PHYSIOLOGY
Adrenergic Receptors - types and location
Alpha receptors
alpha1 - postjunctional
alpha2 - pre/postjunctional
Beta receptors
beta1 - heart, JG cells (kidney)
beta2 - bronchi, blood vessels, uterus, liver, GIT, Urinary tract, eye
beta3 - adipose tissue
actions of Acetylcholine
CVS - negative chronotropic, inotropic, dromotropic, vasodilation, fall in BP
GIT - increases peristalsis, secretions
Urinary bladder : promotes emptying - contraction of detrusor muscle, relaxation of urinary sphincter
Bronchi : bronchoconstriction, stimulate secretions
•Exocrine glands
Increases salivary, lacrimal, sweat, bronchial, gastric and other GI secretions.
Contracts sphincter pupillae – miosis
Contracts ciliary muscle – spasm of accommodation
what are the naturally occurring sympathomimetics
Adrenaline
Noradenaline
Dopamine
Name 2 Selective Alpha2 agonists
and the ratio of alpha1:alpha2 agonism
Clonidine 1:400
Dexmedetomidine 1:1600
side effect of abruptly discontinuing of chronically administered clonidine
severe rebound hypertension within 8-36 hours of discontinuation
sympathetic and parasympathetic outflow
sympathetic
lumbar sympathetic chain
parasympathetic
cranial nerves 3 (ciliary),7(pterygopalatine & submandibular),9(otic), 10(cardiac, pulmonary, coeliac, inferior mesenteric, hypogastric plexus)
s2, s3, s4
doses for NMB reversal
neostigmine
atropine
glycopyrrolate
Neostigmine 60-80mcg/kg
Atropine 7-10 mcg/kg
Glycopyrrolate 7-15 mcg/kg
dose of dobutamine infusion
2.5-10 mcg/kg/min
Adverse effects of beta blockers
bronchoconstriction
suppression of insulin secretion
blunting of the catecholamine response to hypoglycemia
excessive myocardial depression
atrioventricular heart block
accentuated increases in plasma concentrations of potassium with intravenous infusion of potassium chloride
fatigue
rebound tachycardia associated with abrupt drug discontinuation.
A 30 year old female patient suffering from PONV was treated with a patch. Following application, if one's hands are not properly washed, and any drug remains on the fingertips, rubbing an eye can lead to unilateral pupillary dilatation. What is the drug patch used in this scenario ?
SCOPOLAMINE
half life of pseudocholinesterase
Pseudocholinesterase (also called plasma cholinesterase) is an enzyme found in plasma and most other tissues (except erythrocytes).
Pseudocholinesterase metabolizes the acetylcholine released at the neuromuscular junction, as well as certain drugs such as succinylcholine, mivacurium, and ester-type local anesthetics.
It is produced in the liver and has a half-life of approximately 8 to 16 hours.
Pseudocholinesterase levels may be reduced in patients with advanced liver disease. The decrease must be greater than 75% before significant prolongation of neuromuscular blockade occurs with succinylcholine
compare and contrast aropine and glycopyrrolate
A G
Antisialagogue effect + ++
Sedative and amnesic effects + 0
Increased gastric fluid pH 0 0/+
Relaxation of lower esophageal sphincter ++ ++
Mydriasis and cycloplegia + 0
Heart rate ++ +
phenylephrine
Synthetic non catecholamine
Direct action by stimulating alpha 1 adrenergic receptors, indirect effect by release of norepinephrine, Minimal effect on beta
Causes more venoconstriction than arterial constriction
dose :
50-200mcg bolus (0.5-1mcg/kg)
20-100 mcg/min infusion (0.25-1mcg/kg/min)
reflex bradycardia
increases coronary perfusion
decreases renal blood flow
treatment of bradycardia from beta blockade
Symptomatic bradycardia as a result of excessive β-adrenergic receptor blockade can be treated with a variety of drugs, as well as with a pacemaker.
Treatment depends upon severity of symptoms.
Atropine can block any parasympathetic nervous system contribution to the bradycardia. If atropine is not effective, then a pure β-adrenergic receptor agonist can be tried.
