Dr Shinde Viraj Ashok
Jr – 1
Department of Pharmacology
Guided by
Dr V. M. Motghare
Professor &
Head of department of
Pharmacology


Introduction
Definition
Classification
Sympathomimetic drugs
Therapeutic uses
Overview


Sympathetic “Fight or
Flight”


Parasympathetic “Rest &
Maintain”
Rest
Repair
Renew

Sympathetic Parasympathetic
Origin Thoracolumbar Craniosacral
Distribution Wide 3,7,9,10, s1 -4
Pre ganglionic fibre Short myelinated Long myelinated
Post ganglionic Long, non-myelinated
Except Adrenal
medulla
Short, non-
myelinated. Except
eye
Result Diffuse, generalised Localised
Neutotransmitter Pregang- Ach
Post gang- NA
Pregang- Ach
Post gang - Ach






 Drugs that partially or completely mimic the actions
of norepinephrine (NE) or epinephrine (Epi).
Definition of
Sympathomimetic drugs

SYNTHESIS
TYROSINE
DOPA
DOPAMINE
NA
ADRENALINE
Tyrosine hydroxylase
DOPA decarbxylase
Dopamine β-
hydroxylase
N-methyltransferase
Phenylalanine
Phenylalanine
hydroxylase


Where are the adrenergic
receptors?
Receptor α1 α2 β1 β2 β3
localization Blood
vessels
α1B/1D
CNS Heart Lungs Adipose
tissue
Prostatic
urethra &
eye α1 A
Blood
vessels
Kidney-
juxta
glomerular
cells
Uterus
GIT GIT
Bladder

Adrenergic receptors, Subtypes,
agonists and antagonists
Receptors Agonists Antagonists
α1a
Phenylephrine/ Methoxamine Prazosin/terazocine
α1b
Phenylephrine/Methoxamine Prazosin/terazocine
α2a
Oxymetazoline/ Clonidine Yohimbine/ Rauwolscine
α2b
Oxymetazoline/ Clonidine Yohimbine/ Rauwolscine
β1 Dobutamine/ Xamoterol Atenolol, acebutolol
β2 Terbutaline/ Salbutamol
β3 BRL 37344
D1 Fenoldopam
D2 Bromocriptine, Lysoride


Classification
 Classification is based on
mechanism of action
 Direct-acting agonists
e.g. epinephrine,
norepinephrine.
 Indirect-acting agonists
e.g. amphetamine,
Cocaine.
 Mixed-action agonists
e.g. Ephedrine,
pseudo ephedrine.


Catecholamines Non catecholamines
Sympathomimetic amines having
catechol nucleus
Devoid of catechol nucleus
Not effective orally Effective orally
Easily metabolised by monoamine
oxidase
Relatively resistant to monoamine
oxidase enzyme
Action quick compared to non
catecholamines
Action prolonged as compared to
catecholamines
Doesn’t readily crossess BBB Easily crossess BBB
No significant CNS effects Have significant CNS effects
Act directly on receptors Act indirectly as well as directly
Eg – epinephrine , nor - epinephrine Eg – amphetamine , ephedrine
Classification


 Epinephrine interacts with both α and ß receptors.
 At low doses – β2 effects (vasodilation) on the vascular system
predominate,
 At high doses – α1 effects (vasoconstriction) are strongest.
 Actions
1. Cardiovascular –
Strengthens the contractility of the myocardium (positive
inotropic: β 1 action) and increases its rate of contraction (positive
chronotropic: β 1 action) .
Activates β 1receptors on the kidney to cause renin release.
Constricts arterioles in the skin, mucous membranes, and
viscera (α1 effects), and it dilates vessels going to the liver and
skeletal muscle (β 2 effects).
Cumulative effect is an increase in systolic blood pressure
& slight decrease in diastolic pressure.
Direct acting adrenergic
agonist


Intravenous injection of adrenaline normally
causes increase in blood pressure (α1 effect)
followed by prolonged fall (β 2 effect).
If it is administered after giving α blockers, only
fall in blood pressure is seen.
This phenomenon is called as Dales vasomotor
reversal.
Dales vasomotor reversal
phenomenon


2. Respiratory - powerful bronchodilation by acting directly
on bronchial smooth muscle (ß 2 action).
3. Hyperglycemia - significant hyperglycemic effect because
of
- increased glycogenolysis in the liver (β 2 effect),
- increased release of glucagon (β 2 effect), and
- decreased release of insulin (α 2 effect).
4. Lipolysis – agonist activity on the β 3 receptors of adipose
tissue.


