Vasodilators (antihypertensives) and vasoconstrictors (antihypotensives)
Vasodilators
(antihypertensives) and vasoconstrictors (antihypotensives)
The distribution of blood within the circulation 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
vasculature determines peripheral resistance. Cardiac output and peripheral
resistance are prime determinants of arterial blood
pressure. The clinically most important vasodilators are presented in the order
of approximate frequency of therapeutic use. Some of these agents possess
different efficacy in affecting the venous
and arterial limbs of the circulation.
Possible uses. Arteriolar vasodilatorsare given to
lower blood pressure in hypertension, to reduce cardiac work in angina
pectoris, and to reduce ventricular afterload (pressure load) in cardiac
failure. Venous vasodilators are used to reduce venous filling pressure
(preload) in angina pectoris or cardiac failure. Practical uses are indicated
for each drug group.
Counter-regulation in acute hypotension
due to vasodilators. Increased sympathetic drive
raises heart rate (reflex tachycardia) and cardiac output and thus helps to
elevate blood pressure. Patients experience palpitations. Activation of the renin-angiotensin-
aldosterone (RAA) system serves to increase blood volume, hence cardiac output. Fluid retention
leads to an increase in body weight and, possibly, edemas. These
counter-regulatory processes are susceptible to pharmacological inhibition
(ß-blockers, ACE inhibitors, AT1-antagonists, diuretics).
Mechanisms of action. The tonus of vascular smooth muscle can be decreased by various means.
ACE inhibitors, antagonists at AT1-receptors and antagonists at ß-adrenoceptors
protect against the effects of excitatory mediators such as angiotensin II and
norepinephrine, respectively. Prostacyclin analogues such as iloprost, or
prostaglandin E1 analogues such as
alprostanil, mimic the actions of relaxant mediators. Ca2+ antagonists reduce depolarizing inward Ca2+ currents, while K+-channel activators promote outward
(hyperpolarizing) K+ currents.
Organic nitrovasodilators give rise to NO, an endogenous activator of guanylate
cyclase.
Vasodilators
(Antihypertensives)
The drugs that decrease arterial pressure with direct or
indirect mechanism of action
Classification
I.
Remedies that decrease the influence of
adrenergic enervation upon
cardiovascular system:
A. Remedies decreasing the tonus of vasomotor center
(with central action)
- clonidine
- methyldopa
- guanfacine
- moxonidine
B. Remedies with peripheral action
1. Ganglioblockers
- hexamethonium
- triperium
iodide
- trimetaphan
- azamethonium
2. Adrenoblockers: (the
remedies that inhibit adrenoreceptors)
a) a
adrenoplockers
1)
nonselective 2)
selective
- pnentolamine - prasosine
- tropodiphen -
doxasosine
b) b
adrenoblockers
- propranolol - atenolol
- metoprolol - talynolol
c) ab adrenoblockers
- labetolol
3. Sympapholitics:
- rezerpine
- guanethidine (octadine)
II.
Remedies that act on renin-angiotensin system.
a)
inhibitors of angiotensin II synthesis
- captopril - ramipril -trandolapril - kinapril
- enalapril
maleat -fosinapril - pirindopril
b)
angiotensin II receptor blockers (AT 1A, AT2B)
- saralasin - telmisartan - eprosartan
- losartan - valsartan - irbesartan
c) renin
inhibitors (direct mechanism): enalkiren, remikiren
d)
vasopeptidase inhibitors (inhibitors of angiotensinII and endopeptidase)
- omapatrilat
III.
Remedies with direct action on the vessels
muscle (Musculatropic vasodilators )
1. Remedies
that act on the ionic channel
a) Ca++
channels blocker: nifedipine, verapamil, diltiazem, felodipin
b) K +channels
activators: minoxidil, diazoxide
2. Donators
of NO (nitric oxide) group:
- sodium
nitropruside
3. Various
musculotrop drugs:
- hydralazine
- bendazol
- magnesium
sulfate
IV.
