Dopamine ,Dobutamine

and other VASOPRESSORS

DR AFTAB HUSSAIN

Vasopressors VASO-vessels, PRESSORS- pressure.Increase the blood vessel pressure thereby increasing blood pressure.

Vasopressors are class of drugs that elevate Mean Arterial Pressure (MAP) by inducing vasoconstriction.

Many drugs have both vasopressor and inotropic effects.

Vasopressors are indicated for a decrease of >30 mmHg from baseline systolic blood pressure or MAP <60 mmHg, when either condition results in end-organ dysfunction secondary to hypoperfusion.

Introduction

CLASSIFICATION OF VASOPRESSORS NATURAL CATECHOLAMINES: Epinephrine , Norepinephrine , Dopamine

SYNTHETIC CATECHOLAMINES Isoproterenol , Dobutamine

SYNTHETIC NONCATECHOLAMINES INDIRECT ACTING:Ephedrine, Mephentermine , Metarminol

DIRECT ACTING: Phenylephrine, Methoxamine

Adrenergic receptors are divided into two general categories- a and b receptors.

They have various subtypes. a1 receptors – mostly postsynaptic, present in smooth

muscles throughout the body. Activation leads to vasoconstriction, bronchconstriction, constriction of sphinctors

Most important cardiovascular effect is vasoconstriction which increases peripheral vascular resistance, left ventricular afterload and arterial blood pressure.

Receptor physiology

a2 receptors- mostly presynaptic, Central a2 receptors cause sedation and anxiolysis.

b1 receptors- Mostly cardiogenic, postsynaptic membranes of heart, have positive chronotropic, ionotropic and dromotropic effect.

b2 receptors- Primarily postsynaptic on smooth and gland cells. Relaxes smoooth muscles.

b3 receptors- Gall bladder, brain and adipose tissue. Pay role in thermogenesis and lipolysis of brown fat.

Dopaminergic receptors- D1 and D2

Description and Pharmacology The function of dopamine as a neurotransmitter was

discovered in 1958 by ARVID CARLSSON. It was named dopamine because it was a monoamine,

and its synthetic precursor was 3,4-dihydroxyphenylalanine .

Dopamine

Dopamine is an endogenous catecholamine that serve as both a neurotransmitter and a precursor of nor epinephrine synthesis.

When given as an exogenous drug dopamine activates a variety of receptors in dose dependent manner.

Regulates cardiac, vascular and endocrine function.

SYNTHESIS

o Dopamine acts through D1 , D2 as well as adrenergic alpha and b1 receptors ( But not b2)

o D1 and D2 receptors are the most abundant and widespread in areas receiving a dopaminergic innervation ( namely the striatum ,limbic system, thalamus and hypothalamus) as are D2 receptors, which also occur in the pituitry gland

RECEPTORS

Pharmacokinetics-

Onset – 5 minsDuration of action- < 10 min

Metabolism- metabolized in liver, kidney and plasma by monoamine oxidase and COMT.

Elimination- T ½- 2 min Excretion – urine (80%)

AT LOW DOSE (0.5 to 3 mic /kg /min

Selectively activates dopamine specific receptors in the renal and splanchnic circulation.

Increase blood flow in these region. Low dose dopamine also directly affects renal

tubular epithelial cells. It causes an increase in urinary Na excretion

MECHANISM OF ACTION

INTERMEDIATE DOSE (3 to 10 mic /kg /min )

It stimulates b1 receptors in the heart and peripheral circulation.

Increases myocardial contractility, increases heart rate and peripheral vasodilatation

It increases myocardial oxygen demand, so when ever dopamine is to be used oxygen must be supplemented

Over all increase in cardiac output Contractile response to dopamine is modest when

compared to dobutamine

Contd….

AT HIGH DOSE (> 10 mic /kg / min ):- Dopamine produces a progressive activation of alpha

receptors in the systemic and pulmonary circulation resulting in progressive pulmonary and systemic vasoconstriction

This vassopressor effect is by virtue of increasing ventricular afterload

Dopamine not effective orally and does not cross blood brain barrier in sufficient amounts to cause CNS effects.

Contd…

Clinical uses and Indications

Dopamine is often used in situation where both cardiac stimulation and peripheral vasoconstriction is desired such as cardiogenic shock

Also used to correct the hypotension in the septic shock .But norepinephrine has become the preferred vassopressor in this condition

Low dose is often used in an attempt to prevent or reverse acute renal failure

Drug initially administered at a rate of 2 to 5 m/ kg /min .During infusion,pt require clinical assessments of myocardial function perfusion of vitals organs such as the brain , and the production of urine

Most pts should receive intensive care with monitoring of arterial and venous pressures and ECG

Reduction in urine flow ,tachycardia or the development of arrhythmias may be indications to slow or terminate the infusion

Contd…

The sympathomimetic amines dopamine is potent ionotropic agents

Used in pulmonary edema

Forcefully contracts the heart and thus decreases the pulmonary load

DOPAMINE IN PULMONARY OEDEMA

Commercial preparation of dopamine are concentrated drug solution [Containing 40 mg /80 mg dopamine HCL /ml]

Preparation must be diluted to prevent intense vasoconstriction during drug infusion.

