Tài liệu Color Atlas of Pharmacology (Part 11): Vasodilators pdf

Venous tone regulates the volume of blood returned to the heart, hence, stroke volume and cardiac output.. Cardiac output and peripheral resistance are prime determinants of arterial

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118 Vasodilators

Vasodilators-Overview

The distribution of blood within the cir-

culation is a function of vascular caliber

Venous tone regulates the volume of

blood returned to the heart, hence,

stroke volume and cardiac output The

luminal diameter of the arterial vascula-

ture determines peripheral resistance

Cardiac output and peripheral resis-

tance are prime determinants of arterial

blood pressure (p 314)

In A, the clinically most important

vasodilators are presented in the order

of approximate frequency of therapeu-

tic use Some of these agents possess

different efficacy in affecting the venous

and arterial limbs of the circulation

(width of beam)

Possible uses Arteriolar vasodila-

tors are given to lower blood pressure in

hypertension (p 312), to reduce cardiac

work in angina pectoris (p 308), and to

reduce ventricular afterload (pressure

load) in cardiac failure (p 132) Venous

vasodilators are used to reduce venous

filling pressure (preload) in angina pec-

toris (p 308) or cardiac failure (p 132)

Practical uses are indicated for each

drug group

Counter-regulation in acute hy-

potension due to vasodilators (B) In-

creased sympathetic drive raises heart

rate (reflex tachycardia) and cardiac

output and thus helps to elevate blood

pressure Patients experience palpita-

tions Activation of the renin-angioten-

sin-aldosterone (RAA) system serves to

increase blood volume, hence cardiac

output Fluid retention leads to an in-

crease in body weight and, possibly,

edemas These counter-regulatory pro-

cesses are susceptible to pharmacologi-

cal inhibition (f-blockers, ACE inhibi-

tors, AT1-antagonists, diuretics)

Mechanisms of action The tonus

of vascular smooth muscle can be de-

creased by various means ACE inhibi-

tors, antagonists at AT1-receptors and

antagonists at a-adrenoceptors protect

against the effects of excitatory media-

tors such as angiotensin II and norepi-

nephrine, respectively Prostacyclin an-

alogues such as iloprost, or prostaglan-

din E, analogues such as alprostanil,

mimic the actions of relaxant mediators Ca2+ antagonists reduce depolarizing in-

ward Ca* currents, while K*-channel ac-

tivators promote outward (hyperpolar- izing) K* currents Organic nitrovasodi- lators give rise to NO, an endogenous activator of guanylate cyclase Individual vasodilators Nitrates (p 120) Ca“-antagonists (p 122) ơœi- antagonists (p 90), ACE-inhibitors, AT1- antagonists (p 124); and sodium nitroprusside (p 120) are discussed else- where

Dihydralazine and minoxidil (via its sulfate-conjugated metabolite) dilate arterioles and are used in antihyperten- sive therapy They are, however, unsuit- able for monotherapy because of com- pensatory circulatory reflexes The mechanism of action of dihydralazine is unclear Minoxidil probably activates Kt channels, leading to hyperpolarization

of smooth muscle cells Particular adverse reactions are lupus erythemato- sus with dihydralazine and hirsutism with minoxidil—used topically for the treatment of baldness (alopecia androg- enetica)

Diazoxide given i.v causes promi-

nent arteriolar dilation; it can be em-

ployed in hypertensive crises After its

oral administration, insulin secretion is

inhibited Accordingly, diazoxide can be used in the management of insulin-se- creting pancreatic tumors Both effects are probably due to opening of (ATP- gated) Kt channels

The methylxanthine theophylline (p 326), the phosphodiesterase inhibi- tor amrinone (p 132), prostacyclins (p 197), and nicotinic acid derivatives (p 156) also possess vasodilating activity

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Venous bed Arterial bed Nitrates

