SYMPATHOMIMETICS

AND
SYMPATHOLYTICS
NAME-BISWAJIT SAHOO
H.T NO – 23PH201A01
M. PHARM PHARMACOLOGY
SCHOOL OF PHARMAY
DEPARTMENT OF PHARMACOLOGY
ANURAG UNIVERSITY
 OVERVIEW
INTRODUCTION
RELEASE OF ADRENERGIC NEUROTRANSMITTER

ADRENERGIC RECEPTOR
CLASSIFICATION OF SYMPATHOMIMETICS
MECHANISM OF ACTION OF DRUG

PHARMACOLOGICAL ACTION & ADVERSE EFFECT

THERAPEUTIC USES
Sympathomimetic :

• Also known as adrenergic drugs and adrenergic amines.

• In sympathetic system

- Neurotransmitter – NA , Ach
- Pre ganglion – shorter
-Post ganglion – longer
RELEASE OF ADRENERGIC NEUROTRANSMITTER
Step involve in release of neurotransmitter
synthesis :

• L-tyrosine is converted in to DOPA by tyrosine hydroxylase [rate limiting step] tyrosine

hydroxylase occurs in only catecholaminergic neurons .

• DOPA is converted in to dopamine by dopa decarboxylase .

• Dopamine is converted in to noradrenaline by dopamine beta hydroxylase[DBH],located in

synaptic vesicle .

• In adrenal medulla noradrenaline is converted in to adrenaline by phenylethanolamine N-

methyltransferase.
. NA storage in a synaptic vesicles or granules in adrenergic nerve terminal .

. vesicular membrane actively take up dopamine from cytoplasm and final step of synthesis of
NA takes place in side the vesicles

. NA is stored and complex with an ATP

. In Adrenal medulla NA is formed with in chromaffin granules diffuse out in to cytoplasm and
methylated then adrenaline is formed
 CLASSIFICATION OF SYMPATHOMIMETICS

DIRECT SYMPATHOMIMETICS :-These are the drugs which are directly acts to the alfa or
beta receptors or both of the receptor
ex .Adrenaline ,noradrenaline ,isoprenaline ,methixamine,xylometazoline,solbutamol.

INDIRECT ACTING SYMPATHOMIMETICS :- These drugs acts to the adrenergic neurons to

release noradrenaline which then acts to the adrenoreceptors
ex. Tyramine ,amphetamine

MIXED ACTION SYMPATHOMIMETICS :- These drugs acts as directly as well as indirectly

ex.Ephedrine .
Dopamine (D1 > β1 > α1)
• Natural CNS neurotransmitter.
• Direct acting, catecholamine .
• Given parenterally via infusion .
• vasodilatation of mesenteric, coronary, renal blood vessels - improves blood
flow to viscera
• Has diuretic action
• High dose (α1): vasoconstriction
• On heart : Inotropic, chronotropic effect
Uses
• Doc for Cardiogenic shock: septic, hypovolemia or cardiogenic (I.V infusion)
increase BP & CO ,
• without causing renal impairment (D1)
 MECHANISM OF ACTION

Dopamine binds to the post synaptic receptor

Biological response : activation of post synaptic Cell

Dopamine is converted in to noradrenaline by dopamine

beta hydroxylase, located in synaptic vesicle .

Then NE bind to the respective receptors

Then stimulation or inhibition occurs

Isoprenaline
• A synthetic, direct acting catecholamine
• Longer effect (no reuptake-no destruction by MAO)
• non-selective β agonist (β 1, β 2 & β3 )
• β1 + inotropic effect, + chronotropic effect, increase cardiac output (CO).
• β2 Vasodilatation of blood vessels of skeletal muscles and coronaries.
• β2 Bronchodilatation .
• β2 Relaxation of uterus.
• β2 Hyperglycaemia
• β3 lipolysis

• Uses:
• Used mainly in cardiac arrest (Parenteral).
• Rarely in acute attack of asthma (inhalation).
• Contraindicated in hyperthyroidism & CHD
 MECHANISM OF ACTION

