SYMPATHOMIMETICS
– Dr Kalyani R
Department of Periodontology
KVG Dental college & Hospital

Sympathetic “Fight or Flight

Parasympathetic “Rest & Maintain”

Definition of
Sympathomimetic drugs
– Drugs that partially or completely mimic
the actions of epinephrine (Epi) or
norepinephrine (NE)
– They produce effects similar to the effects
of sympathetic nerve fibers.

Classification

Synthesis of catecholamines

Storage of catecholamines
NA is stored in the synaptic vesicles or ‘granules’ within the
adrenergic nerve terminal.
The granular membrane actively takes up the Dopamine from the
cytoplasm.
The final step of synthesis of NA takes place inside the granule that
contains dopamine β- hydroxylase.
NA is stored as a complex with ATP absorbed onto protein
chromogranin.
In the adrenal medulla the NA thus forms will diffuse out into the
cytoplasm and gets methylated to form the Adr.

Release of catecholamines
– The release of CA takes place by exocytosis.
– the granular contents: NA or Adr, ATP, Dopamine β-
hydroxylase, chromogranin are all poured out.
– The release is modulated by the presynaptic receptors.
– Indirectly acting sympathomimetic amines also induce
release of NA but this is not exocytotic and does not require
Ca ions.

Uptake of catecholamines
– Uptake of CAs takes place by 2 steps:
1. Axonal uptake: an active amine pump is present at the the
neuronal membrane which transport the NA at a higher rate than
Adr.
This uptake is most important mechanism for terminating the
postjunctional action of NA.
This inhibited by cocaine, desipramine and many H1 antihistamines.

2. Granular uptake : The membrane of intracellular
granules has another amine pump that transports CAs
from the cytoplasm to within the granule.
The granular NA that is constantly leaking into the
cytoplasm is captured by this mechanism.
3. An extraneuronal uptake of CAs also occurs in other
tissue cells.

Metabolism of catecholamines
Part of the NA leaking out of the granules into cytoplasm and those
taken up by the axonal transport is first attacked by Monoamine
Oxidase (MAO) enzyme..
The part that diffuses into the circulation is first acted upon by
catechol-o-methyl transferase(COMT) enzyme in liver and other
tissues.
The other enzymes subsequently produces vanillylmandelic
acid(VMA).
The major metabolites are excreted in urine.
These metabolites are mostly conjugated with glucuronic acid or
sulfate before excretion in urine.

Adrenergic receptors
They are membrane bound G-protein coupled receptors .
function primarily by increasing or decreasing the intra cellular
production of second messengers cAMP/DAG.
On the basis of 2 different potencies of adrenergic agonist, adrenergic
receptors are classifies into 2 types:
α adrenergic receptor β adrenergic receptor
• α 1(α1a, α1b, α1d)
• α2(α2a, α2b, α2c)
• β1 and β2
• β3( recently)

Where are the adrenergic receptors?

CLASSIFICATION BASED ON MECHANISM
OF ACTION
Direct-acting agonists :
They act directly as agonist on α/ β
adrenoceptors.
• Epinephrine/ adrenaline
• Norepinephrine
• Dopamine
• Dobutamine
• Fenoldopam
α1 agonist
• Phenylephrine
• Methoxamine
• Naphazoline
• Oxymetazoline
• Midodrine

α2 agonist
• Clonidine
α2 selective agonist
• Methyldopa
• Dexmedatomidine
β2 selective agonist
• Salbutamol
• Salmeterol
• Ritodrine

Indirect-acting agonists:
They act on adrenergic neurons to release NA which then acts on adrenoceptors
• Amphetamine
• Cocaine
• Tyramine
 Mixed-action agonists:
They act directly as well as indirectly.
• Ephedrine
• Pseudo ephedrine
• Amphetamine
• Mephentermine

Pharmacokinetis
CAs are absorbed from the intestine but are rapidly degraded by the Monoamine
Oxidase (MAO) enzyme. and COMT present in the intestinal wall and liver. Thus
oral use is inactive.
1. Adrenaline/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.
 Mode of administration:
0.2-0.5mg SC, IM
0.5% by aerosol
action last for upto ½ to 2 hrs.

