SYMPATHOMIMETIC

DRUGS
Dr. Shazana Rana
Learning Objectives

• At the end of the session the students should be able to;

• Classify sympathomimetic drugs
• Identify receptors selectivity of sympathomimetic drugs
• Describe MOA of sympathomimetic drugs
• Discuss structure activity relationship
• Differences between catecholamines and non catecholamines
• Discuss epinephrine,
• Discuss other sympathomimetic in comparison with epinephrine
Adrenergic Transmission
 Metabolic Pathway for the synthesis of
Catecholamines from tyrosine
TYROSINE
Rate limiting step inhibited by (Tyrosine hydroxylase)
metyrosine
DOPA
(Dopa Decarboxylase)

DOPAMINE

(Dopamine -hydroxylase )
NOREPINEPHRINE
In adrenal Medulla & certain areas (Phenylethanolamine N-Methyltransferase)
of brain.
EPINEPHRINE
Distribution of Adrenoceptor Subtypes
Type Tissue Actions
α1 Most vascular smooth muscle Contraction
Pupillary dilator muscle Contraction (dilates pupil)
Pilomotor smooth muscle Erects hair
Prostate Contraction
Heart Increases force of contraction
α2 Postsynaptic CNS adrenoceptors Modulate dopamine release
Platelets Aggregation
Adrenergic and cholinergic presynaptic
Inhibition of transmitter release
nerve terminals
Some vascular smooth muscle Contraction
Fat cells Inhibition of lipolysis
Distribution of Adrenoceptor Subtypes
Type Tissue Actions

β1 Increases force and rate of contraction;

Heart, juxtaglomerular cells
increases renin release

β2 Respiratory, uterine, and vascular

Promotes smooth muscle relaxation
smooth muscle
Skeletal muscle Promotes potassium uptake
Liver Activates glycogenolysis

β3 Fat cells Activates lipolysis

D1
Smooth muscle Dilates renal blood vessels
D2
Nerve endings Modulates transmitter release
Activation of Alpha-1 receptors
Activation of Alpha 2 &
Beta Receptors
ADRENERGIC DRUGS
CLASSIFICATIONS

I. Chemical Classification
II. Classification according to Receptors.
III. Classification according to Mode of Action
IV. Therapeutic Classification.
Chemical Classification
• Catecholamines
Naturals
Epinephrine (Adrenaline)
Nor epinephrine (Noradrenaline)
Dopamine
Synthetic
Isoprenaline
Dobutamine
Rimiterol
• Non-Catecholamines
Ephedrine
Pseudoephedrine
Amphetamine
Dexamphetamine
Orciprenaline
Metaraminol
Terbutaline
Classification According to
Mode of Action
• Direct Acting Sympathomimetics
Epinephrine, Nor-epinephrine,
• Indirect Acting Sympathomimetics
a: Releasers of Nor epinephrine
Amphtamine , Methylamphetamine, Tyramine
b: Inhibitors of Reuptake of nor epinephrine already released
Cocaine , Tricyclic antidepressant
• Drugs with mixed action (direct , Indirect acting)
Ephedrine , Metraminol
Classification Based on
Receptor Selectivity
• α-Receptors Agonists:
• α1-Receptors Agonists
Phenylephrine , Methoxamine
Xylometazoline , Modafinil , Midodrine
• α2-Receptors Agonists
Clonidine ,  -Methyldopa
Guanfacine, Guanabenz, Dexmedetomidine , Apraclonidine,
Brimonidine
• α1, α2 combined agonists
Oxymetazoline
• Beta (β) Receptor Agonists:
• β1 Selective Agonists
Dobutamine, Prenalterol
• β2 Selective Agonists
Salbutamol , Terbutaline , Metaproterenol ,
Pirbuterol , Salmeterol , Formeoerol
Ritodrine
1 & 2 Agonists
Isoprenaline, Orciprenaline
Both  &  Agonists
Epinephrine , Nor epinephrine, Ephedrine
Adrenergic & Dopaminergic receptor Agonist:
Dopamine
Receptors selectivity
Alpha Agonists