Ca-antagonists ACE- inhibitors

Dihydralazine

Minoxidil a,-Antagonists

Nitroprusside sodium

A Vasodilators

f

Vasodilation

ood-

7 pressure

pressure

output ft -) T a5

ar —

Heart rate t

Blood volumef

| Angiotensinogen | | Aldosterone S |

converting

enzyme

| Angiotensin II aa Vasoconstriction

ACE-inhibitors |

Renin-angiotensin-aldosterone-system

B Counter-regulatory responses in hypotension due to vasodilators

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120 Vasodilators

Organic Nitrates

Various esters of nitric acid (HNO3) and

polyvalent alcohols relax vascular

smooth muscle, e.g., nitroglycerin (gly-

ceryltrinitrate) and isosorbide dinitrate

The effect is more pronounced in venous

than in arterial beds

These vasodilator effects produce

hemodynamic consequences that can

be put to therapeutic use Due to a de-

crease in both venous return (preload)

and arterial afterload, cardiac work is

decreased (p 308) As a result, the car-

diac oxygen balance improves Spas-

modic constriction of larger coronary

vessels (coronary spasm) is prevented

Uses Organic nitrates are used

chiefly in angina pectoris (p 308, 310),

less frequently in severe forms of chron-

ic and acute congestive heart failure

Continuous intake of higher doses with

maintenance of steady plasma levels

leads to loss of efficacy, inasmuch as the

organism becomes refractory (tachy-

phylactic) This “nitrate tolerance” can

be avoided if a daily “nitrate-free inter-

val” is maintained, e.g., overnight

At the start of therapy, unwanted

reactions occur frequently in the form

of a throbbing headache, probably

caused by dilation of cephalic vessels

This effect also exhibits tolerance, even

when daily “nitrate pauses” are kept

Excessive dosages give rise to hypoten-

sion, reflex tachycardia, and circulatory

collapse

Mechanism of action The reduc-

tion in vascular smooth muscle tone is

presumably due to activation of guany-

late cyclase and elevation of cyclic GMP

levels The causative agent is most likely

nitric oxide (NO) generated from the or-

ganic nitrate NO is a physiological mes-

senger molecule that endothelial cells

release onto subjacent smooth muscle

cells (“endothelium-derived relaxing

factor,” EDRF) Organic nitrates would

thus utilize a pre-existing pathway,

hence their high efficacy The genera-

tion of NO within the smooth muscle

cell depends on a supply of free sulfhy-

dryl (-SH) groups; “nitrate-tolerance”

has been attributed to a cellular exhaus- tion of SH-donors but this may be not the only reason

Nitroglycerin (NTG) ¡is distin- guished by high membrane penetrabil- ity and very low stability It is the drug

of choice in the treatment of angina pectoris attacks For this purpose, it is administered as a spray, or in sublingual or buccal tablets for transmucosal deliv- ery The onset of action is between 1 and

3 min Due to a nearly complete presystemic elimination, it is poorly suited for oral administration Transdermal de- livery (nitroglycerin patch) also avoids presystemic elimination Isosorbide dinitrate (ISDN) penetrates’ well through membranes, is more stable than NTG, and is partly degraded into

the weaker, but much longer acting, 5-

isosorbide mononitrate (ISMN) ISDN can also be applied sublingually; however, it is mainly administered orally in order to achieve a prolonged effect ISMN is not suitable for sublingual use because of its higher polarity and slower rate of absorption Taken orally, it is ab- sorbed and is not subject to first-pass elimination

Molsidomine itself is inactive Af-

ter oral intake, it is slowly converted

into an active metabolite Apparently, there is little likelihood of “nitrate tolerance”,

Sodium nitroprusside contains a nitroso (-NO) group, but is not an ester

It dilates venous and arterial beds equally It is administered by infusion to achieve controlled hypotension under continuous close monitoring Cyanide ions liberated from nitroprusside can be inactivated with sodium thiosulfate (Na2S203) (p 304)

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Preload +

Oz-demand }

Blood pressure}

Peripheral resistance |

coronary artery

spasm

Venous blood return

to heart |

“Nitrate- tolerance”