2. Noradrenaline: 2-4µg/ min IV infusion.
local tissue necrosis occurs if the solution extravasates.
Rarely used now as a pressor agent.
3. Isoprenaline: 20 mg sublingual,
1-2 mg IM
5-10 µg/min IV Infusion
Action lasts 1-3hrs.

Actions of Epinephrine,
Nor epinephrine and
Dopamine

Epinephrine/ Adrenaline
 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 and increases its rate of
contraction.
– 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.

Dales vasomotor reversal
phenomenon
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.

2. Respiratory – causes 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 – it has agonist activity on the β 3 receptors of adipose tissue

Therapeutic uses
1. Anaphylactic shock :
 Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to
allergens.
2. Relieves Bronchospasm :
3. Cardiac arrest :
 Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest like drowning &
electrocution.
4. with local Anesthetics :
 Local anesthetic solutions - contain 1:100,000 parts epinephrine - to increase the duration action of the
local anesthesia.
5. To control epistaxis :
 Very weak solution (1:100,000) - used topically to vasoconstrict the mucous membranes to control oozing
of capillary blood.

Adverse effects:
a. CNS disturbances:
- anxiety, fear, tension, headache, and tremor.
b. Haemorrhage :
- cerebral haemorrhage - 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.

Contraindications :
1. Hyperthyroidism :
 Epinephrine – enhances the 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 to hypersensitive
response.
2. Diabetes :
 Epinephrine increases the release of endogenous stores of glucose.
 In the diabetic, dosages of insulin may have to be increased.

Interactions:
a. Cocaine:
 Cocaine + epinephrine exaggerated cardiovascular actions
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

Nor Epinephrine/Nor Adrenaline
 They are agonist at α1, α 2 and β 1 receptors with similar potency as
epinephrine, but has relatively little effect on β 2 receptors.
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 subcutaneous, intra muscular or undiluted iv
injection – danger of necrosis

Dopamine
Definition of neurotransmitters
– 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)

Dopamine
Immediate precursor of nor-epinephrine & epinephrine
Endogenous dopamine may have more important effects in
regulating sodium excretion and renal function.
Features distinguishing from nor-epinephrine &
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

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.

Therapeutic classification of drugs
I. Pressor agents
• Noradrenaline Phenylephrine
• Ephedrine Amphetamine
• Dopamine Mephentermine
• Methoxamine
II. Cardiac stimulants
• Adrenaline Dobuatmine
• Isoprenaline
III.Bronchodilators
• Adrenaline Terbutaline
• Isoprenaline Salmeterol
• Salbutamol Formoterol

IV. Nasal decongestants
• Phenylephrine
• Naphazoline
• Xylometazoline
• Pseudoephirine
• Oxymetazoline
• Phenyl propanolamine
V. CNS stimulants
• Amphetamine
• Methamphetamine
• Dexamphetamine
VI. Anorectics
• Fenfluramine
• Sibutramine
• Dexfenfluramine
VII.Uterine relaxants and
vasodilators
• Ritodrine
• Salbutamol
• Isoxsuprine
• Terbutaline

Pressor agents
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 non-catechol ,it has high bioavailability and a relatively
long duration of action.
 It releases NE and activates β2 receptors directly.
 Crosses BBB, it is a powerful stimulant.
 Nowadays its use is restricted only to treat hypotension with spinal
anesthesia and mild chronic bronchial asthma.
 Repeated dosing - tachyphylaxis

Phenylephrine
 Selective α 1 agonist.
 It raises BP by causing vasoconstriction.
 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

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.

CNS Stimulant
Amphetamine
Synthetic compounds having same pharmacological profile as
ephedrine.
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 The CNS effect include alertness,
increased concentration and attention span, euphoria,
talkativeness, increased capacity to work.

Performance of simple mental tasks are improved but number of errors
increased due to over confidence
Athletic performance is improved temporarily followed by
deterioration. It is one of the drugs included in the ‘dope-test’ for
athletes.
Depressant effect on appetite as a result of inhibition of hypothalamic
feeding center.
Drug of abuse & is capable of psychological dependence but little or no
physical dependence.
High doses produce: euphoria, hallucinations, acute psychotic state.
Toxicity includes: vasomotor effects, palpitations, arrhythmias,
vomiting, abdominal cramps and vascular collapse.
Death is precede by convulsion and coma.