Phenylephrine , Methoxamine α1 > α2 >>>>> β

Clonidine, Methylnorepinephrine α2 > α1 >>>>> β

Mixed Alpha & Beta Agonists

Norepinephrine α1 = α2 ; β1>> β2

Epinephrine α1 = α2 ; β1= β2
Beta Agonist
Dobutamine β1> β2 >>>> α
Isoproterenol β1= β2 >>>> α
Terbutaline, Metaproterenol, Albuterol, β2>> β1 >>>> α
Ritodrine

Dopamine Agonist
Dopamine D1 = D2 >> β >> α
Fenoldopam D1 >> D2
CATECHOLAMINES

Natural: Epinephrine
Nor epinephrine
Dopamine
Synthetic: Isoprenaline
Dobutamine
Rimiterol
Isoetharine
Hexoprenaline
CATECHOLAMINES
CATECHOLAMINES,
CHEMISTRY
• Benzene ring
• Ethylamine side chain.
CHARACTERISTICS OF
CATECHOLAMINES
 Catechol nucleus
 Can not be given orally
 Short duration of action
 Metabolized by MAO & COMT
 Can not cross BBB
 Act directly on adrenergic receptors
STRUCTURE ACTIVITY
RELATIONSHIP
Substitution on
benzene ring
Substitution on the
Amino Group
Substitution on the
Alpha Carbon

* Phenylisopropylamines
Substitution on the
Beta Carbon
EPINEPHRINE/ADRENALINE

• Source:
Natural catecholamine
Produced by adrenal medulla
Certain areas of brain
PHARMACOKINETICS

1. Derivatives of catechol (3,4 dihydroxy benzene)

2. Not effective orally, given par-enterally or by inhalation
3. Given in small doses
4. Substrate for enzymes COMT and MAO
5. Do not cross blood-brain barrier.
6. Product of metabolism is metanephrine and VMA.
MECHANISM OF ACTION

Acts on Adrenergic Receptors:

• Alpha-Receptors
• Beta -Receptors
PHARMACOLOGICAL EFFECTS

• Cardiovascular system
• Respiratory system
• Gastrointestinal system
• Genitourinary system
• Eye
• Brain
• Metabolic and skeletal muscles
Cardiovascular System

• Heart
• Blood vessels
• Blood pressure
• ECG
Heart
Mainly acts on β1  ↑ Ca+ influx in cardiac cells.
• HR ----- ↑ +ve chronotropic effect .Pace maker activity of both SA node &
purkinje fibers is ↑
• Contractility --↑↑ +ve inotropic effect, relaxation is accelerated.
• Excitability & Automaticity --- ↑
• Conduction velocity.---- ↑in AV node & Refractory period is ↓
• Stroke volume ---- ↑ & cardiac output ---- ↑.
• Work load ---- ↑  ↑ oxygen demand.
• Mechanical efficiency of heart is decreased.
Blood Vessels
• Cutaneous, (α1 ) constricted
• Skeletal muscle (β2 , α ) mainly dilated or constricted
• Renal (α1 ) constricted
• Coronary (Mainly β2 ) ----- dilated
• Cerebral ---- no significant change related to systemic blood
pressure.
• Veins (α1 ) constricted-- ↑venous tone
Blood Pressure
• Systolic ↑↑
• Diastolic ↑ (large doses) or ↓ (small doses)
• Mean ↑
• Pulse pressure --- ↑↑
ECG
• ↓ amplitude of T-wave in normal doses
• Depression of T-wave in large doses
Respiratory system

Lungs
• Smooth muscles– Bronchodilation , stimulation of β2
• BV (α1 ) constricted--- decongestion .
• ↓ release of mediators from mast cells.
• Inhibit microvascular leakage & ↑ muco-ciliary transport by
↑ ciliary activity.
Gastero-intestinal
system
• Smooth muscles relaxed via β receptors directly.
• α2 presynaptic receptors ↓ muscle activity indirectly by ↓
release of Ach. & other stimulant in ENS.
• α1 receptors in sphincters --- contraction
• α2 receptors also ↓ salt & water retention into the lumen of
intestines.
Secretions:
• Salivary secretion: scanty ↑ in secretion of amylase & water.
• No marked effect on other secretions.
Genito –urinary
system
• Uterine smooth muscles relaxed via β2 .
• Urinary bladder smooth muscles relaxed via β2 .
• Ejaculation depends on α activation in ductus deference,
seminal vesicles, & prostate.
• Urinary bladder base, sphincter & prostate contracted via α1A .
Sweat glands.
• ↑ secretion of Apocrine sweat gland ( Non thermoregulatory)
on the palms of the hands & few other areas.
Eye