Dopamine solution diluted in isotonic saline to prepare the infusate. It can be prepared in NS,D5 but not in RL and DNS.

DOSE AND ADMINISTRATION

Weight based There are two recommended doses:- 3 to 10 mic /kg /min is for augmenting cardiac

output thereby increasing BP More than 10 mic /kg /min is recommended to

increase the blood pressure directly

DOSING REGIMEN

Use 5 ml 2 ampoule / vials containing 40 mg /ml dopamine HCL add to 500 ml isotonic saline [Final concentration= 40mic /drop ]

Precaution- Before dopamine is administered to pt in

shock ,hypovolemia should be corrected by transfusion of whole blood , plasma or other appropriate fluid

Infusate-

Contraindications

Pt receiving MAO inhibitors Tricyclic antidepressants agents Pheochromocytoma Uncorrected tachyarrhythmia Ventricular fibrillation

Adverse effects-

o Tachyarrhythmia's are the most common adverse effects of dopamine

o Malignant tachyarrhythmia [ Multifocal ventricular ectopic , ventricular tachycardia ]

o The most feared complication of dopamine infusion is limb (Fingers /toes ) necrosis

o Extravasations of drug through a peripheral vein can be treated with local injection of phentolamine [5 to 10 mg in 15 ml saline ]

Ocular- Increases IOP. Hyperglycemia that is commonly present in pts

receiving a continuous infusion of dopamine is likely to reflect drug induced inhibition of insulin secretion.

Respiratory- Dyspnoea CNS- headache, anxiety

Contd…

Use in Pregnancy – Category C

Lactation- Unknown whether drug is excreted in breast milk. To be used with caution

Dobutamine

Description and pharmacology Synthetic catchecholamine

Mechanism of action Primarily b1, mild b2. Dose dependent increase in stroke volume and cardiac output,

accompanied by decreased filling pressures. SVR may decrease, baroreceptor mediated in response to

SV. BP may or may not change, depending on disease state. Favorable effect on myocardial oxygen balance is believed to

make dobutamine a choice for patients with CHF and CAD.

Pharmacokinetics

Onset- 1-10 min Duration -10 min Metabolism- tissues and liver by COMT Elimination- T ½- 2 min Excretion- urine mainly Dose- Administered as infusion @ 2-20mcg/kg/min.

Indication and uses Useful in right and left heart failure. May be useful in septic shock.

Contraindication Pt receiving MAO inhibitors Tricyclic antidepressants agents Pheochromocytoma Patients having tachyarrythmias.

Adverse effects-

TachyarrythmiasHypertensionEosinophillic myocarditisPalpitationNausea ,headache

Use in Pregnancy- category BLactation- unknown whether it is excreted in milk or

not.

Epinephrine

Description and Pharmacology Endogenous catchecholamine.

Mechanism of action b activity at very low doses, a at higher doses. Direct stimulation of b1 receptors of myocardium

raises blood pressure , cardiac output and even myocardial O2 demand.

a1 stimulation decrease splanchnic and renal blood flow. Some effects on metabolic rate, inflammation.

Onset- 5-10 min (SC) , 1 min (inhalational)

Duration- 4 hrs

Metabolism- enzymes (COMT) and monoamine oxidase (MAO)

Excretion- Urine

Pharmacokinetics

Indication and uses-

In emergency(cardiac arrest and shock) administered in IV dose of 0.05-1 mg. Continous infusion is given @ 0.015m/kg/min.

In Severe asthma and anaphylaxis epinephrine is uesd in the dose of 100-500mcg.

Also used to reduce bleeding from operative site.

Contraindications-

Patient on MAOI Patient on anti arrythmic drugs like procainamide and

quinidine.

Adverse effects-

Angina, arrythmias, palpitations. Anxiety, dizziness, flushing Sweating, tachycardia, resp. difficulty

Ampules are available in conc of 1:1000 (1000mcg/ml).

In paediatric patient conc of 1:100000 is used.

Use in Pregnancy- category B Lactation- unknown if excreted in breast milk or not

Description and Pharmacology-

It is also called as norepinephrine . The two structures differ only in that epinephrine has

a methyl group attached to its nitrogen, while the methyl group is replaced by a hydrogen atom in norepinephrine.

