INTRODUCTION TO

SYMPATHETIC
DRUGS
Department of Pharmacology,
Faculty of Medicine,
King Abdulaziz University
 Adrenergic agonists

Direct Indirect Mixed

Endogenous Exdogenous

Ephedrine
Tyramine
Amphetamine
Norepinephrine α Receptor Agonists
Epinephrine β Receptor Agonists Cocaine
Dopamine Dopamine Agonists
MAO –COMT
inhibitors
 Norepinephrine(α1=α2; β1>>β2)
Pharmacologic effects:
α effect: marked vasoconstriction
Β1 effect :postive inotropic and chronotropic
Increase BP reflex bradycardia

▪ NOT given orally, S.C , I.M

▪ Given as IV infusion only, why
If you give it IV bolus could cause tissue necrosis

Therapeutic uses
•Shock (if BP less than 70)
•Pulmonary embolism
Epinephrine(α1=α2; β1=β2)
Pharmacologic effects:
Cardiovascular
Cardiac contractility(ß)
Heart rate(ß1)
Vasoconstriction (α1)
Vasodilatation(β2)
Bronchodilation(β2)
GI: Hyperglycemia(β2);
Lipolysis(β3);
SM relaxation ( α;ß).
Therapeutic use:
Bronchospasm, Glaucoma,
Anaphylactic Shock.
Preparations & dosage of epinephrine

▪ Acute anaphylactic shock

▪ * Given as S.C , I.M
▪ Do not give it as IV ( could cause ventricular
fibrillation)
• * cardiac arrest. Treatment: Epinephrine IV (1:10,000)
+CPR if Not efficient
Intracardiac:
* Epinephrine inhalation (1:100) in asthma.
* Topical (1:100) in bleeding states
 Anaphylaxis

bronchoconstriction
↑secretions
↓blood pressure

Epinephrine
- Bronchodilation - vasoconstriction
 Adverse Effects
• Restlessness, Throbbing
headache, Tremor, Palpitations

• Cerebral haemorrhage, cardiac

arrhythmias.
Contra-indication (C/I) of Epinephrine
1. HTN
2. C.V problems (I.H.D)
3. Large dose of local anesthetic + epinephrine (sever VC); Tissue
necrosis (gangrene)
4. Cardiac outflow obstruction (Hydrotrophic obstruction cardiomyopathy
(HOCM)
5. Hyperthyroidism ( T3 and T4)
T4: 1- Increase the number of β-1 receptors in the body (up-regulation)
2- Increase the sensitivity of β-1 receptors
3- COMT enzyme is those patient is inhibited
4- Cause sympathetic over activity
 DIRECT-ACTING DOPAMINE RECEPTOR AGONISTS

Dopamine
(1) Activates D1 receptors leads to vasodilatation (low dose).
(2) Activates β1receptors in the heart (moderate dose).
(3) Vasoconstriction (high dose) like NE

Therapeutic uses:
Improve myocardial function in acute HF& cardiogenic shock.
Chronic refractory heart failure.

• Ineffective orally, IV use only,

• Short T 1/2 (3-5minutes)
 EXogenous Direct-Acting
adrenergic agonists

Selective α1 agonists
 Exogenous Direct-Acting adrenergic agonists

Phenylephrine(α1>α2)
Pharmacologic effects: pure α agonist
a. It is not inactivated by COMT has longer duration

b.Vasoconstriction, increased BP, reflex bradycardia.

Therapeutic uses:
a. As a nasal decongestant
b. As a pressor agent
c.To provide local vasoconstriction
(1)A10% ophthalmic solution
(2)An adjunct for use with local anesthetics

d.For relief of paroxysmal atrial tachycardia

e.Postural hypotension
 Selective α1 agonists (cont.)
Methoxamine:
It is used in hypotensive states(parenteral)
Midodrine :
It is mainly used in postural hypotension

Adverse effects of α1 agonists:

1- Hypertension and reflex bradycardia
2- Atrophic rhinitis & Rebound nasal congestion (if local)
 SELECTIVE α2 AGONISTS (CENTRALLY-
ACTING SYMPATHOLYTICS)
Members:
Alpha-methyl dopa, Clonidine, Rilmenidine
NB.
* They are α2 agonists, but they are sympatholytics
(if given systemically) and not sympathomimetics.
* Alpha-methyl dopa and Clonidine in the brain
stimulate central postsynaptic α2 adrenoceptors
to inhibit central sympathetic outflow. Also they
may stimulate presynaptic α2 adrenoceptors to
reduce norepinephrine release.
EXogenous Direct-Acting
adrenergic agonists

Β agonists
 Exogenous Direct-Acting adrenergic agonists

Isoproterenol(β1=β2)
Therapeutic uses:
▪Bronchodilator

▪Cardiac stimulant for heart block or severe bradycardia

Adverse effects:
Palpitations, Tachycardia, Coronary insufficiency
 Exogenous Direct-Acting adrenergic agonists