• Mydriasis
• Decrease in IOP– due to ↑ out flow
• No significant effect on Accommodation
• Pallor of conjunctiva-- BV (α1 ) constricted
• Direct protection of neuronal cells in retina.
Metabolic effects

• Blood glucose-- activation of β2 --- ↑glycogenolysis in liver,

↑ glucose release into the circulation.
Insulin secretion --- α2 ↓ & β ↑ .
• Lipocytes contain β3 & α2: β3 ↑ lipolysis--- ↑ fatty acids &
glycerol (predominant effect) , α2 ↓ lipolysis.
• Metabolic acidosis in high doses.
• K+ Level (β2 ) ↓ in EC K+ due to uptake of K+ into the cells.
Effects on Endocrine
functions.
Release of Renin: ↑ β1 & inhibited by α2.
• Insulin secretion --- α2 ↓ & β ↑ .
• Secretion of parathyroid hormoe, calcitonin, thyroxine &
gastrin are also modulated.
Pilomotor muscles: contracted α1
Blood: leukocytosis in high doses.
Central nervous system

Adverse effects
• Anxiety
• restlessness
Therapeutic uses

• Anaphylactic shock
• Acute severe asthma
• To prolong action of infiltration L.A & to
↓systemic toxicity.
• Topical Haemostatic
• Cardiac Resuscitation
• Wide angle glaucoma
Adverse effects

• Cardiac arrhythmias
• Anginal pain.
• Cerebral haemorrhage.
• Tissue necrosis.
• Anxiety
• Restlessness
• Effects only at high doses, does not cross BBB at
therapeutic doses.
• Fear, Anxiety, Restlessness ,Headache ,Tremors.
Contraindications

• Pheochromocytoma
• Ischemic heart disease
• Hyperthyroidism
Nor-epinephrine

Blood vessels & BP

• ↑ peripheral resistance , both diastolic & systolic blood
pressure rise
On Heart:
• Reflex bradycardia because compensatory vagal reflexes
overcome the direct positive chronotropic effect.
• Positive inotropic effects are maintained.
Limited therapeutic use,
• May be used for treatment of hypotensive
emergency to preserve cerebral or coronary blood
flow
(Drug of choice is Dopamine & Dobutamine).
Adverse Effects:
Necrosis  Gangrene of extremities
ISOPROTERENOL (ISOPRENALINE)

• Chemistry
• Structure activity Relationship
Pharmacological Effects
• CVS
• Smooth Muscles
• Metabolic Effects
Therapeutic Uses:
• In emergencies (bradycardia , heart blocks) to
stimulate HR specially before insertion of artificial
pace maker.
• Bronchial asthma (β2 selective drugs preferred).
DOPAMINE
• Natural catecholamine , also prepared synthetically
Acts on:
• Dopamine receptor
At Periphery important effects on CVS , Activates:
D1 receptors in renal BV ---- vasodilatation (low doses).
Presynaptic D2 receptors ---- ↓ Nor- epinephrine release.
• Activates β1 receptors (moderate doses)—in heart
• α1 receptors (high doses) in BV
Therapeutic Uses:
• Drug of choice in cardiogenic / hypovolumic / traumatic shock
specially shock with oliguria.
• Refractory CHF.
• Dopamine agonists with central actions----valuable in
Parkinson’s disease & Hyperprolactinemia.
DOBUTAMINE

• Synthetic Catecholamine
• Relative β1 selective agonist also acts on α1 receptors
Therapeutic Uses:
Shorter treatment of cardiac decompensation in patients with
cardiac surgery , acute myocardial Infarction
PHENYLEPHRINE
CLONIDINE
SELECTIVE BETA-2 AGONISTS

• SALBUTAMOL,
• TERBUTALINE
• RITODRINE
• SALMETROLOL
• FORMETROLOL
Therapeutic uses
• Bronchial asthma
• Chronic obstructive pulmonary disease
• Premature labour (Ritodrine)
Adverse effects
• Tachycardia
• Tremors
MIXED ACTING
SYMPATHOMIMETICS
• Ephedrine
• Metraminol
Ephedrine