Therapeutic uses:
– Narcolepsy
– Attention deficit hyperactive disorder
– Weak anticonvulsant, analgesic and antiemetic action
– 5-15mg oral.
Treatment of toxicity:
– acidification of urine
– Administration of chlorpromazine.

Methamphetamine
– Very similar to amphetamine with an even higher ratio of central
to peripheral actions.
– Dosage: 5-10mg orally
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.

Modafinil
 Psychostimulant.
 Inhibits both NE and DA transporters.
Therapeutic uses:
1. Improve wakefulness in narcolepsy.
2. In shift workers.
3. To relieve fatigue in multiple sclerosis
4. Adjunct in obstructive sleep apnoea.
Associated with increase in BP and heart rate, usually mild.

Cardiac stimulant
Dobutamine
 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 inotropicaction caused by the isomer with predominantly
β1 receptor activity.
 It has relatively greater inotropic than chronotropic effect.
Therapeutic uses:
Patients of heart failure associated with myocardial infarction , cardiac surgery & for
short term management of acute congestive heart failure.

Mephentermine
 Produces both cardiac stimulation and vasoconstriction by directly activating α
and β adrenergic receptors.
 Cardiac pressure, systolic and diastolic BP are increased.
 Active orally for longer duration of time: 2-6hrs.
 Crosses BBB and may produce excitatory effect at high doses.
 Use restricted to prevent and treat hypotension due to spinal anaesthesia
and surgical procedures, shock in myocardial infarctions and other
hypotensive states.
Adverse effects – hallucinations ,convulsions

Clonidine
Antihypertensive effect
 Stimulates α 2A receptors at vasomotor centre – central sympathetic outflow reduced
– fall in BP & HR.
Therapeutic uses:
 Moderate hypertension
 To control diarrhoea in diabetic patients with autonomic neuropathy
 In prophylaxis of migraine
 Menopausal hot flushes
Adverse effects:
 Rebound hypertension
 Dry mouth
 Sedation

Bronchodilators
Salbutamol, terbutaline
1. Selective β2 agonist that causes 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 comparing to salmeterol
3. Formoterol is used to prevent attacks of nocturnal asthma and prophylaxis of exercise
induced bronchospasm & COPD

Nasal decongestants
Naphazoline & xylometazoline
 Nasal decongestants in rhinorrhoea& to check epistaxis
Oxymetazoline
 Direct-acting α 1 agonists.
 Used as topical decongestants because of promoting the 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.

Phenylpropanolamine
 Was a common component in appetite suppressants.
 It was removed from the market because its use was associated
with hemorrhagic strokes in young women.
Pseudoephedrine
 One of four ephedrine enantiomers.
 Available as a component of many decongestant mixtures.

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 its discontinuation.
Sibutramine & R – sibutramine
 Inhibit NA reuptake in hypothalamus.
 These drugs are banned in India & USA.

Vasodilator
Tyramine
High concentrations in some fermented foods -cheese.
Readily metabolized 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

Uterine relaxant
Ritodrine
– may cause uterine relaxation in premature
labour.

Therapeutic Uses of Sympathomimetics
1. Cardiovascular Applications
a. 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.

b. With local Anesthetics :
 Local anesthetic solutions - contain 1:100,000parts epinephrine - to
increase the duration of the local anesthesia and systemic toxicity of LA is
reduced.
c. Nasal decongestant:
 In colds, rhinitis, sinusitis, blocked Eustachian tube – used as nasal drops.
 Shrinkage of mucosa provides relief, but atrophy of mucosa on prolonged
use is seen.
 Pseudoephedrine, phenylephrine and phenylpropanolamine is used orally.

d. Peripheral vascular diseases:
Vasodilators including Isoxsuprine is used in treatment of
• Reynaud’s phenomenon
• diabetic vascular insufficiency
• Gangrene
• frost bite
• ischemic ulcers
• night leg cramps
• cerebral vascular inadequacy

