
D-glucose; D-digitoxose
Bufadienolide
Steroidal nucleus
A-B: cis; B-C: trans; C-D: Cis (U-shape).
Two angular methyl groups at C-10 and C-13
Two -hydroxyl groups at C-3 (sugar attachment) and C-14 (free)
17 lactone, The size and degree of unsaturation varies with the source of the glycosides: cardenolides; bufadenolides

58. cardinolides
Digoxin is widely used in the treatment of: Atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medications.
Digoxin
Digitoxin
Similar structure and effects to digoxin. The effects are longer-lasting?
it is eliminated via the liver, so could be used in patients with poor or erratic kidney function

59. free -hydroxyl group at C-14.
Structure Activity Relationship (SAR):
I- Cardiotonic steroids:
Steroidal nucleus: cis configuration at rings A/B and C/D.
Stereoselectivity
Unsaturated - Lactone structure at C-17.
Modification of the C-17substituent: Saturated -lactone analogues are Inactive. Inactive: -CH=CH-COOH; -CH=CH-CONH2; -CH=N-NH-CO-NH Active: CN; - CH=N-NH-CNH-NH2 (guanyl hydrazone)
free -hydroxyl group at C-14.
II- The sugar Moiety at C-3: (Pharmacokinetic)
No intrinsic activity;
The number of sugar units and the number of OH groups control the lipophilicity of cardiac glycoside.
2-Deoxysugars (Digitoxose) more lipophilic, but less stability.
Acetylation; methylation and esterification of the OH groups enhance the lipophilic properties

60. Non-steroidal cardiotonics:
PDE-III Inhibitors
1) Inamrinone:
5-Amino-(3,4/-bipyridine)-6-(1H)-one
Potent inotropic-vasodilator drug,
used for treatment of CHF cases which
are not responding to cardiac glycosides therapy or intolerant to these drugs.
Inamrinone used only parenterally since it cause GI diturbances.
2) Milrinone:
Similar pharamcological effects and acts by the same mechanism of Inamrinone, but is more safe; no side efects.

61. Mode of Action of PDE-III inhibitors
Phosphodiesterase III is responsible for the degradation of cAMP in myocardial cells and vascular smooth muscles.
This inhibition leads to elevated levels of cAMP, which through a complex chain of biochemical events leads to an increase in the intracellular Ca2+ and ultimately an increase in myocadiac muscle contractility.
. The inhibition based on structural and electronic similarity between the cyclic amidic moiety of the drug and the phosphate ester moiety in cAMP. .

62. Blood Affecting Drugs Antithrombotics
A class of Cardiovascular Drugs involving:
Antithrombotics 2) Thrombolytics.
Coagulants. 3) Plasma Extenders.
Antithrombotics
Drugs used for prevention of thrombus formation.
Not dissolve already formed thrombus.
Also known as Anticoagulants.
Thrombus is a clot adhered to the vascular wall.
Embolus is a free floating clot within the vasculature.
Clot formation proceeds through a series of consecutive
events known as Coagulation Cascade.

63. The Coagulation Cascade
a: activated factor
boxed factors affected
by heparin.
Circled factors affected
by oral anticoagulants

64. Therapeutic Applications of anticaogulants
Cardiac:
Acute Myocardial infarction (AMI)
Vascular heart disease.
Unstable angina.
Atrial fibrilation.
Cardiac surgical operations.
Vasculature:
Venous thrombo-
embolism
Arterial thrombo-
embolism.
Peripheral vascular diseases (pulmonary embolism; brain thrombus.
Therapeutic classes:
Parenteral anticoagulants: Heparin and the heparinoids
Oral anticoagulants: (Vit. K. antagonists) Warfarin;
anisindione.

65. 1) Oral Anticoagulants
Their anticoagulant action is based on inhibition of vit K
processing, which is required for the synthesis and
maturation of several clotting factors including
prothrombin.
they are slow acting, requiring days to have an effect.
1.1) Warfarin
4-hydroxycoumarin derivatives
available as sodium salt for oral use.
Slow onset of action and longer
duration. t1/2 = hours
(RS)-4-Hydroxy-3-(3-oxo-1-phenylbutyl)- 2H-chromen-2-one
MOA:  inhibiting vitamin K epoxide reductase enzyme that recycles oxidized vitamin K1 to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombinand factor VII.

66. The role of Vit. K in blood clotting process

67. Synthesis:
starts with condensation of o-hydroxy-acetophenone with ethyl carbonate to give the β-ketoester as intermediate.
Attack of the phenoxide on the ester grouping leads to cyclization and formation of the coumarin.
Conjugate addition of the anion from that product to methyl styryl ketone gives the corresponding Michael adduct and thus warfarin.

68. SAR of Coumarins:
Weakly acidic compounds, due to the 4-hydroxy substitution.
Available as water soluble sodium salts.
The coumarin ring bearing substituent at C-3 and C-4 is essential for activity.
Additional methoxy group at C-8 inreases the anticoagulant activity.
Warfarin has a chiral center (C-α) and exhibits stereoselective activity; S-enantiomer is 4 times more active than the R-form.

69. 1.2) Indandiones
Indan-1,3-diones are also lipophilic orally active anti-coagulants by virtue of their structural similarity to Vit. K.
1,3-Indandione
Phenindione
Anisindione
Indandiones characterized by acidic proton on C-2?.
Anisindione has longer duration than phenindione?
Analytically, these compounds can be assayed
bromometrically on basis of the substitution of C2-H ?.

70. Dabigatran etexilate (DABE)
Oral anticoagulant from the class of direct thrombin inhibitors.
Alternative to warfarin.
Not require frequent monitoring of the clotting tendency of blood.
DABE is a prodrug
that is metabolized by serum esterase to its active metabolite; dabigatran (DAB).

71. 2) Parenteral anticoagulants
2.1) Heparin
Heparin, a highly-sulfated glucosaminoglycan is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule
It is a mixture of naturally occurring muccopoly-saccharides produced primarilly in the liver and lungs.
Acts as anticoagulant through acceleration of the binding of antithrombin III (a protease enzyme) to thrombin.
Meanwhile it inactivate several factors in the coagulation cascade (Factor IX; X; XI).
It is a fast acting, short-lived drug.
Pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine lung

72. It is a polymeric molecule with M.Wt. ≈ 5 – 30 kD.
It is a strong acidic compd. Since it contains both COOH and SO42- groups.
The polysaccharide polymer chains are composed of two alternating sugar units linked by α,1---4 bonds:
N,O- sulfated-D-glucosamine
D-glucuronic acid

73. 2.2) Low molecular weight heparins (LMWH):
Heparin fractions with M.Wt ≈ 4 – 6 kD.
isolated as fractions from High molecular weight heparin
(HMWH) using gel filtration chromatography or
differential precipitation with ethanol.
They have superior pharmacokinetic and
pharmacodymic profiles relative to standard heparin.
They have specific affinity for factor X and less against
factor II (thrombin).
Three LMWHs are commercially available:
Enoxaparin ( 2 – 6 kD).
Dalteparin (2 – 9 kD).
Tinzaparin (2.5 – 5.5 kD)
Mainly indicated for preoperative prevention of thrombo-
embolism in some surgeries.