Isoprenaline binding to the beta1 and beta 2 receptor

Activation of adenylate cyclase convert ATP to cyclic

AMP/deactivation of AC {beta 2 }

Increased cyclic AMP activates pka /decrsesed cyclic AMP deactivate

PKA

Stimulation / inhibition activity occurs

 Indirect-Acting Sympathomimetics

Amphetamine
• Synthetic non-catecholamine.
• amphetamine addicts use sodium bicarbonate to obtain the “kick”.
• Acts indirectly, it depletes vesicles from stored NE -Tachyphylaxis
• has CNS stimulant effect
• Increase euphoria - causes its abuse
• decrease Weight - decrease appetite - increase energy expenditure
 Mixed-Acting Sympathomimetics -

Ephedrine
• use for treatment of bronchial asthma and hay fever .
• It is the vasopressor of choice in pregnancy because due to β2
mediated vasodilatory action
• Ephedrine is a non-catechol ,it has high bioavailability and a relatively long
duration.
• Crosses BBB, it is a powerful stimulant.
• Repeated dosing – tachyphylaxis
PHARMACOLOGICAL ACTION
CVS :
Heart
Increase in heart rate and force of contraction
Followed by reflex bradycardia. Increase
cardiac output.

Blood vessels :
Adrenaline constricts artery due to alpha effect
Dilation due to action
Beta receptor more sensitive than alpha receptor.
• Blood pressure :
NA increase systolic ,diastolic and mean BP
Respiratory System:
• Adrenaline and isoprenaline produce a powerful relaxation of smooth
muscle of bronchi, through stimulation of adrenoceptors.
• Adrenaline produce transient apnoea due to inhibition of respiratory centre.
High dose of Adrenaline cause pulmonary edema by shifting blood from systemic
to pulmonary circuit.
• Noradrenaline does not produce any significant action .

GIT:
• Both a and ß adrenoceptor are inhibitory in nature.
• Produce relaxation of smooth muscle.
• Thus decrease in tone and motility.
 Eye:
• Mydriasis occur due to contraction of radial muscle of iris (al).
This effect is minimum after topical application because Adrenaline
penetrate cornea poorly.
• Intraocular tension tends to fall in wide angle glaucoma

Urinary Bladder:
• Detrusor muscle is relaxed and trigone is constricted.
• Cause retention of urine.
 Uterus:
•Response of uterus is dependent on state of uterus.
• Human uterus is constricted by adr. and noradr., if it is non
pregnant.
• This action is mediated through a adrenoceptor.
• Pregnant uterus is again constricted in first two trimester by
adrenaline.

• In last trimester, particularly in last month of pregnancy, it is Relaxed .

• This action is mediated through ß adrenoceptor .

 CNS:
• Does not produce any CNS effect, because It is poorly penetrated
in brain.

• Directly injected into brain, it produce excitation followed by

depression.

• Metabolic:
• Produce hyperglycemia by enhancing glycogenolysis.

• Increase blood lactate.

Lipolysis.
•
Hyperkalaemia

• Stimulation of a receptor inhibit and stimulation of ß receptor

activate insulin secretion.

ADVERSE EFFECT

1.Palpitations
2.Anxiety
3.Trachycardia
4.Loss of appetite
5.Insomnia
6.Hypertension
 Adrenergic Antagonist /Sympatholytics
• An adrenergic antagonist is a drug that inhibits the function of adrenergic
receptors .

• A sympatholytic drug is a medication that opposes the downstream effects of

postganglionic nerve firing in effector organs innervated by the sympathetic
nervous system (SNS).
Beta blockers Action
 Non-Selective α- Adrenoceptor Antagonists
Phenoxybenzamine
• Block alpha 1 and alpha 2 by linking covalently
• Non selective block alpha 1 and alpha 2 Block is irreversibly and new receptors
are made
CVS
• Vasodilatation – arteriolar and venous decrease BP
• postural hypotension
• Baroreflex activation – reflex tachycardia – tends to oppose the fall by increase
HR and CO
OTHER EFFECT
• ↓contraction of trigone and sphincter in blood vessels
• Increase urine flow
• increase insulin secretion from islet cells
• Miosis
• decrease adrenergic sweating
Clinical uses
• Reduce blood pressure -Hypertensive emergencies ,Long term
treatment ,Phaeochromocytoma