Remedies that act hydrosaline metabolism
(diuretics)
- frusemide
(furosemide)
- hydrochlorothiaside
- spironolactone
- ethacrinic
acid
Classification of antihypotensions according to the
pathogenic principle:
1. Remedies
increasing cardiac output and tonus of peripheral vessels
Adrenomimetics (epinephrine and
ephedrine)
2. Remedies
increasing peripheral vessels tonus
a) adrenomimetics
(norepinephrine, ethylephrine and phenylephrine)
b) vasoactive
peptides (angiotensinamide, vasopresine)
c) izothyoureic
derivates (izoturon, difetur, profetur)
3. Remedies
increasing the cardiac output
a) cardiac
glycosides
b) adrenomimetics
(doputamine, izoprenaline)
c) dopamine
d) glucagons
4 . Remedies that substitute the blood volume
a) blood,
plasma,
b) plasma’s
substituents
c) isotonic
solutions.
Remedies with central action
Clonidine has
selective action on α 2 central adrenoreceptors, and inhibits the
release of noradrenalin. The essential consists in the increase of sensibility
of vasomotor center because of the reflex inhibition of the baroreceptors from
vessels. The activity of parasympathetic nerves increases and produces
bradycardia. The intravenous administration of clonidine produces hypertension
at the beginning, because of the excitement of α2 postsynaptic
adrenoreceptors.
Effects:
1. increase
in cardiac minute-volume and rate.
2. relaxation
of vessels smooth muscle
3. sedative,
hypnotic, analgesic and tranquillizing action.
Pharmacokinetics:
Good absorption from the intestine. Duration of action
is 6-12 hours. It dissociates in lipids and rapid circulates and goes through
brain-membrane. Elimination- trough urine and by liver.
Drug interactions: Clonidine
1. With
rezerpine produces somnolence, depression.
2. with
antidepressants decreases antidepressant effect
3. with
quinidine increases bradycardia
4. with
digoxin decreases its elimination by
urine
5. with
alcohol potencies its central effects.
Side effects:
1. hyposecresion
of exocrine glands
2. collapse
3. deregulation
of the cerebral circulation
4. somnolence
5. decreases
libido
6. Rebound
syndrome
7. constipation
8. respiratory
depression
Indications:
1. hypertension
disease, IIB state.
2. cerebral
aterosclerosis with minimum manifestations
3. premedication
4. anesthesia
Methyldopa.
In the body methyldopa is transformed in the falls
mediator (methylnoradrenalin) with the same action as clonidine that stimulates
central α2adrenoreceptors.
Effects:
1. decreases
the peripheral resistance
2. decreases
the cardiac rhythm
3. increases
the contractility
4. increases
renal circulation
5. decreases
the activity of CNS
Pharmacokinetics: For the orally administration it has
4-6 hours of hypotensive effect. It is keeped for 24 hours in the body.
Elimination-by urine. Drug interactions the same as clonidine.
Side effects:
1. collapse
2. flu
like symptoms (headache, high temperature, nausea, vomiting)
3. ginecomasty,
galactorea, sexual dysfunction, libido decrease.
4. hemolytic
anemia
5. skin
eruptions
6. edema
(retention of water and Na in the body)
7. liver
dysfunction
8. Rebound
syndrome
Indication: hypertonic
disease (light and medium forms)
Moxonidine is a new selective drag. It is binned with imidazoline I1
receptors and inhibits activity of vasomotor center.
Pharmacological effects:
1. decreases
the peripheral resistance
2. decreases
the cardiac rate
3. decreases
hypertrophy of the left ventricle
4. insulin-
like action
Interactions: It enhances
action of the alcohol, hypnotic, sedative drugs.
Side effects:
1. collapse
2. paradox hypertension increase
3. dyspeptic
phenomena
4. allergy
5. bradycardia
Indications:
1. the
essential arterial hypertension
2. the
symptomatic hypertension in II type of diabetes
Ganglioblockers:
-these drugs block
sympathetic and parasympathetic ganglions.
Indications:
1. hypertension
crises
2. controlled
hypertension during the surgical interventions.
Side effects:
1 Atropine-like
effect (paralyze of the intestine, bladder, gall bladder, deregulation of
accommodation) 2 Collapse
α-adrenoblockers
Phentolamine
on the one hand inhibits α
1 adrenoreceptors postsynaptic and produces vasodilatation and on
the other hand inhibits α2 adrenoreceptors presynaptic and increases the noradrenalin releasing.
Noradrenalin stimulates β1 adrenoreceptors and increases the cardiac
contractility, and stimulation of β2 adrenoreceptors contributes to
the vasodilatation.
Acetylcholine exits M cholinoreceptors and produces
hypersalivation, increasing of the intestine motility and produces diarrhea.
Effects: histamine-like effect (gastric hypersecretion
and permeability of the capillaries).
