Chapter 8 cardiovascular drugs

Cardiac glycosides

Catecholamines

Phosphodiesterase inhibitor

Calcium sensitizers8.1 Cardiac agents

(Digitoxin)(Digoxin)C(Lanatoside C)(Convallatoxin)K(-trophanthin-K)8.1.1 Cardiac glycosides

Digitoxin Lanatoside C

-Strophanthin-KConvallatoxin

Mechanism of Cardiac Glycosides Na+-K+ATP enzyme inhibitor: Ca2+, Ca2+Na+-K+ATPNa+-K+ATP3Na+2K+Na+-K+ATPCa2+,Na+-K+ATP

Structural characteristics of Cardiac glycosides(Cardenolide) (Bufadienolide) A-BC-D B-C UC-10C-133-3

- D- - D- - L- -D-: Potentiate the heartStronger when fewer glycosylations on hydroxy-3. -or -body glycosylation has nothing with the activity

structure-activity relationship of Cardiac Glycosides17 - or -unsaturated lactone and steroid ring are very important structure to enzyme inhibitors: Steroid ring of Cardiac Glycosides is necessary to activity, whereas the singleor -unsaturated lactone ring is non-cardiotonic. Particularly, the combination of the four rings of steroid such as cis formation of ring C and D is utmost importort.The introduction of hydroxy on steroid, such as the location of C1, C5, C11, C12 and C16, oral absorption will be dereased for the polarity increasing, the drug will sustaine short time in vivo. when hydroxyl were esterified, a little longer time acting. However, intravenous injection of cardiac function than the free hydroxy compounds weak.Enhanced activity when C19 methyl was oxidized to hydroxymethyl or aldehyde. significantly reduced activity if further oxidized to carboxyl group. In terms of C19-methyl is substituted by hydrogen, a significant reduction in activity.If cardiac glycosides were hydrolyzed into aglycones, the cardiotonic effect will decrease for the reduced water-solubility, whereas aglycone easily access to the central nervous system so have serious side effects.

Digoxin(3,5,12)-3-[(O-2,6---D---(14) O-2,6---D---(14)-2,6---D--)-12,14--20(22) (3,5,12)-3-[(O-2,6-Dideoxy--D-ribo-hexopyranosyl-(14)-O-2,6-dideo-xy--D-ribo-hexopyranosyl-(14)-2,6-dideoxy--D-ribo-hexopyranosyl)oxy]-12,14-dihydroxycard-20(22)-enolide Clinically for the treatment of acute or chronic heart failure, particularly for atrial fibrillation and supraventricular tachycardia

8.1.2 CatecholaminesMechanism: 1-receptor antagonistsTo excite cardiac 1-receptors, resulting in cardiac contraction. Its mechanism is to activate adenylyl cyclase, so that ATP into cAMP, calcium ions come into the myocardial cell membrane, thereby enhancing myocardial contraction. However, because most of the adrenergic agonists can accelerate the heart rate and vasoconstriction, so limited the value of the treatment of heart failure.epinephrine dopamine Dobutamine)

(Ibopamine) (Denopamine) (Dopexamine) (Butopamine)

8.1.3 othersMechanism: to inhibit the activity of phosphodiesterase on myocardial cell membrane, reduce the degradation of cAMP of myocardial cells, so increase Ca2 + in the cell, thereby lead to the increasing myocardial contraction.(Amirinone) (Milrinone) 8.1.3.1phosphodiesterase inhibitors

(Enoximone) (Piroximone)

1. 1 Amrinone Milrinone Enoximone Piroximone

8.1.3.2 Calcium sensitizers

8.2 Drugs acting in ion channelsCalcium channel blockersSodium channel blockersPotassium channel blockersPotassium channel openers

8.2.1 Calcium antagonists

(Calcium channel blockers)

Role and clinical applicationAntianginal

Anti-heart disorders

Antihypertensive

Other usage

Class of calcium antagonist Dihydropyridines, DHP Aralkylamines Benzothiazepines Diphenylpiperazines

1

NameR1R2R3X NifedipineCH3CH3CH32'-NO2 NitrendipineC2H5CH3CH33'-NO2 NisoldipineCH3CH2CH(CH3)2CH32'-NO2 NiludipineCH2CH2OC3H7CH2CH2OC3H7CH33'-NO2

3

R1R2R3X NicardipineCH3CH33'-NO2 NimodipineCH(CH3)2CH2CH2OCH3CH33'-NO2 FelodipineC2H5CH3CH32'-Cl, 3'-Cl AmlodipineCH3C2H5CH2OCH2CH2NH22'-Cl

SAR of Dihydropyridine1,4 - dihydro-pyridine structure is essential. No activity in case of being Oxidized to pyridine, weak activity in case of being reduced of double bond. NH at dihydropyridine ring can not be replaced by any ohter substituents, or else can not maintain the best activity. Substituents at 2 and 6 should be small alkyls. Carboxylic acid ester at 3,5 is better than the other groups, and it is better when the one group is different from another.

The substituent at 4 has relationship with the strength of activity, phenyl is appropriate. Ortho- and meta- electron-absorption group from phenyl can enhance activity, para- substituted will lead to disappearance of the activity. S configuration has stronger activity. The smaller twist angle between benzene ring and dihydropyridine ring, the stronger activity.

Nifedipine1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl esterClinically for the prevention and treatment of coronary heart disease,heart angina, anti-hypertension, but not for anti-arrhythmic.