Ka

NO ty~ 2 min

Inactivation

SH-donors

e.g., glutathione

metabolite

A Vasodilators: Nitrates

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122 Vasodilators

Calcium Antagonists

During electrical excitation of the cell

membrane of heart or smooth muscle,

different ionic currents are activated,

including an inward Ca?* current The

term Ca?* antagonist is applied to drugs

that inhibit the influx of Ca2* ions with-

out affecting inward Na* or outward K+

currents to a significant degree Other

labels are Ca-entry blocker or Ca-channel

blocker Therapeutically used Ca?* an-

tagonists can be divided into three

groups according to their effects on

heart and vasculature

I Dihydropyridine derivatives

The dihydropyridines, e.g., nifedipine,

are uncharged hydrophobic substances

They induce a relaxation of vascular

smooth muscle in arterial beds An effect

on cardiac function is practically absent

at therapeutic dosage (However, in

pharmacological experiments on isolat-

ed cardiac muscle preparations a clear

negative inotropic effect is demon-

strable.) They are thus regarded as va-

soselective Ca2* antagonists Because of

the dilatation of resistance vessels,

blood pressure falls Cardiac afterload is

diminished (p 306) and, therefore, also

oxygen demand Spasms of coronary ar-

teries are prevented

Indications for nifedipine include

angina pectoris (p 308) and, — when ap-

plied as a sustained release preparation,

— hypertension (p 312) In angina pec-

toris, it is effective when given either

prophylactically or during acute attacks

Adverse effects are palpitation (reflex

tachycardia due to hypotension), head-

ache, and pretibial edema

Nitrendipine and felodipine are used

in the treatment of hypertension Ni-

modipine is given prophylactically after

subarachnoidal hemorrhage to prevent

vasospasms due to depolarization by

excess K+ liberated from disintegrating

erythrocytes or blockade of NO by free

hemoglobin

II Verapamil and other catamphi-

philic Ca** antagonists Verapamil con-

tains a nitrogen atom bearing a positive

charge at physiological pH and thus rep-

resents a cationic amphiphilic molecule

It exerts inhibitory effects not only on arterial smooth muscle, but also on heart muscle In the heart, Ca2* inward currents are important in generating depolarization of sinoatrial node cells (impulse generation), in impulse propaga- tion through the AV- junction (atrioven-

tricular conduction), and in electrome-

chanical coupling in the ventricular car- diomyocytes Verapamil thus produces negative chrono-, dromo-, and inotropic effects

Indications Verapamil is used as

an antiarrhythmic drug in supraventric- ular tachyarrhythmias In atrial flutter

or fibrillation, it is effective in reducing

ventricular rate by virtue of inhibiting AV-conduction Verapamil is also em- ployed in the prophylaxis of angina pectoris attacks (p 308) and the treatment

of hypertension (p 312) Adverse effects: Because of verapamil’s effects on the sinus node, a drop in blood pressure fails to evoke a reflex tachycardia Heart rate hardly changes; bradycardia may even develop AV-block and myocardial insufficiency can occur Patients frequently complain of constipation Gallopamil (= methoxyverapamil) is closely related to verapamil in both structure and biological activity Diltiazem is a catamphiphilic ben- zothiazepine derivative with an activity profile resembling that of verapamil

HI T-channel selective blockers

Ca*t-channel blockers, such as verapa-

mil and mibefradil, may block both L- and T-type Ca2* channels Mibefradil shows relative selectivity for the latter and is devoid of a negative inotropic ef-

fect; its therapeutic usefulness is com-

promised by numerous interactions with other drugs due to inhibition of cy-

tochrome P4zo-dependent enzymes

(CYP 1A2, 2D6 and, especially, 3A4)

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Smooth muscle cell

Oa-demand }

Blood pressure ‡

Peripheral resistance}

Ca2t

blood vessel

Vasodilation in arterial bed

“

2

Na' Ca22+s

(dihydropyridine derivative)

Q-CHs

8

hóc ý thị 5 HC, CA

=

(cationic amphiphilic)

Nu Inhibition of cardiac functions

Ca?*

Heart muscle cell

Impulse

Bae node generation wey

Impulse

a

| | SO Ventricul Electro-

entricular_ / mechanical muscle coupling

Heart rate } Reflex tachycardia with nifedipine

AV- conduction}

Contractility }

A.Vasodilators: calcium antagonists

Tiêu đề	Vasodilators
Tác giả	Lüllmann
Chuyên ngành	Pharmacology
Thể loại	Chương sách
Năm xuất bản	2000
Thành phố	Stuttgart

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Số trang	6
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