Side effects: vertigo, pruritus, hyperemia, nausea,
vomiting, diarrhea, exacerbating of the gastric ulcer, tachycardia,
arrhythmias, collapse.
Indications: acute and chronic cardiac failure,
hypertension crises, hypertension disease.
Prasosine:
blocks α2 postsynaptic adrenoreceptors.
Effects:
1. hypotension
2. hypotension
in the small circulation
3. ameliorates
the cardiac contractility
4. glycogenolises
inhibition.
Side effects:
1.collapse (syncope after the first doses)
2. headache, vertigo, dizziness, insomnia, skin
eruptions, dyspeptic deregulations, dry mouth, edema, hypoglycemia.
Indications: Chronic cardiac failure, and all forms of
hypertension.
Β-adrenoblockers
They block presynaptic receptors of vessels and
juxtaglomerular system. In this way inhibit rennin releasing and decrease
vessels tonus and produce hypotension.
Sympatholitics
Rezerpine
inhibits reuptake of monoamines (noradrenaline, serotonine and dopamine)
it decreases the quantity of monoamines at the peripheral, in CNS, and in the
kidneys. At last, it decreases rennin releasing and produces hypotension.
Effects:
deceases peripheral resistance, cardiac rhythm, and
minute-volume
Side effects:
extrapyramidal deregulations, gynecomasty, , chest
cancer, gastric hyperacidity, edemas,
miosis, bronchospasm, salivation,
diarrhea, and it increases the quantity of prolactine.
II.
Remedies that act rennin-angiotensin system.
Angiotensin-converting enzyme (ACE) is a component of the antihypotensive
renin-angiotensin-aldosterone (RAA) system. Renin is produced by specialized
cells in the wall of the afferent arteriole of the renal glomerulus. These
cells belong to the juxtaglomerular apparatus of the nephron, the site of
contact between afferent arteriole and distal tubule, and play an important
part in controlling nephron function. Stimuli
eliciting release of renin are: a
drop in renal perfusion pressure, decreased rate of delivery of Na+ or Cl– to the distal tubules, as well as ß-adrenoceptor-mediated
sympathoactivation. The glycoprotein renin enzymatically cleaves the
decapeptide angiotensin I from its circulating precursor substrate
angiotensinogen.
ACE, in turn, produces biologically active
angiotensin II (ANG II) from angiotensin I (ANG I).
ACE is a
rather nonspecific peptidase that can cleave C-terminal dipeptides from various
peptides (dipeptidyl carboxypeptidase). As “kininase II,” it contributes to the
inactivation of kinins, such as bradykinin. ACE is also present in blood
plasma; however, enzyme localized in the luminal side of vascular endothelium
is primarily responsible for the formation of angiotensin II. The lung is rich
in ACE, but kidneys, heart, and other organs also contain the enzyme.
Angiotensin II can raise blood pressure in different ways, including
(1)vasoconstriction in both the arterial and venous limbs of the circulation;
(2) stimulation of aldosterone secretion, leading to increased renal
reabsorption of NaCl and water, hence an increased blood volume; (3) a central
increase in sympathotonus and, peripherally, enhancement of the release and
effects of norepinephrine.
ACE inhibitors, such as captopril and enalaprilat, the active metabolite of enalapril, occupy
the enzyme as false substrates. Affinity significantly influences efficacy and
rate of elimination. Enalaprilat has a stronger and longerlasting effect than
does captopril. Indications are hypertension and cardiac
failure.
Lowering of an elevated blood pressure is
predominantly brought about by diminished production of angiotensin II.
Impaired degradation of kinins that exert vasodilating actions may contribute
to the effect. In heart failure, cardiac output rises again because ventricular
afterload diminishes due to a fall in peripheral resistance. Venous congestion
abates as a result of (1) increased cardiac output and (2) reduction in venous
return (decreased aldosterone secretion, decreased tonus of venous capacitance
vessels).
Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors
depends on the functional state of the RAA
system. When the latter has been activated by loss of electrolytes and water
(resulting from treatment with diuretic drugs), cardiac failure, or renal
arterial stenosis, administration of ACE inhibitors may initially cause an
excessive fall in blood pressure. In renal arterial stenosis, the RAA system
may be
needed for maintaining renal function and
ACE inhibitors may precipitate renal failure. Dry cough is a fairly frequent side effect, possibly caused by reduced
inactivation of kinins in the bronchial mucosa. Rarely, disturbances of taste
sensation, exanthema, neutropenia, proteinuria, and angioneurotic edema may
occur. In most cases, ACE inhibitors are well tolerated and effective. Newer
analogues include lisinopril, perindopril, ramipril, quinapril, fosinopril,
benazepril, cilazapril, and trandolapril.
