Vasodilator &

Vasoconstrictor

• Vasodilating drugs act by reducing the contraction of vascular smooth muscle cells through a reduction in cytoplasmic Ca2+ concentration [Ca2+].

Vascular smooth muscle relaxation may be mediated by the following:

● Increased intracellular cyclic adenosine monophosphate

(e.g., β2-adrenoceptor agonists, epoprostenol)

● Increased intracellular cyclic guanosine monophosphate

(e.g., nitric oxide, nitroglycerin, sodium nitroprusside,

brain natriuretic peptide)

● KATP channel-opening-related hyperpolarization (e.g.,diazoxide)

● α1-Adrenoceptor antagonism (e.g., phentolamine)

● Ca2+ channel blockade (e.g.,diltiazem,nicardipine,verapamil)

● Reduction of central sympathetic tone (e.g., clonidine)

• HYDRALAZINE• Hydralazine, a hydrazine derivative, • dilates arterioles but not veins.• more effectively, in severe hypertension• combination of hydralazine with nitrates is

effective in heart failure • patients with both hypertension and heart

failure

• Pharmacokinetics & Dosage• well absorbed and rapidly metabolized

by the liver during the first pass, bioavailability is low (averaging 25%)

• metabolized in part by acetylation • half-life ranges from 1.5 to 3 hours,• vascular effects persist longer than do

blood concentrations, possibly due to avid binding to vascular tissue.

• Usual dosage ranges from 40 mg/d to 200 mg/d.

• higher dosages result in greater vasodilation

• Dosing two or three times daily provides smooth control of blood pressure.

• Toxicity• most common adverse

effects :headache, nausea, anorexia, palpitations, sweating, and flushing.

• In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias.

• With dosages of 400 mg/d or more, there is arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus.

• reversed by discontinuance of hydralazine.

• Peripheral neuropathy and drug fever are uncommon adverse effects.

• MINOXIDIL• very efficacious orally active vasodilator. • effect results from the opening of potassium channels in

smooth muscle membranes by minoxidil sulfate, the active metabolite.

• Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely.

• Like hydralazine, minoxidil dilates arterioles but not veins.

• greater potential antihypertensive effect

• Pharmacokinetics & Dosage• use of minoxidil is associated

with reflex sympathetic stimulation and sodium and fluid retention.

• Minoxidil must be used in combination with a blocker and a loop diuretic.

• Toxicity• Tachycardia, palpitations, angina, and

edema are observed when doses of beta blockers and diuretics are inadequate.

• Headache, sweating,and hypertrichosis, are relatively common.

• Minoxidil illustrates how one person's toxicity may become another person's therapy.

• Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness.

• SODIUM NITROPRUSSIDE• powerful parenterally administered

vasodilator :• used in treating hypertensive emergencies

as well as severe heart failure.• dilates both arterial and venous vessels,

resulting in reduced peripheral vascular resistance and venous return.

• action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme.

• The result is increased intracellular cGMP, which relaxes vascular smooth muscle

• Pharmacokinetics & Dosage• Complex of iron, cyanide groups, and a nitroso moiety.• rapidly metabolized by uptake into red blood cells with

liberation of cyanide. • in turn is metabolized by the mitochondrial enzyme

rhodanase, in the presence of a sulfur donor, to the less toxic thiocyanate.

• Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney.

• rapidly lowers blood pressure, and its effects disappear within 10 minutes after discontinuation.

• given by intravenous infusion.• made up fresh before each administration• Dosage typically begins at 0.5 mcg/kg/min and may be

increased up to 10 mcg/kg/min as necessary to control blood pressure.

• Because of its efficacy and rapid onset of effect, nitroprusside should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording.

• Toxicity• excessive blood pressure lowering• most serious toxicity is related to accumulation of cyanide;

metabolic acidosis, arrhythmias, excessive hypotension, and death have resulted.

• toxicity after relatively low doses :defect in cyanide metabolism. • Administration of sodium thiosulfate as a sulfur donor

facilitates metabolism of cyanide.• Hydroxocobalamin combines with cyanide to form the nontoxic

cyanocobalamin. • Thiocyanate may accumulate over the course of prolonged

administration, usually several days or more, particularly in patients with renal insufficiency who do not excrete thiocyanate at a normal rate.

• Thiocyanate toxicity is manifested as weakness, disorientation, psychosis, muscle spasms, and convulsions.

• Diagnosis > 10 mg/dL. • Rarely, delayed hypothyroidism occurs, owing to thiocyanate

inhibition of iodide uptake by the thyroid. • Methemoglobinemia also been reported.

• DIAZOXIDE• effective and relatively long-acting

parenterally administered • arteriolar dilator • occasionally used to treat hypertensive

emergencies.• Injection of diazoxide results in a

rapid fall in systemic vascular resistance and mean arterial blood pressure

• associated with substantial tachycardia and increase in cardiac output.

• Studies of its mechanism suggest that it prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level.

