Vasopressors
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Dopamine ,Dobutamine
and other VASOPRESSORS
DR AFTAB HUSSAIN
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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
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CLASSIFICATION OF VASOPRESSORS NATURAL CATECHOLAMINES: Epinephrine , Norepinephrine , Dopamine
SYNTHETIC CATECHOLAMINES Isoproterenol , Dobutamine
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SYNTHETIC NONCATECHOLAMINES INDIRECT ACTING:Ephedrine, Mephentermine , Metarminol
DIRECT ACTING: Phenylephrine, Methoxamine
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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
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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
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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
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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.
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SYNTHESIS
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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
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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%)
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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
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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….
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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…
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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
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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…
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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
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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
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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
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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-
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Contraindications
Pt receiving MAO inhibitors Tricyclic antidepressants agents Pheochromocytoma Uncorrected tachyarrhythmia Ventricular fibrillation
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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 ]
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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…
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Use in Pregnancy – Category C
Lactation- Unknown whether drug is excreted in breast milk. To be used with caution
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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.
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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.
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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.
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Adverse effects-
TachyarrythmiasHypertensionEosinophillic myocarditisPalpitationNausea ,headache
Use in Pregnancy- category BLactation- unknown whether it is excreted in milk or
not.
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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.
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Onset- 5-10 min (SC) , 1 min (inhalational)
Duration- 4 hrs
Metabolism- enzymes (COMT) and monoamine oxidase (MAO)
Excretion- Urine
Pharmacokinetics
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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.
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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
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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
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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
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• 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.
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synthesis of nor epinephrine: tyrosine
dihydroxyphenylalanine
dopamine
norepinephrine
epinephrine
tyrosine hydroxylase
L-aromatic amino acid decarboxylase
dopamine-B-hydroxylase
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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.
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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%)
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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.
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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.
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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
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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
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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.
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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.
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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.
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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)
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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
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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
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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)
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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.
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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.
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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.
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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).
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Precautions: • Cardiovascular disease• Chronically ill patients • Hemorrhagic shock• Hyperthyroidism
Adverse effects:
CNS: anxiety, confusion, drowsiness, incoherence, tremors.
CVS: hypertension, palpitations, tachydardia, AV blocks
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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
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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.
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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 .
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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.
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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.
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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
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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%)
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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.
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Contraindication-
Hypersensitivity Chronic nephritis Pateints with polyuria.
Use in Pregnancy- Category C Lactation- Unknown if secreted in milk or not.
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