The metabolites are excreted in urine as:
Vinyl mandelic acid , 3,4 dihydroxy mandelic acid
Presynaptic regulation of NE release:
By Autoreceptors: autoregulation of the release of
β1---- positive feed back
α2 ----- Negative feed back
Subtypes/Locations & Characteristics of Adrenoceptors
Location Pharmacologic effects Result of Agonist
smooth muscles of BV
specially of skin & mucosa.
Radial muscle of eye
SM of prostate& bladder base
phospholipase C ↑IP3,
DAG , ↑ intracellular
Adrenergic Receptors : Different types. All are GPCR.
subtypes/locations & characteristics of Adrenoceptors
Presynaptic nerve terminals
Postsynaptic effector cells of
Some vascular SM
N E release
Inhibition of lipolysis
outflow & sedation
subtypes/locations & characteristics of Adrenoceptors
Location Pharmacologic effect Result of Agonist
Postsynaptic effector cells
JGA of renal tubules
ciliary body epithelium
Presynaptic adrenergic &
↑ HR & force of contraction
↑ renin release
↑ secretion of aqueous humor
↑ transmitter release
subtypes/locations & characteristics of Adrenoceptors
Receptor Location Pharmacologic effects Result of
Postsynaptic effector cells
Smooth Msl of some BV ,
specially of skeletal M
Promotes potassium uptake
Postsynaptic effector cells
lipocytes,(fat cells) Activates lipolysis
subtypes/locations & characteristics of peripheral Dopamine
Receptor Location Pharmacologic
Result of Agonist
SM of renal & other
Dilation of BV
Stimulation of Adenylyl
Presynaptic Nerve terminals Modulates
Up regulation of β receptors: Increase in number of receptors
Seen on prolonged use of β antagonists.
Desensitization / Down regulation:
Prolonged exposure to catecholamines (agonists)reduces the
Example: The therapeutic effect of β2 agonists (
bronchodilation )-decreases on prolonged in Asthma.
Natural: Epinephrine (Adrenaline)
Nor epinephrine (Noradrenaline)
II. Non- Catecholamines
& many more
Source: Natural Catecholamine produced by
cells of adrenal medulla & certain areas of brain.
Released into the circulation 80-90% along with
Nor-epinephrine 10-20 %
MOA of Epinephrine
Acts as agonist on adrenergic receptors
Epinephrine is the drug of first choice.
IV Dose 100-500mcg repeated if necessary followed by
IM - 1:1000 sol 0.3-0.5 ml. May be repeated after 10-20
Status Asthmatics / Acute severe Asthma:
S/C injection of epinephrine 0.3 ml of 1 in 1,000 solution, .
Repeated in 20. min (max. 3 dose).
To prolong action of infiltration L.A & to
1 in 200,000 solution of Epinephrine is added to LA.
This prolongs the DOA due to vasoconstriction & ↓systemic
1 : 200,000 or 1:400,000 Nasal packs for epistaxis or
gingival string for gingivectomy.
Cardiac Resuscitation: in complete heart block &
cardiac arrest. dosage - .5 – 1 mg repeated over 3-5 min.
Cardiac arrhythmias: due to increased automaticity of latent
Pulmonary edema may be produced.
CNS : Only at high doses
fear, Anxiety, Restlessness, Headache ,Tremors.
Hyperthyroidism: Enhanced CVS effects
With Cocaine: Enhanced CVS effects
Diabetes: Risk of Hyperglycemia
Beta blockers: Marked effect on alpha receptors--- Rise in blood
With Inhalational General anesthetics:
Inhalational General anesthetics sensitize the heart to action of
epinephrine---- risk of Cardiac arrhythmias
released from postganglionic sympathetic nerve endings
Also released from adrenal medulla (10-20 %) with Epinephrine.
In pheochromocytoma ,it may be 97%
Effects similar to epinephrine on α & β1 receptors.
Relative little effects on β2 receptors
Direct α1-stimulation in the absence of β2-activity induces intense
vasoconstriction of arterial and venous vessels.