For excessive cardioselective β1 blockade, dobutamine can be used;
for a noncardiac selective β1 and β2 blockade, isoproterenol can be chosen.
Dopamine is not recommended because the high doses needed to overcome β-adrenergic receptor blockade will cause significant α-adrenergic receptor–induced vasoconstriction.
Glucagon at an initial dose of 1 to 10mg intravenously followed by an infusion of 5mg/hr often is believed to be the drug of choice for β-adrenergic blockade overdosage. Glucagon increases myocardial contractility and heart rate, primarily by increasing cAMP formation (not via β-adrenergic receptor stimulation) and, to a lesser extent, by stimulating the release of catecholamines.
Aminophylline inhibits phosphodiesterase, resulting in an increase in cAMP. Thus, like glucagon, aminophylline increases cardiac output and heart rate via a non–β-adrenergic receptor–mediated mechanism.
Calcium chloride may prove useful to counteract any decrease in myocardial contractility induced by the β-blockade; however, this effect may be transient
Which of the following medications would be most appropriate to treat symptomatic bradycardia 1 month after cardiac transplant
atropine
glycopyrrolate
isoprenaline
phenylephrine
Different surgical techniques are used to suture the donor heart to the cuff of the recipient heart.
In any case, donor sinoatrial (SA) node is severed of its autonomic nervous system connections.
As a result, all of the drugs that use SA node and normal conduction system of the heart to produce their cardiac effects fail to produce their effects in a transplanted heart.
Although α1 receptors are found in the heart, their stimulation with phenylephrine is not associated with chronotropic effects.
Only drugs that are able to directly stimulate the adrenergic receptors found in the myocardium are useful in treating bradycardia in a transplanted heart.
Isoproterenol being a direct β1 stimulant is the drug of choice to treat an episode of bradycardia under these circumstances
metabolism of epinephrine
reuptake at post ganglionic nerve endiings
diffusion from the receptor sites
Metabolism of NE and Epinephrine is by MAO and COMT.
The primary urinary metabolite produced by MAO/COMT is VMA (vanillylmandelic acid) is 2-4mg in 24hours,elevated levels suggest pheochromocytoma
anticholinesterase that crosses the blood brain barrier.
used in the treatment of which condition ?
Physostigmine
central anticholinergic syndrome
ephedrine uses
Indirectly acting synthetic sympathomimetic (non catecholamine)
Direct action on adrenergic receptors and indirect action by release of norepinephrine.
5-10 mg IV is used to increase SBP during regional anaesthesia
Uterine blood flow is not affected, safer to administer in pregnant women following spinal anaesthesia
Can be used to treat asthma as an oral medication due to beta 2 agonistic activity, in symptomatic relief of coryza
Antiemetic effect is useful in patients undergoing laparoscopy under GA (0.5mg/kg IM)
Increased myocardial contractility by activation of beta 1 receptors
elimination half life of Esmolol
how is it metabolized?
9 minutes
by plasma cholinesterase
drugs that exhibit tachyphylaxis
ephedrine
dobutamine
mephentermine
phentolamine
The hemodynamic consequences mainly result from sympathetic blockade on venous territories - triggers the distension of the capacitive system, and storage of blood in dependent parts, resulting in decreased venous return and a reduction of cardiac output causing hypotension.
Bradycardia may also occur for lower block levels because of the significant decrease in heart preload . This can trigger different reflexes that result in severe bradycardia or asystole .
One of these reflexes is triggered by mechanoreceptors located in the left ventricule,are activated by a rapid decrease in ventricular volume and feedback occurs through the vagus nerve, which triggers a vasodepressor response by increasing the activity of the PNS.
As a consequence, systemic vasodilatation, hypotension, and bradycardia occurs. This reflex is called the Bezold-Jarisch reflex, or vasovagal syncope, or neurocardiogenic syncope.
It can be triggered centrally by psychological stress, pain, or changes in position, but can also be peripherally initiated by a decrease in venous return.