 Epinephrine - rapid onset - brief duration of action (due
to rapid degradation).
 Oral administration is ineffective, because epinephrine
and the other catecholamines are inactivated by intestinal
enzymes.
 Only the metabolites are excreted in urine.
Pharmacokinetics:

 Anaphylactic shock :
 Intramuscular – 1: 1000
 Subcutaneous – 1: 1000
 Intravenous - 1:10000
 Epinephrine is the drug of choice for the treatment of
Type I hypersensitivity reactions in response to
allergens.
 Bronchospasm :
 Epinephrine relieves brochospasm .
 Cardiac arrest :
 Epinephrine may be used to restore cardiac rhythm in
patients with cardiac arrest like drowning &
electrocution.
Therapeutic uses


 With local Anaesthetics :
Local anesthetic solutions - contain 1:100,000parts
epinephrine - to greatly increase the duration of the local
anesthesia.
 To control epistaxis :
Very weak solution (1:100,000) - used topically to
vasoconstrict mucous membranes to control oozing of
capillary blood.


a. CNS disturbances:
- anxiety, fear, tension, headache, and tremor.
b. Hemorrhage :
- cerebral hemorrhage - marked elevation of blood
pressure.
c. Cardiac arrhythmias:
- trigger cardiac arrhythmias , particularly if the patient
is receiving digoxin.
d. Pulmonary oedema:
- can induce pulmonary oedema.
Adverse effects:

a. Hyperthyroidism :
 Epinephrine - enhanced cardiovascular actions in
hyperthyroidism {dose of epinephrine must be
reduced}.
 Increased production/up regulation of α receptors on
the vasculature & β receptors in heart of the
hyperthyroid individual - leading hypersensitive
response.
b. Diabetes :
 Epinephrine increases the release of endogenous
stores of glucose. In the diabetic, dosages of insulin
may have to be increased.
Contraindications :


a. Cocaine:
Cocaine + epinephrine exaggerated cardiovascular
actions, because cocaine prevents reuptake of
catecholamines into the adrenergic neuron
b. β - Blockers:
Prevent epinephrine effects on β receptors, leaving a
receptor stimulation unopposed increase in
peripheral resistance and an increase in blood pressure.
c. Inhalation anaesthetics:
Halothane like agents sensitize the heart to the effects of
epinephrine, which may lead to tachycardia.
Interactions:


 Agonist at α1, α 2 and β 1 receptors with similar potency as
epinephrine, but has relatively little effect on β 2 receptors.
 Increases peripheral resistance 𝜶 𝟏 and both diastolic and
systolic blood pressure β1.
 Compensatory baroreflex activation tends to overcome the
direct positive chronotropic effects of norepinephrine; however,
the positive inotropic effects on the heart are maintained.
Nor Epinephrine/Nor
Adrenaline


 Therapeutic uses - carefully used to treat cardiogenic shock
but dopamine is preferred as nor epinephrine is associated
with renal shutdown.
 Adverse effects –
 Excessive doses can cause severe hypertension.
 Not suitable for sc ,im or undiluted iv injection – danger of
necrosis


 A substance that is released when axon terminal of a
presynaptic neuron is excited & acts by exciting or
inhibiting a target cell.( E.g nor epinephrine , acetyl
choline or dopamine)
Definition of
neurotransmitters


Criteria for
Neurotransmitters
 Substance must be synthesized in the neuron
 Enzymes and substrates for synthesis must be
present in it
 Substance must be present in the neuron.
 Calcium dependant release
 Exogenous synthetic neurotransmitter must mimic
the actions of true transmitter.
 There must be a mechanism for rapid termination of
action.


The Seven Steps in
Neurotransmission
1) Synthesis
2) Storage
3) Release
4) Receptor interaction
5) Inactivation
6) Reuptake
7) Degradation


 Immediate precursor of norepinephrine &
epinephrine
 Endogenous dopamine may have more important
effects in regulating sodium excretion and renal
function.
 Features distinguishing from norepinehrine &
epinephrine
 2-5 µg/kg /min – D1 receptors – renal vasodilation
 5-10 µg/kg /min – β1 receptors - ↑ cardiac output
 >10 µg/kg /min –α 1 receptors – vasoconstriction
Dopamine

 Its deficiency in the basal ganglia leads to
Parkinson's disease, which is treated with its
precursor levodopa.
 Dopamine antagonists are antipsychotic drugs.
 Therapeutic uses – used in conditions with low
cardiac output with compromised renal function
 Iv infusion regulated by monitoring of BP & rate of
urine formation.
Dopamine contd..