It acts as transmitter at postganglionic sympathetic sites.

Norepinephrine is a catecholamine and a ethylamine.

Noradrenaline

• The prefix nor-, is derived from the German abbreviation for "N ohne Radikal" (N, the symbol for nitrogen, without radical) referring to the absence of the methyl functional group at the nitrogen atom.

synthesis of nor epinephrine: tyrosine

dihydroxyphenylalanine

dopamine

norepinephrine

epinephrine

tyrosine hydroxylase

L-aromatic amino acid decarboxylase

dopamine-B-hydroxylase

Pharmacological action of noradrenaline

Potent action-both a1 & b1 receptors◦ Little action on b2◦ Causes potent vasoconstriction (α) as well as a less

pronounced increase in cardiac output◦ Lacks bronchodilating effect◦ ↑ systolic, diastolic & MAP

Causes Reflex bradycardia

May decrease tissue blood flow leading to metabolic acidocis.

Pharmacokinetics

Absorption Orally ingested noradrenaline is destroyed in the GI tract

and the drug is poorly absorbed after subcutaneous injection.

Onset- 1-2 minDuration- 1-2 minMetabolism- by COMT and MAODistribution Localises mainly in sympathetic nervous tissue. Crosses the placenta but not the blood-brain barrier.Excretion- mainly urine (84-96%)

Uses:

Used to maintain BP in hypotensive states It causes rise in systolic ,diastolic and mean arterial

pressure  Used as an adjunct to correct hemodynamic imbalances

in the treatment of shock that persists after adequate fluid volume therapy

First-line therapy for the maintenance of blood pressure and tissue perfusion in septic shock.

Uses (cont)

Adjunctive Treatment in Cardiac Arrest Infusions of noradrenaline are usually given during

cardiac arrest to restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means.

Adjunctive to Local Anesthesia It is added to solutions of some local anesthetics to

decrease the rate of absorption thereby localizing anaesthesia and prolonging the duration of action.

Dosage

The usual dose range is 0.01-0.1 m/kg/min Average adult maintenance dosage: 2–4 mcg/minute May require 8–30 mcg/minute in cases of refractory

shock

Dilution- Drug is diluted with 5% dextrose or dextrose

normal saline Should not be mixed with alkaline solution

Norepinephrine infusion

Noradrenaline should be administered through central venous devices to minimize the risk of extravasation and subsequent tissue necrosis

The infusion should be at a control rate and the patient should be monitored carefully for the duration of noradrenaline (norepinephrine) therapy.

The infusion must not be stopped suddenly but should be gradually withdrawn to avoid disastrous falls in blood pressure

Adverse effects-

Hypertension , bradycardia, arrhythmias, palpitations ischemic injury due to potent vasoconstrictor action

may result in coldness and paleness in periphery. anxiety, insomnia,Confusion,Headaches,psychosis Weakness,Tremor anorexia, nausea and vomiting.

Extravasation effect and management

The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of noradrenaline into the tissues, as local necrosis might ensue due to the vasoconstrictive action of the drug.

If blanching occurs, the infusion site should be changed at intervals to allow the effects of local vasoconstriction to subside.

To prevent sloughing and necrosis in areas in which extravasation has taken place, the area should be infiltrated as soon as possible with 10 ml to 15 ml of saline solution containing 5 mg to 10 mg of phentolamine, an adrenergic blocking agent.

Drug interaction-

Non-selective MAO inhibitors selective MAO inhibitors Linezolid Thyroid hormones Cardiac glycosides Ergot alkaloids or oxytocin All of these enhance the vasopressor and

vasoconstrictive effects.

Contraindications-

Patient with pheochromocytoma Noradrenaline should also not be given to patients

with mesenteric or peripheral vascular thrombosis (because of the risk of increasing ischaemia and extending the area of infarction)

Differences between Epinephrine and Norepinephrine Epinephrine >> norepinephrine – in terms of cardiac

stimulation leading to greater cardiac output ( stimulation).

Epinephrine < norepinephrine – in terms of constriction of blood vessels – leading to increased peripheral resistance – increased arterial pressure.

Epinephrine >> norepinephrine – in terms of increasing metabolism

Maintaining adequate MAP ,hepatic blood flow and oxygen exchange with dopamine required a consequent increased cardiac output. Which was responsible for increase global oxygen demand

Dopamine also impairs hepatic energy balance.

Dopamine vrs Noradrenaline

MephentermineDescription and pharmacology-It is synthetic, non catchecholamine and indirect acting.

Pharmacokinetics-MECHANISM OF ACTION: Indirectly acting by

evoking release of endogenous neurotransmitter norepinephrine from postganglionic sympathetic nerve endings.