β1 stimulation – increased contractility of myocardium
Incease systemic vascular resistance, diastolic &systolic blood pressure ,
mean arterial pressure& minimal change in heart rate( baroreceptor
refractory hypotention in severe sepsis
Septic shock bolus (0.1mcg/kg) or infusion at a rate of 3–12 μ
Adverse effects :
Use cautiously in pt with right ventricular failure
Extravasation of norepinephrine at the site of intravenous
administration can cause tissue necrosis.
Dopamine is an endogenous catecholamine
D1-vasodialation in renal, mesentric, coronary & cerebral vascular
D2- inhibit release of norepinephrine ,leading vasodialation.
Activate emetic center in medulla- nausea & vomiting ,
suppress secretion &function of ant. Pitutatary harmone
Act on β1 & α receptor (high dose)
The clinical effects of dopamine (DA), a nonselective direct and
indirect adrenergic agonist, vary markedly with the dose.
Small doses ( .5-2 μg/kg/min) renal dose– d1 and d2 receptors.
moderate doses (2–10 μ g/kg/min)- β1-stimulation .
higher doses(>10μg/kg/min)-α1-effects become prominent
Shock to improve cardiac output, support blood pressure, and
maintain renal function.
Combination therapy dopamine with dobutamine to increase
cardiac output & coronary perfusion
as a continuous infusion at a rate of 1–20 μg/kg/min.
Synthetic Catecholamine - 50:50 racemic mixture of two
o Levorotary (- ) potent α1 adrenergic agonist & weak β1 ,β2
o Dextrorotary (+) α1 adrenergic antagonist & potent β1 ,β2
Its primary cardiovascular effect is a rise in cardiac output as a
result of increased myocardial contractility.
Minimal effect on mean arterial pressure as increased cardiac
output offset decreased in peripheral vascular resistance.
Heart rate increases are less marked than dopamine &
isoproterenol but may be greater than norepinephrine
Favorable effects on myocardial oxygen balance make
dobutamine a good choice for patients with the
combination of congestive heart failure and coronary artery
disease, particularly if peripheral vascular resistance
infusion at a rate of 2.5–10 μg/kg/min.
Relative βselective agonist
Activates both β1 & β2 receptors equally . β 1-Effects increase heart
rate, contractility, and cardiac output.
β2-decreases PVR and diastolic BP .Myocardial oxygen demand
increases while oxygen supply falls, making isoproterenol or any
pure β -agonist a poor inotropic choice in most situations.
In emergencies (bradycardia , heart blocks) to stimulate HR
specially before insertion of artificial pace maker.
Pulmonary hypertention & right ventricular dysfunction
Bronchial asthma (β2 selective drugs preferred).
To overcome the cardiac effects of beta blockers overdose---
cardiodepression ,heart blocks.
Noncatecholamine with predominantly α1-agonist activity
(high doses may stimulate α2- and β-receptors) & small part
due to release of norepinephrine.
Increase systemic bp with decrease co (baroreceptor
mediated reflex bradycardia)
Oral clonidine premedication augment pressor response of
phenylephrine (potentiat α1 mediated vasoconstriction).
Continuous infusion during acute potassium loading
interfere with transfer of k in to cells
Systemic blood pressure decreases in presence of
sympathetic blockade produce by regional anesthesia or
hypotention due to inhaled or injected anesthetic.
Maternal hypotention in cesarean section because not
altered uterine blood flow & higher umblical artery ph
compare to ephedrine
Small intravenous boluses of 40–100 μg of phenylephrine
rapidly reverse reductions in blood pressure caused by
peripheral vasodilation (eg, spinal anesthesia).
continuous infusion (10-20 μg/min) in adult to
maintane normal blood pressure during surgery.
Nasal spray 1% for nasal decongestant
Non catecholamine sympathmimetic act partly due to direct
stimulation of adrenergic receptors ( α & β ) & partly due to
stimulation of release of endogenous norepinephrine (indirect)
Increase systolic & diastolic blood pressure, heart rate, cardiac output
Renal ,splanchnic blood flow decrease & coronary ,skeleton muscle
Increase systemic bp in presence of sympathetic blockade produce by
regional anaesthesia or hypotension due to inhaled or injected
Dosage – adults: bolus of 2.5–25 mg IV 25-50 mg IM
children :bolus of 0.1 mg/kg. Subsequent doses produce
less effect ( tachyphylaxis) due to depletion N E store
α 2 adrenergic receptor agonists
An α2-agonist by negative feedback - decrease norepinephrine
Inhibit insulin , increase glucagon release
have sedative properties.
on withdrawal present with rebound effect – increase in heart
rate and hypertension
Uses- in regional anesthesia, including peripheral nerve
block, clonidine prolongs the duration of the block..