 Very potent β 1 & β 2 – receptor agonist and has
negligible effect on α receptors.
 Positive chronotropic and inotropic actions (β 1) .
 Activates β receptors almost exclusively, it is a potent
vasodilator.
 These actions lead to marked increase in cardiac output
and fall in diastolic and mean arterial pressure and
lesser decrease or a slight increase in systolic pressure.
 Therapeutic uses – may be used in complete heart block
to maintain sufficient idioventricular rate till external
pacemaker can be implanted.
Isoproterenol/Isoprenaline

 It resembles dopamine, but its actions are mediated by
activation of α and β receptors.
 Dobutamine is a racemic mixture of (levo) and (dextro) isomers.
 The dextro isomer is a potent β 1 agonist and an α 1 receptor
antagonist.
 The levo isomer is a potent α 1 agonist
 The resultant effects of dobutamine is β 1 stimulation.
 Dobutamine has a positive inotropic action caused by the
isomer with predominantly β1 receptor activity. It has relatively
greater inotropic than chronotropic effect compared with
isoproterenol.
 Therapeutic uses – patients of heart failure associated with
myocardial infarction , cardiac surgery & for short term
management of acute congestive heart failure .
Dobutamine


 D1-receptor agonist - selectively leads to peripheral
vasodilation
 Oral bioavailability poor hence given by IV route.
 Primary indication for fenoldopam is in the IV
treatment of short term management of severe
hypertension in pateints with renal impairement.
Fenoldopam

Direct-Acting Sympathomimetics
 Phenylephrine
 Selective α 1 agonist.
 Not a catechol derivative - not inactivated by COMT and
has a longer duration of action than the catecholamines.
 It is an effective mydriatic and nasal decongestant.
 Methoxamine
 A direct-acting α 1 receptor agonist.
 Causes a prolonged increase in BP due to vasoconstriction
& a vagally mediated bradycardia.
 Clinical uses are rare and limited to hypotensive states.
 Naphazoline & xylometazoline
 Nasal decongestants in rhinorrhoea & to check epistaxis
Non catecholamines α1
agonist drugs


Oxymetazoline
 Direct-acting α 1 agonists.
 Used as topical decongestants because of promoting
constriction of the nasal mucosa.
 When taken in large doses, oxymetazoline may
cause hypotension, presumably because of a central
clonidine -like effect
 Oxymetazoline has significant affinity for α 2A
receptors.


Midodrine
 A prodrug that is enzymatically hydrolyzed to
desglymidodrine, a selective α 1-receptor agonist.
 Primary indication for midodrine is the treatment of
orthostatic hypotension, due to impaired autonomic
nervous system function.
 Although the drug has efficacy in diminishing the fall of
blood pressure when the patient is standing, it may cause
hypertension when the subject is supine.


Clonidine -
 Antihypertensive effect
 Stimulates α 2A receptors at vasomotor centre –
central sympathetic outflow reduced – fall in BP &
HR.
 I 1 Imidazoline receptors in brain to which clonidine
binds- activates G coupled receptor – modulates
central α 2 receptor activity.
 Activates α 2B receptors present on sympathetic post
ganglionic neurons
α 2 agonists


 Therapeutic uses
 Moderate hypertension
 To control diarrhoea in diabetic patients with autonomic
neuropathy
 In prophylaxis of migraine
 Menopausal hot flushes
 Adverse effects
 Rebound hypertension-
 Sudden removal of central sympathetic inhibition results in
release of large quantities of stored catecholamines
 Due to super sensitivity of newly formed α 2 receptors
 Dry mouth
 Sedation
Clonidine contd..


Therapeutic window phenomenon –
 Rapid i.v. Injection – raises BP – due to activation of
peripheral α 2B receptors
 Oral doses – fall in BP – clonidine has lower intrinsic
activity on α 2B receptors
Clonidine contd..


 Clonidine, methyldopa, guanfacine
are useful in the treatment of hypertension
 Dexmedetomidine
 Centrally acting α 2A-selective agonist that is indicated for
sedation of initially intubated and mechanically ventilated
patients during treatment in an intensive care setting.
 It also reduces the requirements for opioids in pain control.
 Analgesia & sedation are produced with little respiratory
depression , amnesia or anaesthesia
α 2 selective agonists


Salbutamol, terbutaline
1. Selective β2 agonist smooth muscle relaxation of bronchi &
uterus
2. Important in the treatment of asthma.
Salmeterol & formoterol
1. Selective β2 agonist – longer duration of action (12hrs)
2. Formoterol has quicker onset of action while salmeterol has
slow onset of action
3. Formoterol is used to prevent attacks of nocturnal asthma
prophylaxis of exercise induced bronchospasm & COPD
Ritodrine
may cause uterine relaxation in premature labor.
Beta2-selective agents