• Pharmacokinetics & Dosage• chemically to the thiazide diuretics• bound extensively to serum albumin and to vascular tissue. • partially metabolized;• half-life is approximately 24 hours, • The blood pressure-lowering effect after a rapid injection is established

within 5 minutes and lasts for 12 hours.• that excessive hypotension can be avoided by beginning with smaller

doses (150 mg). If necessary, doses of 150 mg may be repeated every 5 minutes until blood pressure is lowered satisfactorily. Nearly all patients respond to a maximum of three or four doses.

• Alternatively, diazoxide may be administered by intravenous infusion at rates of 30 mg/min.

• Because of reduced protein binding, hypotension occurs after smaller doses in persons with chronic renal failure, and smaller doses should be administered to these patients.

• The hypotensive effects of diazoxide are also greater when patients are pretreated with blockers to prevent the reflex tachycardia and associated increase in cardiac output.

• Toxicity• excessive hypotension• The reflex sympathetic response can provoke angina,

electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation.

• inhibits insulin release from the pancreas (probably by opening potassium channels in the beta cell membrane) and is used to treat hypoglycemia secondary to insulinoma.

• Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency.

• In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem.

• FENOLDOPAM• peripheral arteriolar dilator used for hypertensive emergencies and

postoperative hypertension.• acts primarily as an agonist of dopamine D1 receptors, resulting in

dilation of peripheral arteries and natriuresis. • commercial product is a racemic mixture with the (R)-isomer

mediating the pharmacologic activity.• rapidly metabolized, primarily by conjugation. • half-life is 10 minutes.• administered by continuous intravenous infusion. • initiated at a low dosage (0.1 mcg/kg/min), then titrated upward

every 15 or 20 minutes to a maximum dose of 1.6 mcg/kg/min or until the desired blood pressure reduction is achieved.

• As with other direct vasodilators, the major toxicities are reflex tachycardia, headache, and flushing.

• also increases intraocular pressure and should be avoided in patients with glaucoma.

VASODILATORS USED IN HYPERTENSIONDiazoxide (Hyperstat IV)Parenteral: 15 mg/mL ampuleOral (Proglycem): 50 mg capsule; 50 mg/mL oral suspension (for insulinoma)Fenoldopam (generic, Corlopam)Parenteral: 10 mg/mL for IV infusionHydralazine (generic, Apresoline)Oral: 10, 25, 50, 100 mg tabletsParenteral: 20 mg/mL for injectionMinoxidil (generic, Loniten)Oral: 2.5, 10 mg tabletsTopical (generic, Rogaine): 2% lotionNitroprusside (generic, Nitropress)Parenteral: 50 mg/vial

Drugs Used in Angina Pectoris

PREPARATIONS AVAILABLENITRATES & NITRITES•Amyl nitrite (generic)Inhalant: 0.3 mL capsules•Isosorbide dinitrate (generic, Isordil)Oral: 5, 10, 20, 30, 40 mg tablets; 5, 10 mg chewable tabletsOral sustained-release (Isochron, Dilatrate SR): 40 mg tablets and capsulesSublingual: 2.5, 5 mg sublingual tablets•Isosorbide mononitrate (Ismo, others)Oral: 10, 20 mg tablets; extended-release 30, 60, 120 mg tablets•NitroglycerinSublingual or buccal: 0.3, 0.4, 0.6 mg tablets; 0.4 mg/metered dose aerosol sprayOral sustained-release (generic, Nitro-Time): 2.5, 6.5, 9 mg capsulesParenteral (generic): 5 mg/mL for IV administration; 100, 200, 400 mcg/mL in dextrose for IV infusionTransdermal patches (generic, Nitrek, NitroDur, Transderm-Nitro): to release at rates of 0.1, 0.2, 0.3, 0.4, 0.6, or 0.8 mg/hTopical ointment (generic, Nitro-Bid): 20 mg/ mL ointment (1 inch, or 25 mm, of ointment contains about 15 mg nitroglycerin)

• OTHER NITRO-VASODILATORS

• Nicorandil is a nicotinamide nitrate ester that has vasodilating properties in normal coronary arteries but more complex effects in patients with angina.

• it reduces both preload and afterload.

• It also provides some myocardial protection via preconditioning by activation of cardiac KATP channels.

• Vasoconstriction::• Vaso refers to blood vessels • Constriction means to close Down

• Adrenergic Receptor Physiology• Alpha-1• Beta-1• Beta-2• Dopamine

• Alpha Adrenergic Receptors

• α1 Located in vascular walls

– Induces significant vasoconstriction• Present in heart

– Increase the duration of the contraction without increased chronotropy.

• Beta Adrenergic Receptors• Beta-1 adrenergic receptors are most common in the heart

– Mediate increases in inotropy and chronotropy with minimal vasoconstriction.