The use of mixed sympathomimetic agents is most suitable in the management of hemodynamic changes. Ephedrine, as an alpha and beta agonist agent, is effective in both increasing blood pressure and correcting bradycardia, which mostly arises from a decrease in venous return. in profound bradycardia, atropine or adrenaline may ne necessary.
A 58-year-old patient is brought to the emergency room with the following symptoms: miosis, abdominal cramping, salivation, loss of bowel and bladder control, bradycardia, ataxia, and skeletal muscle weakness. The most likely diagnosis is
The symptoms described in this patient are consistent with cholinergic stimulation or increased levels of acetylcholine that occur with anticholinesterase (OP) poisoning.
Stimulation of the parasympathetic nervous system produces miosis, abdominal cramping, excess salivation, loss of bowel and bladder control, bradycardia, and bronchoconstriction.
These symptoms are treated with atropine. The acetylcholinesterase reactivator pralidoxime sometimes is added to treat the nicotinic effects of elevation of acetylcholine at the neuromuscular junction of skeletal muscle (i.e., skeletal muscle weakness, apnea).
Atropine is administered in doses of 2 to 6mg and is repeated every 5 to 10 minutes until secretions begin to decrease. In most cases, 2mg every 8 hours is needed. However, doses of 15 to 20mg are not uncommon and occasionally doses over 1000mg have been needed.
Pralidoxime 600mg removes the organophosphate compounds from acetylcholinesterase and is often used in conjunction with atropine.
CNS effects of elevated acetylcholine levels can include confusion, ataxia, and coma. In addition, supportive therapy (the ABCs of resuscitation [Airway, Breathing, Circulation, etc.]) is provided as needed
isoprenaline
Synthetic catecholamine
Beta 1 and beta 2 receptor stimulation
Devoid of alpha agonistic effects – no vasoconstriction
At 1-5mcg/min, increases heart rate, myocardial contractility, cardiac automaticity and causes vasodilation in skeletal muscles(↓SVR), may decrease MAP.
Rapid metabolism by COMT in liver
Effective in increasing the heart rate in patients with heart block.
For sustained increase in HR before insertion of pacemakers
Decrease in pulmonary vascular resistance maybe used in the treatment of PAH and RV dysfunction.
Adverse effects : Vasodilation and decreased DBP, tachyarrhythmia – decrease in coronary blood flow and increase in oxygen demand - MYOCARDIAL ISCHAEMIA
Phentolamine
mechanism of action,metabolism, adverse effects, uses, dose
non selective alpha blocker
alpha 1 blockade - peripheral vasodilation, decrease SBP
alpha 2 blockade - enhanced release of norepinephrine + baroreceptor mediated reflex cardiac stimulation = increased HR and CO
a/e - Hyperperistalsis, diarrhoea and vomiting may occur due to parasympathetic predominance
onset 2 min, duration 10-15 min
Hepatic metabolism, excreted in urine.
Principally used in acute hypertensive emergencies during manipulation of phaeochromocytoma
dose : 30-70 mcg/kg IV (intermittent boluses 1-5mg)
Continuous infusion at 0.1-2 mg/min can be used to maintain normal BP
Can be used to treat extravasation of sympathomimetics – 5-15mg in 10ml NS
A 75-year-old woman is scheduled for mitral valve repair. High-dose fentanyl is used to induce anesthesia. In order to counteract the bradycardia caused by fentanyl, pancuronium is administered. Pancuronium blocks the bradycardia caused by fentanyl by acting on which receptors?
Patients with valvular heart disease are sometimes extremely sensitive to abrupt changes in the heart rate.
High-dose fentanyl has been shown to cause bradycardia through its effect on the vagus nerve. To some extent, this may be desirable in a patient with stenotic valvular lesion. In case of regurgitant lesions, this may lead to critical decrease in cardiac output.
In order to counteract this bradycardia action of the fentanyl, some anesthesiologists like to use a muscle relaxant that causes tachycardia. Pancuronium and an older nondepolarizing muscle-relaxant gallamine were used for this purpose.
Effect of pancuronium on the heart rate is elicited at the level of sinoatrial node by blockade of the muscarinic receptors.
On the other hand, effect of fentanyl that caused bradycardia was more through central nuclei of the vagus nerve.