 BRL -37344 & AD- 9677
 β 3 receptors might prove potential target for new
antiobesity drugs.
 Main problem – short lived transient action.
β 3 agonists


 First, they may enter the sympathetic nerve ending
and displace stored catecholamine transmitter.
Such drugs have been called amphetamine-like or
displacers.
 Second, they may inhibit the reuptake of released
transmitter by interfering with the action of the NE
transporter, NET.
Indirect-Acting Sympathomimetics


 Racemic mixture is important because of its use and
misuse as a CNS stimulant
 Readily enters the CNS, where it has marked stimulant
effects on mood and alertness and a depressant effect on
appetite.
 Its D-isomer is more potent than the L-isomer.
Amphetamine's actions are mediated through the release
of NE and, to some extent, dopamine.
 Performance of simple mental tasks improved but
number of errors increased due to over confidence.
Amphetamine


 Drug of abuse & is capable of psychological
dependence but little or no physical dependence
 Therapeutic uses –
 Narcolepsy
 Attention deficit hyperactive disorder
 Treatment of toxicity – acidification of urine .
Amphetamine contd..


 Methamphetamine
Very similar to amphetamine with an even higher
ratio of central to peripheral actions.
 Methylphenidate
Amphetamine variant whose major pharmacologic
effects and abuse potential are similar to those of
amphetamine.
More effective than amphetamine in treating
narcolepsy & attention deficit hyperactivity
disorder.


 Psychostimulant.
 Inhibits both NE and DA transporters.
 Therapeutic uses -
 Improve wakefulness in narcolepsy.
 In shift workers.
 To relieve fatigue in multiple sclerosis
 Adjunct in obstructive sleep apnea.
 Associated with increase in BP and heart
rate, usually mild.
Modafinil


 High concentrations in some fermented foods -cheese.
 Readily metabolized by MAO in the liver and is normally
inactive when taken orally because of a very high first-
pass effect
 If administered parenterally, it has an indirect
sympathomimetic action caused by the release of stored
catecholamines.
 In patients treated with MAO inhibitors , tyramine may
cause marked increases in blood pressure(cheese
reaction).
 Patients taking MAO inhibitors must be very careful to
avoid tyramine -containing foods
Tyramine


Mixed-Acting
Sympathomimetics
Ephedrine
 The plant Ephedra vulgaris, has been used in
traditional Chinese medicine for 2,000 years
for the treatment of asthma and hay fever, as
well as for the common cold
 Ephedrine is a noncatechol ,it has high
bioavailability and a relatively long duration.
 It releases NE and activates β2 receptors
directly.
 Crossess BBB, it is a powerful stimulant.
 Nowadays only used to treat hypotension
with spinal anaesthesia
 Repeated dosing - tachyphylaxis


Pseudoephedrine
 One of four ephedrine enantiomers.
 Available over the counter as a component of many
decongestant mixtures.
Mephenteramine
 Use restricted to maintain blood pressure in
hypotensive states.
 Adverse effects – hallucinations ,convulsions.


Phenylpropanolamine
 Was a common component in over-the-counter
appetite suppressants.
 It was removed from the market because its use was
associated with hemorrhagic strokes in young
women.
 The mechanism of this potential adverse effect is
unknown.


Anorectic agents
 Fenfluramine & dexfenfluramine –
Reduce food seeking behaviour – enhancing
serotonergic transmission in hypothalamus.
Tolerance to anorectic action develops in 2 – 3months.
U S – FDA has recommended discontinuation.
 Sibutramine & R – sibutramine –
Inhibit both NA & 5HT reuptake in hypothalamus.
These drugs are banned in India & USA.


Cardiovascular Applications
 Treatment of Acute Hypotension
Used in hypotensive emergency to preserve cerebral
and coronary blood flow.
 The treatment is usually of short duration while the
appropriate intravenous fluid or blood is being
administered.
 Direct-acting agonists such as NE, phenylephrine,
and methoxamine have been used when
vasoconstriction is desired.
Therapeutic Uses of
Sympathomimetics

Cardiogenic shock and acute heart failure
Usually due to massive myocardial infarction.
 Positive inotropic agents such as dopamine or
dobutamine may provide short-term relief of heart
failure symptoms in patients with advanced
ventricular dysfunction.
 In low to moderate doses, these drugs may increase
cardiac output and cause relatively little peripheral
vasoconstriction.