Dobutamine(β1)

Pharmacologic effects:

Dobutamine resembles dopamine

Direct activates β1-receptor.
Greater inotropic than chronotropic effect.
Minimal changes in HR and systolic BP.
 Dopamine Dobutamine
Uses Acute HF & cardiac shock
if there is if there is
- hypotension (α1) and - normal BP and
- renal impairment (D1) - preserved renal function

Chronic refractory heart failure

IV infusion: IV infusion:
low dose→ gradually ↑ to low dose → gradually ↑ to
a maximum dose maximum dose
2 ug/kg/min → 50 ug/kg/min 2.5 ug/kg/min → 10 ug/kg/min
 DIRECT-ACTING β−ADRENERGIC AGONISTS

Selective β2 agonists
* Short acting: salbutamol, terbutaline, ritodrine
* Long acting: salmeterol, formoterol, bambuterol.

Advantages over the nonselective agents:

1- No cardiac complications in regular doses
2- Longer duration (not metabolized by MAO or COMT)
3- Used by many routes (oral, inhalation, parentral)
Uses:
1- Bronchial asthma (salbutamol, salmeterol)
2- Prevent premature labor & threatened abortion
(terbutaline, ritodrine)
3- Peripheral vascular disease
 DIRECT-ACTING β−ADRENERGIC AGONISTS

Selective β2 agonists (Cont.)

Adverse effects (less with inhalation therapy):
1- Central stimulation → Anxiety, restlessness and headache
2- Tremors (acting on β2 in skeletal muscles)
3- Tachycardia (high concentration stimulate β1 receptors in the heart).
4- Tolerance on long term systemic use (β receptor down regulation)
5- Hyper-reactive bronchi on sudden withdrawal (Rebound)
6- Hypokalemia and muscle cramps
7- Hyperglycemia and ↑ free fatty acids
8- Hypoxemia: if lung ventilation/perfusion ratio worsens (stimulate β2 → VD
> bronchodilation → insufficient blood oxygenation.
Indirect-Acting Adrenergic
Agonists
 Mechanism of Action

(1)displacement of stored
catecholamines
amphetamine, tyramine

(2)inhibition of reuptake of
catecholamines
cocaine, tricyclic antidepressants
 Indirect-Acting Adrenergic Agonists

Amphetamines
Pharmacologic effects:
Acts by releasing NE.
A) CNS: - CNS stimulation, alertness, ↓fatigue-
↑↑mood elevation - ↓ Appetite
B) CVS: ↑ arterial blood pressure → reflex
bradycardia.

Therapeutic uses
Treatment of narcolepsy.
The appetite-suppressing effect: (Weight)

Attention deficit hyperactivity disorder in children.

 1- Amphetamine(cont)
Adverse Effects:
CNS:
1- Psychological dependence & Schizophrenia-like syndrome.
2- Anorexia & weight loss
3- Insomnia, tremors → depression, fatigue (CA store depletion)
4- Severe toxicity → convulsion, coma & cerebral hemorrhage
CVS: Palpitation, arrhythmia, anginal pain and hypertension.
 Indirect-Acting Adrenergic Agonists

Tyramine
Pharmacologic effects:
Release of stored catecholamines.

It is found in high concentrations in fermented foods

(cheese..)
It metabolized by MAO in liver

With MAO-Is hypertensive crisis

Tyramine Interaction with MAO Inhibitors
Can cause hypertensive crisis (↑BP, ↑HR)
 Indirect-Acting Adrenergic Agonists

Cocaine
Pharmacologic effects:
1. Block norepinephrine reuptake
2. Block sodium channels, as a local anesthetic.

Therapeutic effects
1. A potent central nervous system stimulant.
4. Overdose: causes tachyarrhythmias and a marked
elevation of blood pressure.
Mixed-acting sympathomimetic
Mixed-acting sympathomimetic
• Directly stimulates the receptor by binding
to it
AND
• Indirectly stimulates the receptor by causing
the release of stored neurotransmitters from
the vesicles in the nerve endings
 Mixed-acting adrenergic agonists

Ephedrine
Mechanism of action
(Direct) actions on adrenoceptors
(Indirect) release of stored
catecholamines

It resistant to COMT and MAO,Long

duration of action
 Mixed-acting adrenergic agonists

Ephedrine (cont.)
Uses:
1- Topical hemostatic in epistaxis (ephedrine).
2- Nasal decongestant: ephedrine,
pseudoephedrine (systemic).
3- Spinal shock (IV ephedrine).

Adverse Effects:
1- Minimal CNS (+) → insomnia, anxiety
(sleepiness in children)
2- Minimal CVS (+) → palpitation, arrhythmia,
anginal pain
3- Urinary retention