• Vasodilatation -Peripheral vascular insufficiency , To reverse

vasoconstrictor excess Improve urine flow - Benign prostatic
hyperplasia

Adverse effects
•Postural hypotension ( less with α1 selective - venodilatation is less)
•Reflex tachycardia ( less with α1 selective)
•Salt and water retention
•Nasal stuffiness
•Miosis
•Failure of ejaculation
 α1 Selective Blockers

Prazosin & Terazosin:

• Effective in management of hypertension
• Low affinity for α2
• Relative absence of tachycardia
• ↓ Triglycerides & LDL, ↑ HDL (favourable)
• Both are extensively metabolized by liver
• Prazosin shows high 1st Pass effect (50%)
• Oral absorption - good
• Terazosin :Bioavailability >90%;
• >18 h action
Uses: Hypertension and BPH
Adverse effects
• First dose effect
• Postural hypotension
• Salt & water retention ( long term use)
 Nonselective β Blocker
Propranolol

• Lacks intrinsic sympathomimetic activity (pure antagonist)

• Equal beta1 and beta2 antagonism

CARDIAC EFFECTS:
• Beta 1 blockade - decrease in Heart rate and myocardial contractility - decreased
Cardiac output .
• Effects on HR and C.O. prominent during exercise or in presence of sympathetic
nervous system activity
• HR slowing lasts longer than negative inotropic effect
• decrease peripheral vascular resistance
• Can relieve myocardial ischemia
• Sodium retention may be associated due to intrarenal hemodynamic changes
(decrease C.O. )
Therapeutic Uses
Propranolol is indicated for the management of various conditions
Hypertension
Angina pectoris
Tachyarrhythmias
Myocardial infarction
Hyperthyroidism
Essential tremor
Side effect
Common side effects of propranolol:
Chronic Trouble Sleeping Less Severe
Feeling Weak Less Severe
Low Energy

Infrequent side effects of propranolol:

Bronchospasm Severe
Chronic Heart Failure Severe
Depression Severe
Diarrhoea
 Selective beta 1 adrenergic receptor
Metoprolol
• Prevents inotropic and chronotropic responses to beta +
• Broncho dilation metabolic effects of beta2 +
• Selectivity is dose related
Large doses: may become non-selective ( beta 2 antagonism less than
propranolol, reversed by terbutaline)

Pharmacokinetics:
• Readily absorbed from GIT, offset by substantial first pass metabolism
• Low protein binding
• No active metabolite
• Two formulations: metoprolol tartarate, metoprolol succinate
• Elimination T ½ =2-3 hours
ESMOLOL
• Rapid onset , Short acting .
• Selective beta1 adrenergic receptor antagonist
• Only IV
• Useful in phaeochromocytoma and perioperative management of thyrotoxicosis,
pregnancy induced HTN, epinephrine or cocaine induced cardiotoxicity)

Pharmacokinetics
• available for IV administration
• PH 4.5-5.5 (commercial preparation)
• compatible with commonly used IVF and NMBD
• Elimination T ½ = 9 minutes
• Rapid hydrolysis in plasma by esterase
• Independent of hepatic and renal clearance
• Poorly lipid soluble
α + β Blocker
LABETALOL
• Selective alpha1 and nonselective beta1 & beta2 adrenergic antagonist effect
• Presynaptic alpha2 receptors are spared
• Beta : alpha potency -oral labetalol - 3:1
• IV labetalol-7:1
• Pharmacokinetic : Conjugation with glucuronic acid
• 5% drug recovered unchanged in urine elimination T ½ =5-8 hours (prolonged in liver
disease, unchanged in renal dysfunction)

CVS EFFECTS:
• alpha blockade - decreases systemic vascular resistance - decrease BP
• Beta blockade - attenuates reflex tachycardia
• Cardia output unchanged
• Vasodilatation is caused by alpha 1 blockade and beta2 agonist activity
CLINICAL USES
• Hypertensive emergencies
• Useful in pheochromocytoma
• clonidine withdrawal
• Excessive doses 2mg/kg iv - excessive decrease in BP
• Small doses 20-80mg - undesirable decrease in BP

Side effect
• Postural hypotension
• Bronchospasm in suspected patients
• In case of prolonged therapy - fluid retention - therefore combined with diuretics
• Rashes and liver damage