8.2.1.2 Arylalkylamines ---calcium antagonists

Verapamil5-[(3,4-Dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile

8.2.1.3 Benzothiazepine calcium antagonistFor various anti-angina, but with strong first-pass effect

Metabolism of Diltiazem in vivoON

8.2.1.4 Diphenyl piperazine calcium antagonistX=H CinnarizineX=F Flunarizine Lidoflazine

Other types of calcium antagonists

8.2.2 Sodium channel blockers: IA

Sodium channel blockersIB

RNHCOCH2N(C2H5)2 LidocaineNHCOCH(CH3)NH2 TocainideOCH2CH(CH3)NH2 MexiletineNHCONH(CH2)3NHCH(CH3)2 RecainamNHCOCH2N+(CH3)(C2H5)2.Cl- Methyllidocaine

IB IC : anti-arrhythmia, coronary artery expansion, spasmolytic

Sodium channel blockersIC

Sodium channel blockersIC

8.2.3 Potassium channel blockers1

Selectively acting in the cardiac potassium channel, the smaller arrhythmogenic side-effects

8.2.4 potassium channel openerRelax vascular smooth muscleAntihypertension Antianginal Protective effects to myocardial ischemia Treatment of peripheral vascular occlusive disease Anti-asthma Anti Smooth muscle algeric and treatment of muscle fatigue Urinary frequency, urinary urgency

8.3 Adrenergic nervous system drugsMg 2+ ---ATP enzyme inhibitor Adrenergic drugs 1 receptor agonist 1-receptor blocker -receptor blocker

8.3.1 Mg 2+ ---ATP enzyme inhibitorMg 2+ ---ATP inhibitor act on adrenergic nerve endings of central and peripheral nervous parts of, combine with the amine pump, inhibite Mg 2 + --- ATP enzyme transporting function, inhibit the reuptake of monoamine neurotransmitters such as norepinephrine, dopamine and then lead to the degradated of amine neurotransmitters by monoamine oxidase, also reduce the synthesis of epinephrine, as the sympathetic neurotransmitter function allows depletion. At last reduce blood pressure, heart rate. such drugs have moderate and long-lasting characteristics.

Reserpine1117--18-[(345-)]-320--16-(11,17-Dimethoxy-18b-(3,4,5-trimethoxy benzoyl)oxy)- 3b,20a-yohimban-16b-carobxylic acid methyl erter)Mg-ATP5-5-

[]23D 118(CHCl3); []26D 164(C = 0.96 ); []26D168(C =0.624 in DMF)pKb6.6mp.264~265C15,C20C17--C16 C18-3-H3-(3-Isoreserpine)Properties of Reserpine

Reserpine and its aqueous solution are stable, the most stable pH of 3.0. However, aqueous solution can hydrolyze undre acid, alkali-catalyzed condition. Alkaline hydrolysis of two ester groups generate Reserpic acid which also have activity. Reserpine has complex metabolic behavior in vivo. a variety of decomposition products in Urine, such as 11 demethoxy reserpic acid, 11 demothoxy reserpine, 3,4,5 - trimethoxy-benzoic acid and 3,5 - dimethoxy- 4 - hydroxy benzoic acid.SAR of Reserpine: esters of 16 and 18, and methoxy of 17 is essential for antihypertensive activity, the activity will disappear in case of hydrolysis or getting rid of them. Activity also disappeare in case of aromatization of C and D rings. Still Active in case of removing the methoxy of 11 and 17.

Synthesis of reserpine

8.3.2 Adrenergic Drugs-receptor antagonist1-receptor antagonist2-receptor agonist Most of the Adrenergic drugs are highly fat-soluble,easily pass through the blood-brain barrier, resulting in moderate intensity of reducing blooding pressure.clonidine hydrochloride Mechanism:Excite inhibitory neurons, reduce the function of peripheral sympathetic nerve, and then reduce blood pressure.

moxonidine rilmenidine Moxonidine has reliable hypotensive effect, efficacy is similar to clonidine hydrochloride. Rilmenidine is oxazoline compounds, do not inhibit contraction of the heart, do not change renal function, less side effects, another importance is to reduce the sodium retention.

II. Renin-Angiotensin-Aldosterone system Drugs Renin-angiotensin-aldosterone system RAS or RAAS

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser AngiotensinogenAsp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-LeuAngiotensin IAsp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensin II Aldosterone ReninAngiotensin-converting enzyme Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg BradykininArg-Pro-Pro-Gly-Phe-Ser-ProACE

Angiotensin converting enzyme inhibitors---ACEIRenin inhibitorAngiotensin II receptor antagonist

Angiotensin converting enzyme inhibitors-ACEI

CaptoprilTwo asymmetric carbons, levorotary, both of SS configuration. Instability, easily oxidized to disulfide under light or in aqueous solution. Identification: change into red nitrosyl thiol esters react with nitrous acid.For hypertension and congestive heart failure. Side effects: skin rash, taste disappearing, cough

Ramipril2S-[1[R*(R*)],2,3a,6a]]-1-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid

8.5 NO donating drugs

Nitrate drugs can be biotransformed into nitric oxide (NO) which is highly fat-soluble, so NO pass through the cell membrane easily, activating guanylate cyclase, so that increase the content of intracellular cGMP, lead to vascular smooth muscle relaxation. NO is relaxation factor, in case of coronary atherosclerosis and acute ischemia, NO release reducedly exogenous nitrate can supply the lack of endogenous NO.

Onset time, maximum time and the enduration time of Nitrate drugs,

Onset time(min)Maximum time(min)Enduration time (min)0.250.51endure28303156015321802070330

Isosorbide Dinitrate1436--D--25-1,4:3,6-dianhydro-D-sorbitol 2,5-dinitrateSynthesis:

Synthesis of 5 - Isosorbide Mononitrate