• Beta-2 adrenergic receptors in blood vessels induce vasodilation.• Dopamine Receptors• Present in the renal, splanchnic, coronary, and cerebral vascular beds.• Stimulation of these receptors leads to vasodilation.• Second subtype of dopamine receptors causes vasoconstriction by

inducing norepinephrine release

• Epinephrine (Adrenalin)• Potent α- and β-agonist

– vasoconstriction ↑ MAP

– ↑contractility and heart rate ↑cardiac output

• Indications

for low cardiac output states

– cardiovascular resuscitation

– anaphylaxis

• Potent beta-1 receptor activity and moderate beta-2 and alpha-1 receptor effects.

• Result is an increased CO, with decreased SVR and variable effects on the MAP.

• Beta-1 receptor stimulation may provoke dysrhythmias.

• Greater degree of splanchnic vasoconstriction.

• Most often used in treatment of anaphylaxis, as a second line agent in septic

shock and for management of hypotension following CABG.

• Norepinephrine (Levophed)

• Potent α1 and β1 agonist with little β2 activity

– α stimulation vasoconstriction

– β1 effects balanced by reflex activity little effect on heart rate and cardiac output

• Indications– an excellent vasopressor

• Dosage: 0.5 – 30 μg/min• Acts on both alpha-1 and beta-1 receptors

– Potent vasoconstriction as well as a less pronounced increase in cardiac output

• Reflex bradycardia usually occurs in response to the increased MAP– Mild chronotropic effect is cancelled out and the HR remains

unchanged or decreases slightly.• Used most commonly to treat septic shock.

• Phenylephrine (Neosynephrine)• Selectively stimulates α1 receptors

– vasoconstriction ↑SVR– as BP increases, vagal reflexes ↓heart rate

• Pure α-adrenergic agent – no ↑inotropy– distributive shock often cardiac depression– restoring MAP without ↑inotropy ↓C.O.

• Purely alpha-adrenergic agonist activity– Vasoconstriction with minimal cardiac inotropy or

chronotropy.• Useful in settings of hypotension with SVR < 700 dynes x

sec/cm5– Hyperdynamic sepsis, neurologic disorders, anesthesia induced

hypotension.• Contraindicated if SVR > 1200 dynes x sec/cm5

• Phenylephrine (Neosynephrine)

• Indications– anesthesia-induced hypotension– spinal shock– useful with tachycardia• arrhythmias with other vasopressors

Dopamine (Intropin)

• Dose-dependent stimulation– Low-dose (< 5 μg/kg/min)

• dopaminergic receptors

receptors in the renal mesenteric, cerebral, and coronary beds, resulting in selective vasodilation.

– Moderate dose (5-10 μg/kg/min)

• β1 stimulation ↑cardiac output

• predominately by increasing SV with variable effects on HR.

• Can result in dose-limiting dysrhythmias– High dose (> 10 μg/kg/min)

• α1 stimulation produces vasoconstriction with↑ SVR

• The dose-dependent effects of dopamine mean that increasing the dose of the drug is akin to switching vasopressors.

• Most often used in hypotension due to sepsis or cardiac failure

• Dopamine (Intropin)• Adverse effects– tachycardia, tachyarrhythmias– vasoconstriction-induced myocardial ischemia– ↓ splanchnic perfusion multiple organ failure

• Dobutamine (Dobutrex)• Not a vasopressor but rather an inotrope that

causes vasodilation.• Predominant beta-1 receptor effect increases

inotropy and chronotropy and reduces LV filling pressures.

• Minimal alpha and beta-2 receptor effects result in overall vasodilation, complemented by reflex vasodilation to the increased CO.

• Net effect is increased CO, with decreased systemic vascular resistance with or without a small reduction in BP.

• Frequently used in severe, medically refractory heart failure and cardiogenic shock.

• Should not be routinely used in sepsis because of the risk of hypotension.

• Does not selectively vasodilate the renal vascular bed.

• Phosphodiesterase Inhibitors• Amrinone and Milrinone• Nonadrenergic drugs with inotropic and

vasodilatory actions.• Effects are similar to dobutamine but with a lower

incidence of dysrhythmias.• Used to treat patients with impaired cardiac

function and medically refractory HF.• Vasodilatory properties limit their use in

hypotensive patients.

• Vasopressin• Usually used in the setting of esophageal variceal

bleeding.• May be useful in treatment of refractory septic shock,

as a second pressor agent.• addition of vasopressin to norepinephrine was more

effective in reversing late vasodilatory shock than norepinephrine alone.

• Complications include coronary and mesenteric ischemia, hyponatremia, pulmonary vasoconstriction, and skin necrosis from peripheral infusion.

• Antidiuretic hormone

– V2 receptors on renal tubules water resorption

• An important stress hormone

– V1 receptors on vessels vasoconstriction

– V3 receptors in pituitary ACTH production

– ↑ BP only with relative hypovolemia• SIADH does not cause hypertension

• Vasopressin• Indications– catecholamine resistance in sepsis– cardiac arrest unresponsive to epinephrine– may be useful for “irreversible” shock

• Dosage– Shock – 0.01 to 0.05 U/min by infusion– ACLS – 40 U as IV bolus

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