 Chronic Orthostatic Hypotension.
 Impairment of autonomic reflexes that regulate BP can lead to
chronic orthostatic hypotension.
 Due to medications that can interfere with autonomic function,
diabetes and other diseases causing peripheral autonomic
neuropathies.
 Midodrine
 Orally active α 1 agonist - used for this indication.
 Other sympathomimetics, such as oral ephedrine or phenylephrine,
can be tried.
 Cardiac Applications
 Isoproterenol and epinephrine have been used in the temporary
emergency management of complete heart block and cardiac
arrest.
 Dobutamine injection is used as pharmacologic cardiac stress
test

Pulmonary Applications
 One of the most important uses of sympathomimetic
drugs is in the therapy of bronchial asthma.
 β 2-selective agents:
Albuterol (Salbutamol), bambuterol, metaproterenol,
terbutaline .

Anaphylaxis
 The syndrome of bronchospasm, mucous membrane
congestion, angioedema, and severe hypotension usually
responds rapidly to the parenteral administration of
epinephrine.
Epinephrine is effective because:
1) β1 increases cardiac output.
2) β2 relaxes constricted bronchioles.
3) α1 constricts capillaries
 Glucocorticoids and antihistamines may be useful as
secondary therapy in anaphylaxis; however, epinephrine
is the initial treatment.

Ophthalmic Applications
 Phenylephrine is an effective mydriatic agent used to facilitate
examination of the retina.
It is also a useful decongestant for minor allergic hyperemia and
itching of the conjunctival membranes.
 Glaucoma responds to a variety of sympathomimetic and
sympathoplegic drugs.
 Epinephrine is now rarely used, but β -blocking agents are
among the most important therapies.
 Apraclonidine & brimonidine
Alpha 2-selective agonist that also lower intraocular pressure is
used in glaucoma.
The mechanism of action of these drugs in treating glaucoma is
still uncertain.

Genitourinary Applications
 β 2 selective agents relax the pregnant uterus.
Ritodrine, terbutaline, and similar drugs have been
used to suppress premature labor.
 Oral sympathomimetic therapy is occassionally
useful in the treatment of stress incontinence (loss of
small amounts of urine associated with coughing,
laughing, sneezing, exercising or other movements
that increase intra-abdominal pressure and thus
increase pressure on the bladder. ) Ephedrine or
pseudoephedrine may be tried.

CNS Applications
 Treatment of narcolepsy.
 Modafinil
A new amphetamine substitute, is claimed to have
fewer disadvantages (excessive mood changes,
insomnia and abuse potential) than amphetamine in
this condition.
 Attention-deficit hyperactivity disorder (ADHD)
Some patients respond well to low doses of
methylphenidate and related agents or to clonidine.
Modafinil may also be useful in ADHD.


 Sympathomimetic class of drugs is a very important class of
drugs because of its use in so many important conditions
like
Cardiogenic shock
Anaphylactic shock
Hypotension
Hypertension
Congestive heart failure
Bronchial asthma
Nasal decongestion
Narcolepsy
Attention deficit / hyperactivity disorder
Summary


 Basic & clinical pharmacology 12th edition
 “ The pharmacological basis of therapeutics”
Goodman and Gilman( 12th edition )
 “Principles of pharmacology” S. K. Sharma, (2nd
edition)
References



“selective” ≈ 50-100 fold


Cocaine
 Mechanism:
 Central: block DAT, NET & SERT
 Peripheral: αβ agonist
 Schedule II (nasal surgery)
Erythroxylon coca powder crack

Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 304.


 Responses mediated by – adrenoceptors are not
constantly same.
 Desensitisation –
 Continued receptor stimulation – desensitisation of
receptors – receptor becomes less sensitive to agonist.
 Of β receptors occurs – due to phosphorylation of its
serine residue by beta adrenergic receptor kinase
enzyme
Receptor regulation


Down regulation Upregulation
Pronlonged exposure to high
concentration of agonist
reduction in number of receptors
for activation
Prolonged exposure to high
concentration of antagonist
increase in number of receptors &
their sensitivity
Due to endocytosis or
internalisation of receptors
Due to externalisation of receptors
Commonly seen with tyrosine
protein kinase receptors
Extreme form of upregulation –
super sensitivity of receptor as well
as organ
Both upregulation & down regulation process takes several days


Directly acting
Endogenous
catecholamines
Epinehrine
Nor
epinephrine
Dopamine
Synthetic
catecholamines
Isoprenaline Dobutamine Fenoldopam