Antagonists at angiotensin II receptors.
Two receptor subtypes can be
distinguished: AT1, which mediates the above actions of AT II; and AT2, whose
physiological role is still unclear. The sartans (candesartan, eprosartan, irbesartan,
losartan, and valsartan) are AT1 antagonists that reliably lower high blood
pressure. They do not inhibit degradation of kinins and cough is not a
frequent side-effect.
Summary
Side effects:
- collapse, vertigo,
syncope, tachycardia, allergy, pain in the stern, eruptions, dry cough,
constipation, hypercalcemia, proteinuria.
Indications:
-the essential
arterial hypertension
-heart failure
-diabetic nephropathy.
Angiotensin blockers:
Saralasine and losartan
Mechanism of action:
they block angiotensin receptors and inhibit vasoconstriction prodused by
angiotensin II.
Side effects:
headache, vertigo, collapse, hypocalcaemia, increase ALAT, cough,
embriotoxicity.
Renin
inhibitors have direct mechanism of action.
Vasodilator musculatropics
Calcium Antagonists
Summary
-Blockers of calcium channels: they block Ca
channels.
Effects: vasodilatation, conductibility and automatism
decrease and hypotension, decrease thrombocytes aggregation.
Side effects:
Headache, vertigo, hypotension, edemas, face hyperemia, bradycardia,
constipation, heart failure.
Indications: essential
hypertension, angina, supraventricular tachycardia, cardiac hypertrophy, thromboses, arteriosclerosis, vesicular deregulation,
narcomany.
During electrical excitation of the cell membrane of heart or smooth
muscle, different ionic currents are activated, including an inward Ca2+ current. The term Ca2+ antagonist
is applied to drugs that inhibit the influx of Ca2+ ions without affecting inward Na+ or outward K+currents to a
significant degree. Other labels are Ca-entry blocker or Ca-channel
blocker. Therapeutically used Ca2+ antagonists 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 isolated cardiac muscle preparations a clear
negative inotropic effect is demonstrable.)
They are thus regarded as vasoselective Ca2+ antagonists. Because of the dilatation of resistance vessels, blood pressure falls.
Cardiac afterload is diminished and,
therefore, also oxygen demand. Spasms of coronary arteries are prevented.
Indications for nifedipine include angina
pectoris and, — when applied as a sustained release preparation, —
hypertension. In angina pectoris, it is effective when given either
prophylactically or during acute attacks.
Adverse effects are palpitation (reflex tachycardia
due to hypotension), headache,
and pretibial edema. Nitrendipine and felodipine are used
in the treatment of hypertension. Nimodipine 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 catamphiphilic Ca2+ antagonists. Verapamil contains
a nitrogen atom bearing a positive charge at physiological pH and thus
represents
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 propagation through the AV- junction (atrioventricular
conduction), and in electromechanical coupling in the ventricular
cardiomyocytes. Verapamil thus produces negative chrono-, dromo-, and inotropic
effects.
Indications. Verapamil is used as an
antiarrhythmic drug in supraventricular
tachyarrhythmias. In atrial flutter or fibrillation, it is effective in
reducing ventricular rate by virtue of inhibiting AV-conduction. Verapamil is
also employed in the prophylaxis of angina pectorisattacks and the
treatment of hypertension .
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 benzothiazepine
derivative with an activity profile resembling that of verapamil.
III. T-channel selective blockers.
Ca2+-channel
blockers, such as verapamil and mibefradil, may block both Land
T-type Ca2+ channels. Mibefradil
shows relative selectivity for the latter and is devoid of a negative inotropic
effect; its therapeutic usefulness is compromised by numerous interactions with
other drugs due to inhibition of cytochrome P450-dependent enzymes
(CYP 1A2, 2D6 and, especially, 3A4).
K channels activators:
Minoxidil probably activates K+channels, leading to hyperpolarization of
smooth muscle cells. The opening of K channels decreases Ca influx
in cell. Particular adverse reactions are lupus
erythematosus with dihydralazine and hirsutism with minoxidil—used topically
for the treatment of baldness (alopecia androgenetica).