Other benefits include decreased postoperative shivering,
inhibition of opioid-induced muscle rigidity, attenuation of
opioid withdrawal symptoms, and the treatment of some
chronic pain syndromes.
Side effects :: bradycardia, hypotension, sedation,
respiratory depression, and dry mouth
intramuscular (2 μg/kg)
intravenous (1–3μ g/kg), transdermal (0.1–0.3 mg
released per day)
Higher affinity for α2-receptors than clonidine. (1600:1)
Uses as sedative, analgesic, due to central sympatholytic effects
iv infusion .1 – 1.5 μg/kg/min
large intravenous bolus( .25-1 μg/kg) over 3 to 5 min.Result
paradoxical hypertension with decrease heart rate
Extensive biotransformation is in liver and excreted in urine.
Physiological dependance- as potent binding and short half life.
Withdrawal phenomenon present as clonodine.
Selective Β 2 Adrenergic Agonists
•Relax bronchiole and uterine smooth muscles
•Used in bronchospasm in asthma
•Metabolic response- hyperglycemia, hypokalemia,
•Side effects- tremors due to direct stimulation of B2
receptors in skeletal muscles.
•Route of administration- oral, sc, MDI
MDI-100 mcg/puff. 2 puffs repeated over 4-6 hrs.max 16-20
Nebulization- 0.5-1 ml .5% solution in 5 ml NS. Rpted every 15
min for 4 doses then hourly in initial hrs.
650 mcg/puff. Max 16 puffs.
SC- .25 mg
MDI- 200mcg/puff. Max 16 puffs.
Blockade of α1 Receptors
Inhibition of α1 mediated contraction of arterial & venous smooth
Inhibition of contraction of other smooth muscles i.e. eye, GIT , UB &
Inhibition of ejaculation in males.
Blockade of α2 Receptors
increase of sympathetic outflow from CNS (VMC ) to periphery
Inhibit Negative feed back control of NE release----- increase NE
Acute HTN emergencies- 30 to 70 mcg/kg IV
Intraop manipulation of pheocrhomocytoma-
infusion 0.1-2 mg/min
Accidental extravascular injection of
local infiltration of phentolamine-containing solution (5
to 15mg in 10ml NS)
erectile dysfunction: phentolamine with papaverine,
Non-selective / irreversable blocker.
Alpha-1 block > Alpha-2 block
Slow onset (up to 60 min to reach peak) IV or PO.
Long time required for structural change of the
molecule needed to render drug active
Elimination half-time: 24 hr (cumulative effect with
Orthostatic hypotension (if HTN or hypovolemia)
Impairement of compensatory vasoconstriction
exaggerated drop in BP in response to blood loss or
vasodilating drugs(e.g. volatile anesthetics)
CO, renal blood flow unchanged (unless
preexisting renal vasoconstriction)
Cerebral/coronary vascular resistances don’t
increases insulin secretion
Catecholamine-induced Glycogenolysis in skeletal
muscle or lipolysis not altered
Nasal stuffiness (d/t unopposed alpha blockade
vasodilation in mucous membranes)
Preoperative treatment of HTN of pt with
pheochromocytoma (0.5-1 mg/kg po)
Given to Pt with excessive vasoconstriction with associated
tissue ischemia (eg. hemorrhagic shock) but only after IV
fluid volume is replenished
Alpha-1 Selective Blockers
Generally reflex tachycardia is less prevalent as negative
feed back by NE ,mediated by α2 is not blocked.
Syncope is noted when first administered in a large group
of patients. Caution should be taken to avoid sudden
Postural hypotension is much less pronounced than the
non-selective α-blockers possibly because of lower effect
mild hypertension alone or in combination with other
benign prostatic hypertrophy: Blockade of α1-
adrenoceptors at the base of the bladder and the prostate
possibly reduces the symptoms of obstruction and the
o Tamsulosin has antagonistic affinity to α1A receptors (in
vas deferens) more than to α1B in vascular smooth
Prototype Alpha-1 Blocker : Prazosin
Highly selective for α1 receptors , 1000 fold > α2
Relaxes vascular smooth muscle ↓ PVR & ↓ blood pressure --
-- useful anti-hypertensive.
preoperative treatment of HTN in pheochromocytoma (0.5-1
Relaxes vascular smooth muscle in the prostate & bladder base
useful in urinary obstruction , improves urinary flow.