2. Cardiac uses
a. Cardiac arrest
In case of drowning and electrocution Adr may be
administered to stimulate heart.
b. Stokes- Adams syndrome
It is cardiac arrest occurring at the the transition of
partial to complete heart block.
Use of Adr is secondary to mechanical and electrical
measures.

c. Partial or complete A_V block
May be used as a temporary measures to maintain sufficient
ventricular rate.
d. congestive heart failure
Adrenergic inotropic drugs are not useful in routine treatment of
CHF.
Controlled IV infusion of Dobutamine can tide over acute cardiac
decompression during myocardial infarction and cardiac surgery.

epinephrine have been used in the temporary emergency
management of complete heart block and cardiac arrest.
Dobutamine injection is used in pharmacologic cardiac
stress test

3. 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
terbutaline .

4. 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.

5. 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.

6. 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 occasionally 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.

7. CNS Applications
a. 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.
b. Attention-deficit hyperactivity disorder (ADHD)
 Used to calm down hyperkinetic children.
 this disorder is the mildest grade of metal retardation or a reduction in the
ability to concentrate.
 Amphetamines increases the attention span and thus help improve behavior.
 Growth retardation may occur due to reduced appetite.

c. Epilepsy
Amphetamines are occasionally used as adjuvants to counteract sedation caused by
antiepileptic.
d. Parkinsonism
Amphetamines improves mood and reduced rigidity of muscles.
e. Obesity
 The anorectic drugs can help obese people to tolerate a reducing diet for short periods.
 Their use is considered in severe obesity, not for cosmetic reasons.
 Most of the subjects tends to regain weight once the slimming regimen is over.
 Fenfluramine and dexfenfluramine have been withdrawn in many countries due to the
side effects.
 Currently Sibutramine is being used.

DENTAL APPLICATION OF ADRENALINE
Adrenaline is used as the vasoconstrictor in Local Anesthetic
solution..
Local anaesthetics cause dilatation of blood vessels. The addition
of a vasoconstrictor such as adrenaline/epinephrine
diminishes local blood flow, slowing the rate of absorption and
thereby prolonging the anaesthetic effect.
Mode of Action - Attach to and directly stimulate adrenergic
receptors . Act indirectly by provoking the release of endogenous
catecholamine from intraneuronal storage sites.

Concentrations of Vasoconstrictor in Local Anesthetics -
1:50,000 ,1:100,000, 1:200,000 - 0.020mg/ml ,0.010mg/ml, 0.005 mg/ml
 Max dose of vasoconstrictors in a healthy patient is approximately 0.2mg
 Patient with significant cardiovascular history: 0.04mg
 In dental surgery, in which small volumes are injected, concentrations of 12.5
micrograms/ml (1:80 000) are commonly used.
PRECAUTIONS
 Local anesthetic Solutions containing epinephrine should be used with
particular caution in patients with hypertension, atherosclerotic heart
disease, cerebral vascular insufficiency, heart block, thyrotoxicosis or
diabetes since severe and sustained variations in blood pressure may occur.

Summary
– Sympathomimetic are class of drugs that partially or completely mimic
the actions of epinephrine (Epi) or norepinephrine (NE)
– They produce effects similar to the effects of sympathetic nerve fibers.
They are the catecholamines or non catecholamines.
Adrenergic receptors are membrane bound G-protein coupled receptors .
function primarily by increasing or decreasing the intra cellular
production of second messengers cAMP/DAG.
On the basis of 2 different potencies of adrenergic agonist, adrenergic
receptors are classifies into 2 types:
Sympathomimetic are classifies based on their mechanism of action and
therapeutic effects.

Sympathomimetic have effects on Cardiovascular system, CNS, respiratory
system, ophthalmic application, genitourinary system.
The therapeutic effects of sympathomimetic are in the treatment of:
– Cardiogenic shock
– Anaphylactic shock
– Hypotension
– Hypertension
– Congestive heart failure
– Bronchial asthma
– Nasal decongestion
– Narcolepsy
– Attention deficit / hyperactivity disorder

References
– KD Tripathi 7th Edition Essentials Of Medical Pharmacology
– Basic & clinical pharmacology 12th edition
– Goodman & Gilman (2011). Pharmacological Basis of
Therapeutics

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