Effects: vasodilatation and hypotension.
Side effects: hirsutism, edemas, hyperglycemia,
increase of uric acid in the blood.
Diazoxide given i.v. causes prominent arteriolar dilation; it can be employed
in hypertensive crises. After its oral
administration, insulin secretion is inhibited. Accordingly, diazoxide can be
used in the management of insulin-secreting pancreatic tumors. Both effects are
probably due to opening of (ATPgated) K+ channels.
The methylxanthine theophylline, the
phosphodiesterase inhibitor amrinone, prostacyclins, and nicotinic acid
derivatives also possess vasodilating activity.
Donators of NO
Sodium
nitroprusside donate NO that stimulates guanylatcyclase and
proteinkinase.
Effects: decrease the quantity of Ca in cell.,
activate K channeland produce depolarization, decrease of quantity of
inosytoltriphosphates. ®Vasodilatation.
Also NO has direct musculotropic action on the vessels.
Side effects: collapse, vertigo, cardiallgy.
Indications: hypertensive
crisis, hypertension during the surgical
intervention, heart failure.
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 (Na2S2O3).
Musculotropics
have direct mechanism of action.
Classification
of systemically vasoconstrictors ( Antihypotensives)
1.Vasoconstrictors 2. Remedies increasing
the cardiac
a) with
central action:
contractility and cardiac output
- niketamide 1. cardiac
glycosides: Strophanthine
- camphor 2.
cardiostimulants:
- sulphocamphocaine b1b2 adrenomimetics
izopenaline
-
pentetrasol
b1 adrenomimetics:
dopamine, doputamine
Vasoactive polypeptides: glucagon
psychostimulants: caffeine
natrio-benzoic caffeine
general tonizants and adaptogenes 3. Remedies increasing the blood
volume
Panax
(Ginseng), Bioginseng,
Dextran 70 (polyglucine)
Eleuterococcus, Rodiola, Leuzea Dextran 40
Pantocrin,
Rantarin Gelatinol
b) with
peripheral action
Haemodes
a and
a,b
adrenomimetics
Human albumin
·
epinephrine 4.
Antihypotensives with mixed action
·
norepinephrine desoxycorticone acetate
·
ephedrine
fludrocortizon
·
etylephrine 5.
antihypotensives with premisive action
·
phenylephrine
glucocorticoids
N-cholinomimetics -
hydrocortisone
·
lobeline
- prednisone
·
cititone
- dexamethasone
musculotropics
1.alkaloids from Ergot
·
ergotal
·
ergotamine tartrate
·
dihydroergotamine
2.vasoactive polypeptides
·
angiotensinamide
·
vasopresine
3. izothyoureic derivates
·
izoturon
·
difetur
·
profetur
Classification
of vasoconstrictors ( Antihypotensives) according with the duration of action
A. Short action (10-15 minutes)
- epinephrine
- norepinephrine
- dopamine]
-angiotensinamide
They are administrated only
intravenous in the hospitals.
B. Medium action (20-90 minutes)
- adrenomimetics
(fenylephrine, izoprenaline)
Way of administration is
intravenous (20-40 minutes-)
intramuscularly
,subcutaneous (40-90 min)
They are administrated in
hospitals and prehospital conditions
C. Long action (60min.-2, 4 hours)
Adrenomimetics (ephedrine, etylephrine)
Izothyoureic derivates (difetur, izoturon)
Intravenous > 60 min.
S/c, i/m 2-4 hours
They are administrated in hospitals and prehospital
conditions also, during the patients transportation.
Classification of
vasoconstrictors ( Antihypotensives) according with the
type
of action
1. Vasoconstricors
with general and systemic action:
a) with the action on the vessels
(arteries and veins)
- sympaphomimetics
(adrenomimetics)
- izothyoureic derivates
b) arterials vasoconstrictors
- angiotensinamide
c) veins vasoconstrictors
- dihydroergotamine
- octapresine
- porlisine
2. vasoconstrictors with
specific territorial action
a) in the carotid zone
-ergotamine (small doses)
b) in the splanhnic zone
- vasopresine
3 vasoconstrictors with
local action
a)
nasal and conjunctive decongestives
- naphazoline - xylomethasoline - phenylephrine
- tetrizoline - ephedrine
b)
adrenaline+lidocaine or procaine for producing a long duration of action of
local anesthetics
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