A/E: First dose phenomenon– marked hypotension with first
dose specially in patients who are volume & salt depleted.. So
first dose should be small & given at bed time.
Selective α2 blocker
improves erectile function
May cause anxiety(crosses BBB)
Reversible non selective α antagonist
uses: persistent pulmonary hypertension in new born
A/E: hypotension, reflex tachycardia, pulmonary and git
-Adrenergic Receptor Blockers
Mode of action:
Bind to Beta adrenergic receptors and block effects of
catecholamines & sympathomimetics on the heart & smooth
muscles of the airways & blood vessels.
Beta blockers should be continued during periop period to avoid
reflex CNS hyperactivity.
Beta blockade can be reversed by Beta agonist by displacement
from occupied receptors if large amount of agonist is given
Significance of Cardioselectivity/
Some drugs like Atenolol block β1 preferentially than β2but the
selectivity may be lost at higher conc.as they are not receptor specific
Use of selective β1 blockers is safer in patients with :
- Asthma /COPD as β2 receptors in bronchial smooth muscles are not
blocked which may produce bronchoconstriction--- worsening of
-Insulin dependent Diabetics--- less chances of hypoglycemia &
recovery is not delayed.
- Severe peripheral vascular disease or spastic disorders.
Intrinsic Sympathomimetic Activity (ISA)
Partial agonistic activity at β- receptors.
ISA can prevent A/E like precipitation of
bronchoconstriction in patients of COPD
Less likely to cause Bradycardia & plasma lipid
Beneficial in patients with brady arrhythmias or
peripheral vascular disease.
Not as effective as pure antagonist in secondary
prevention of Myocardial Infarction.
Examples: Acebutolol, Pindolol, Carteolol, Oxpranolol ,
Effects not related to β- blockade
Membrane stabilizing Activity (MSA)
Local anesthetic action due to Na+ channel blockade.
Not important for systemic effects but for topical use in
Local anesthetic action produces loss of sensation of cornea---
absent corneal reflex ,which is protective.
So β blockers without MSA are used as eye drops in
Glaucoma e.g. Timolol, Betaxolol .
eg: Propranolol, Pindolol, Labetalol, Acebutolol, Metoprolol,
Inverse Agonistic Activity :
Some drugs like Betaxolol ,Metoprolol have inverse agonist
activity– they reduce the constitutive activity of Beta receptors
in some tissues .
Non-selective β blocker with MSA.
First Beta antagonist introduced clinically
Highly lipid soluble ---- crosses BBB(produce some drowsiness)
Low oral bioavailability (30%) due to extensive 1st pass hepatic
Dose- PO dose 40-800mg/day is much higher than IV dose
(0.05mg/kg in increments of 0.5-1mg q5min)
Elimination half life --- 2– 3 hrs
Elimination is decreased when hepatic blood flow decreases.
May decrease its own clearance rate by decreasing C.O. and
hepatic blood flow
Renal failure does not alter elimination half-life BUT
accumulation of metabolites takes place
Propanolol & Local Anesthetics
Decreases clearance of amide L.A. by decrease hepatic blood flow &
inhibition of liver metabolism
Bupivacaine clearance is decreased 35%
Higher chance of systemic toxicity of bupivacaine and other amide
Propanolol & Opioids
Pulmonary first-pass uptake of Fentanyl is highly decreased in pts
2-4 times as much injected Fentanyl enters systemic circulation right
after injection (more chance of overdosing with Fentanyl in pt who
This response reflects ability of one basic lipophilic amine
(propanolol) to inhibit pulmonary uptake of another basic lipophilic
Blood Vessels & Blood Pressure
Initially there is ↑ PVR due to inhibition of β2 receptor
On long term ---- ↓ peripheral resistance & ↓ blood pressure
due to β1-blockade :
a) ↓ CO
b) Anti Renin effects
(B)Effects on Respiratory System:
Bronchoconstriction (blockade of β2) by non-selective β
blockers Increased airway resistance--- worsening of
No β1-Selective antagonist is sufficiently specific for β1 ,
so generally they should be avoided in patients with
β1-Selective antagonists are relatively safe in patients with
(C)Effects on Eye:
↓ IOP---- ↓ synthesis of aqueous humour due to blockade
of β1 in ciliary epithelium.