• Alkaloid, ephedra plant

• Synthetic
• First orally active
• Non –catecholamine
Indirect action
• Promotes release of stored Nor-epinephrine
• This does not require action potential & exocytosis.
• Released Nor-epinephrine enters the synaptic cleft via
Reuptake – 1
Direct action
• Directly on receptors as epinephrine
Therapeutic uses
• In chronic orthostatic hypotension.
• In acute hypotensive states associated with spinal anesthesia
• As bronchodilator in:
• Bronchial asthma
• Obstructive pulmonary disease
• Stress incontinence in women.
• Nasal decongestion (pseudoephedrine)
• Hay fever(pseudoephedrine)
INDIRECT ACTING
SYMPATHOMIMETICS
Nor-epinephrine releaser
• Amphetamine
• Methylamphetamine
• Tyramine
Reuptake inhibitors
• Cocaine
• Tricyclic antidepressants
Amphetamine

• Action is same as ephedrine

• Marked stimulant effect on mood & alertness.
• Depressant effect on appetite.
• It is highly abused drug due to its euphoriant effect.
• Some amphetamine variants also have abuse
potential.
Tyramine
• Normal by-product of tyrosine metabolism in body.
• Non-catecholamine
• Parenteral Indirect acting sympathomimetic
• It releases stored Catecholamines. So Actions are like NE
• Ineffective orally due to high First Pass Met by MAO-A in liver.
• High concentration in fermented food i.e Cheese or yeast.
• In Patients on MAO-A inhibitors, hypertensive crises can occur if
foods rich in Tyramine are taken ,due to increased bioavailability.
So such patients should avoid these foods.
Cocaine

 A local anaesthetic.
 Indirectly acting sympathomimetic drug.
 Inhibits reuptake of released Nor-epinephrine at peripheral
Nor-adrenergic synapses.
 In the CNS it inhibits dopamine reuptake into neurons in the
“pleasure centers” of the brain.
 It is heavily abused drug.
Effects on eye
• Mydriasis
• Light reflex remains present.
• Absent corneal reflex.
• Pallor of scleral conjunctiva.
Differences between catecholamines and non -
catecholamines
Catecholamines
Catechol nucleus
Can not be given orally
Short duration of action
Metabolized by MAO &
COMT
Can not cross BBB
Act directly on adrenergic
receptors
Non-catecholamines
No catechol nucleus
Can be given by oral route
Long duration of action
Not metabolized by MAO &
COMT
Can cross BBB, CNS
stimulants
They may act directly as well
as indirectly
Clinical Application of
Sympathomimetics
Bronchial Asthma:
2 Selective Agonists: Salbutamol (Albuterol), Terbutaline ,
Metaproterenol , Pirbuterol , Salmeterol , Formoterol.
1 & 2 Agonists: Isoprenaline, Orciprenaline
Both  &  Agonists: Epinephrine (status asthamaticus).
Nasal Congestion
Naphazoline, Oxymetazoline Xylometazoline,
Pseudoephedrine
Cardiogenic shock: Dopamine, Dobutamine.
Anaphylactic shock: Epinephrine.
Heart block & Cardiac arrest: Epinephrine.
Heart failure: Dobutamine.
Hypotension: Norepinephrine , Phenylephrine, Methoxamine
Orthostatic hypotension: Ephedrine, Midodrine.
Hypertension: Clonidine ,  -Methyldopa
Guanfacine, Guanabenz , Fenoldopam
Topical haemostatic:
Epinephrine & 1 agonists , 1:200,000.

To prolong DOA of infiltration nerve block:

Epinephrine & 1 agonists, 1:200,000.
Mydriatics , Allergic conjunctivitis:
Phenylephrine , Oxymetazoline , Tetrahydrozoline.
Glaucoma:
Apraclonidine, Brimonidine , Dipivefrin, Epinephrine.
Localization of lesion of Horner’s syndrome:
Hydroxyamphetamine
Premature labour:
Ritodrine (DOC), Terbutaline & other β2 agonists
Attention deficit hyper activity disorder (ADHD) in children.
Clonidine, Modafinil , Methylphenidate.
Narcolepsy:
Modafinil , Methamphetamine (abused drug).
weight reduction as Anorexic agents (in obesity):
Phenmetrazine, Amphetamine, Methylphenidate & Pemoline
Withdrawal symptoms of alcohol, smoking & narcotic analgesics:
Clonidine