ONSET: 5-15min(IM),immediate(IV)

DURATION:4 hrs(IM),30 mins(IV)

Effect on CVS and other system-

It raises BP by increasing Cardiac output and peripheral vascular resistance.

AV conduction and refractory period of AV node is shortened with an increase in ventricular conduction velocity.

Effect becomes more prominent with atropine.

It dilates arterioles in skeletal muscles and mesentric vascular bed.

Increases renal blood flow. No effect on bronchial muscle and respiration. May cause drowsiness or convulsions. Effect fades off with time due to tachyphylaxis.

Indication and use• Hypotension during spinal anesthesia and GAHypotension, secondary to spinal anesthesia (prophylaxis):Intramuscular, 30 to 45 mg, administered ten to twenty minutes prior to anesthesia.(treatment):Intravenous, 10-25 mg given as a single dose(In a 70 kg adult) .6mg iv bolus is in common practice. Dose can be repeated according to response.

Drug interaction and contraindication-

Severe HTN in patients on MAOIs. Risk of arrhythmias in patients on cardiac glycosides,

quinidine,tricyclic antidepressants ,halothane Hypersensitivity Loss of control of HTN in patients on adrenergic

neuron blocking agents(reserpine,methyldopa,

guanethedine).

Precautions: • Cardiovascular disease• Chronically ill patients • Hemorrhagic shock• Hyperthyroidism

Adverse effects:

CNS: anxiety, confusion, drowsiness, incoherence, tremors.

CVS: hypertension, palpitations, tachydardia, AV blocks

It is a non catchecholamine , sympathomimetic drug similar to epinephrine.

MECHANISM OF ACTION :Alpha and b1 adrenergic agonist; indirect effects via

norepinephrine release.Action leads to increase in blod pressure, cardiac output, heart

rate and contractility.

Ephedrine

INDICATIONS: Hypotension due to anaesthesia and regional blocks.

However it is a temporary measure. Used orally for bronchial asthma and coryza Used as antiemetic. To treat diabetic neuropathic edema.

ADULT DOSE: 10 to 25mg iv in hypotension. 3-6mg iv bolus is given.repeated according to patients

response.

Available as:1ml ampoule containing 30mg/ml .

Adverse Effects:

•CVS: tachycardia, cardiac arrhythmias ,angina ,vasoconstriction • anorexia, nausea •difficulty in micturition in patients with BPH•CNS: restlessness, confusion, insomnia, mild euphoria, agitation •Respiratory: dyspnea, pulmonary edema •Headache, tremor, hyperglycemic reactions .

Contraindications- Closed angle glaucoma Pheochromocytoma hypertrophic subaortic stenosis Thyrotoxicosis

Drug ineractions- Prolongs half life of dexamethasone Synergistic bronchodilation but increased adverse effects

with theophylline Increased vasoconstriction with oxytocin. Severe HTN with MAOI interaction may occur upto 2 wks

after cessation of MAOIs therapy.

Choice of vasopressors in pregnancy :

Traditionally ephedrine has been the vasopressor of choice in pregnant women.

Ephedrine readily crosses the placenta,and stimulates fetal metabolism by direct beta effects and also by releasing catecholamines.

Sympathectomy resulting from regional anaesthesia shunts blood primarily into mesentric bed and alpha agonists like phenylephrine selectively constricts the mesentric bed than uteroplacental vasculature.

Phenylephrine has faster onset , shorter duration of action, better titrability and maintainance of fetal pH.

Description and pharmacology- It is Non adrenergic sympathomoimetic Also known as Anti diuretic hormone (ADH) Chemically it is made of peptide chains. Exogenous prep

of ADH

Mechanism of action- Vasoconstrictor without ionotropic or chronotropic effects. Also stimulates smooth muscles in GI tract to cause

peristalsis.

Vasopressin

Pharmacokinetics-Absorption- Destroyed in GI tract. Administered parenteraly or

intranasaly. Onset- IM/SC 2-8 hr (antidiuretic activity) IV- 30-60 min (pressor activity)Metabolism-Metabolism in liver and kidney, rapidly removed from

plasmaElimination- T ½- 10-20 min Excretion- urine (5-10%)

Indication and uses-

Diabetes Insipidus 5-10 units IM/SC Adjunct in GI bleed and esophageal varices. New clinical indication is in pateints with septic shock

and cardiac arrest (40 IU in 40 ml) IV. (dose-0.01-0.04 unit/min IV)

ACLS guidelines recommend Vasopressin in place of epinephrine in pulseless arrest.

Contraindication-

Hypersensitivity Chronic nephritis Pateints with polyuria.

Use in Pregnancy- Category C Lactation- Unknown if secreted in milk or not.

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