β blockers without MSA are used in glaucoma.
e.g. Timolol, Betaxolol – topically as eye drops
1.Effect on lipid metabolism:
↓ lipolysis (β3 blockade)
2. Effect on carbohydrate metabolism:
↓ glycogenolysis in liver (β2 blockade)
Delay in recovery from hypoglycemia in Insulin dependent
Diabetics; specially in patients with low Glucagon reserve
3.Effect on lipoprotiens:
↑ VLDL & ↓ HDL cholesterol ----- ↑ risk of coronary
artery disease (CAD).
Less likely to occur with β blockers possessing ISA.
Most selective Beta1 Blocker
50% of PO dose (50-100mg/day) absorbed by GI
Little/no hepatic metabolism
Elimination half-life: 6-8hrs (more than 24 hrs in renal failure)
IV dose for acute MI (5mg over 5min followed by another 5mg 10min
Periop Tx will decrease incidence of post op MI in CAD pts
Enters CNS in very small amounts but fatigue/depression still occurs
Can be used with caution in IDDM pts whose HTN is not controlled
with other antiHTN (does not potentiate Insulin-Induced
Hypoglycemia seen with nonselective Beta blockers)
Beta 1 selective
High hepatic first-pass metabolism (only 40% reaches systemic
Low protein binding (10% bound)
Elimination half-life 3-4hrs
Can be used in COPD/PVD pts since no Beta2 blocking properties at
normal dose (2-15mg IV).
Rapid onset, short acting Beta1 blocker given ONLY IV (0.5mg/kg)
T1/210min (rapid hydrolysis in blood by plasma esterases,
independent of renal & hepatic function)
Plasma esterases that hydrolyze Esmolol are different than
Dose: 0.5-1mg/kg (peaks 5min). Return of HR to predrug level
Poor lipid solubility limits crossing into CNS/placenta
Esmolol (1mg/kg) iv followed by 250 mcg/kg/min decreases
plasma conc of propofol required to prevent patient movement in
response to surgical incision.
HTN/Tachy in response to intraop noxious stimulation &
intubation (eg 150mg IV 2min before Laryngoscopy)
prior to ECT : attenuation of increased HR & decrease
length of seizure (dose 500 mcg/kg/min)
In Pheochromocytoma, thyrotoxicosis, PIH, epinephrine- or
cocaine-induced cardiovascular toxicity
Therapeutic Uses of β-blockers
(1) Treatment of hypertension:
• Selective β1-blockers are preferable in asthmatic & diabetic
patients and in patients with Raynaud’s disease
• Postural hypotension is not prominent.
• very useful as mono therapy in mild to moderate hypertension
In hypertensive emergencies (Labetalol , Esmolol)
Intraoperative & Postoperative hypertension (Esmolol)
Hypertension with chronic heart failure (Carvedilol , Metoprolol,
Hypertension with pheochromocytoma use β- blocker after α blocker.
(2)Myocardial Infarction (MI):
• given immediately (few hours) after MI reduces the infarct
size and enhance cardiac reperfusion and recovery;
esmolol,atenolol, propranolol, and metoprolol are used
• β-blockers administered 1-4weeks after MI reduce much the
probability of myocardial re-infarction possibly by reducing
Useful for prophylaxis of Classical angina.
They reduce the frequency of anginal attacks.
Improve exercise tolerance.
Not useful in acute attack.
The beneficial effects are related to hemodynamic
effects— ↓ HR ,force of contraction–↓ Work load ----
↓ oxygen demand
(4)Cardiac supraventricular arrhythmias
β1-receptor blockade results in the following:
• decreased firing rate of SA node
• decreased AV conduction & prolongation of AV-nodal
• decreased ventricular response to atrial flutter
Esmolol is a cardio-selective β1-blocker that is used only by IV
route for emergency treatment of supraventricular arrhythmias
arising during surgery
(5)Dissecting aortic aneurysm:
β- blockers decrease the rate of rise in the systolic blood
β- blockers are also useful in selected high risk patients in
the prevention of adverse cardiovascular outcomes
resulting from non-cardiac surgery.
(6) Pheochromocytoma :
β- blockers may be given after Alpha blockers to reverse the
cardiac effects of catecholamines.
If given before Alpha blockers,there will be enhanced
effects of catecholamines on alpha receptors--- further rise
in blood pressure.
β antagonists are beneficial as they :
Block the excessive catecholamine action. (there is upregulation
of β receptors in hyperthyroidism).
Inhibit peripheral conversion of Thyroxine (T4)to
Tri-idothyronine (T3); which is more potent.
Are useful in thyroid storm to control supraventricular
tachycardia that often precipitates cardiac failure.
β blockers without MSA are used in glaucoma.
e.g. Timolol, Betaxolol as topical eye drops.
Propranolol reduces the frequency & intensity of migraine
(10)Skeletal muscle tremor :
β antagonists reduce certain tremors as sympathetic activity may
enhance skeletal muscle tremor through β receptors.
(11)Alcohol withdrawal syndrome:
β antagonists reduce symptoms .
• β antagonists reduce symptoms of anxiety
• Low dose Propranolol ,specially when taken prophylactically ;
is effective to control stage fright--- performance anxiety.
ADVERSE EFFECTS of β-blockers
1.On CVS: Generally the extensions of pharmacologic effects.
Heart failure---- in patients where CO is dependent upon
Antidote: Isoproterenol & glucagon.
Coldness of extremities, fatigue with non -selective β-Blockers ,
specially in patients of peripheral vascular disease or vasospastic
Drug withdrawal in patients of IHD: on abrupt
discontinuation of β-antagonists therapy in IHD after
Angina or acute myocardial infarction may occur:-this
may be due to adrenergic receptor super-sensitivity
mediated by receptor up-regulation or re-enhancement
of sympathetic cardiac drive
So the dose should be tapered over 2-3 weeks in
Hypertension & IHD
Hypoglycemic episodes in insulin dependent diabetics
(type I) with non selective β-Blockers
Masking of premonitory symptoms of
hypoglycemia(such as tachycardia)
Delay in recovery from hypoglycemia
Effect on lipoprotiens:
↑ VLDL & ↓ HDL cholesterol ----- ↑ risk of Coronary
Less common with β blockers possessing ISA.
Worsening of pre-existing disease ---- asthma or COPDs
(with non selective β-Blockers).
Sedation, sleep disturbances, & depression.
5. Drug interactions:
With Verapamil severe hypotension, bradycardia, heart
failure & conduction defects.
CONTRAINDICATIONS of β-blockers
DO NOT use in pts with AV Block or h/o heart failure not caused by
Be cautious in hypovolemic pt since Beta Blockade may cause
Nonselective Beta Blockers or high dose of Selective Beta Blockers
are not recommended for pts with COPD (can cause
broncoconstriction), PVD (can cause peripheral vasoconstriction),
Diabetes (hypoglycemia may be masked no increase in HR)
Combined α & β blocker
Ex:- Labetalol , Carvedilol , Medroxalol
Non selective β & α1 selective blocker.
Used as antihypertensive ----less tachycardia than α blockers .
Highly lipid soluble
Also has antioxidant properties and protect against vascular
Very dramatic results in CHF clinical trials.
Decreased mortality by 65%
Selective Alpha1 and Nonselective Beta Blocker
Presynaptic Alpha2 receptors are spared
Beta to Alpha potency ratio 7:1 (IV) and 3:1 (PO)
T1/2 = 5-8hrs, prolonged in liver dz, unchanged in renal dz
Blood pressure is ↓ed by ↓ PVR without significant change in HR
BP should be lowered within 5-10min of 0.1-0.5mg/kg IV dose
HTN emergencies (eg epi overdose from local)
20-80mg IV q10min
Pheochromocytoma pts with rebound HTN after withdrawal of
Used in surgeries where “Controlled Hypotension” needed (10mg
Orthostatic hypotension (most common)
Bronchospasm (susceptible pts)
Other Beta Blockade S.E.