Sympathomimetics drugs

Ass. Professor
Ahmed Abu Raghif
M B Ch B , M Sc, Ph.D
Classification of adrenoceptors (Adrenergic
receptors)
– two main α-receptor subtypes, α1 and α2, each
divided into three further subtypes
– three β-adrenoceptor subtypes (β1, β2, β3)
• Second messengers:
– α1-receptors activate phospholipase C, producing inositol
trisphosphate and diacylglycerol as second messengers
– α2-receptors inhibit adenylate cyclase, decreasing cAMP
formation
– all types of β-receptor stimulate adenylate cyclase.
• The main effects of receptor activation are as
follows.
– α1-receptors:
vasoconstriction, relaxation of gastrointestinal
smooth muscle, salivary secretion and hepatic
glycogenolysis
– α2-receptors:
inhibition of transmitter release (including
noradrenaline and acetylcholine release from
autonomic nerves), platelet aggregation,
contraction of vascular smooth muscle, inhibition
of insulin release
– β1-receptors:
increased cardiac rate and force
– β2-receptors:
bronchodilatation, vasodilatation,
relaxation of visceral smooth muscle,
hepatic glycogenolysis and muscle tremor
– β3-receptors: lipolysis
 Sympathomimetics

Definition: sympathomimetics are drugs that

produce effects similar to sympathetic nerve
stimulation.

Classifications: There are different classification,

however the most appropriate are:

Classification according to the affinity to

different adrenergic receptors
Direct-acting:(α agonist, ß agonist , α and ß agonist)
 Catecholamines
• Naturally occuring- Norepinephrine (NE), Epinephrine
(E), dopamine
• Synthetic- isoproterenol and dobutamine
 Non catecholamines : e.g Oxymetazoline
Indirect-acting:
 Amphetamine- induces the release of NE
 Cocaine-prevents reuptake of NE
Mixed-acting: Ephedrine and Pseudoephedrine
CATECHOLAMINES
Are compounds containing a catechol moiety (a
benzene ring with two adjacent hydroxyl groups) and
an amine side-chain .
• Norepinephrine (Noradrenaline1), a transmitter
released by sympathetic nerve terminals
• Epinephrine (Adrenaline) a hormone secreted by the
adrenal medulla
• Dopamine, the metabolic precursor of
norepinephrine epinephrine
• Isoproterenol (previously isoprenaline), a synthetic
derivative of norepinephrine , not present in the
body
catecholamines
• Pharmacokinetics of catecholamines
• are rapidly metabolized by catechol-o-
methyltransferase (COMT) and monoamine oxidase
(MAO)
• are inactive by the oral route and must be given
parenterally.
• These agonists have a short duration of action.
• When given parenterally, they do not enter the
central nervous system (CNS) in significant amounts
• Epinephrine, norepinephrine , and dopamine are
natural , while Isoproterenol and dobutamine are
synthetic
-- decreased effect
- - increased effect;
Distribution of adrenergic receptor subtypes and
adrenergic receptor number are important factors
in organ or cellular responses to adrenergic input.
– Adrenergic receptor type in bronchiolar smooth
muscle is principally ß2: epinephrine and
isoproterenol might be expected to be effective
bronchodilators because of their activity at ß2
receptors.
• Norepinphrine is unlikely to have this same
effect due to its relative lack of activity at ß2
sites.
 – Alpha receptor dominate in the cutaneous
vascular beds.
• Norepinephrine and epinephrine cause constriction.
• Isoproterenol with limited activity at alpha recetors
has little effect.
– Both alpha and beta adrenergic receptor are present in
skeletal muscle vascular beds.
• Alpha receptor activation causes vasoconstriction.
• Beta receptor activation promotes vasodilatation.
• Since ß2 receptors are activated at lower,
physiological concentrations, vasodilation results
 A-Direct-acting adrenergic
receptor
• α1-receptors agonist:
PHENYLEPHRINE
• It is a powerful direct-acting, synthetic adrenergic
drug that binds primarily to α receptors and favors
α1 receptors over α2 receptors.
• It is a vasoconstrictor that raises both systolic and
diastolic blood pressures.
• It is often used topically on the nasal mucous
membranes and in ophthalmic solutions for
mydriasis
• Because it is not a catechol derivative, it is not
inactivated by COMT and has a much longer
duration of action than the catecholamines.
• Therapeutic uses of phenylephrine :
 Nasal decongestant in allergic rhinitis, it produces
prolonged vasoconstriction.
 The drug is used to raise blood pressure
accompanying spinal anesthesia.
 As mydriatic to facilitate ocular examination
• Adverse effects:
Large doses can cause hypertensive headache
and cardiac irregularities.
OXYMETAZOLINE
• is a direct-acting synthetic agonist that stimulates
both α1- and little α2-adrenergic receptors.
• It is primarily used locally in the eye or the nose as a
vasoconstrictor
• found in many over-the-counter short-term nasal
spray decongestant products as well as in ophthalmic drops
for the relief of redness of the eyes associated with
swimming, colds, or contact lens. It is used as nasal
decongestant
• α2-receptors agonist:
 CLONIDINE
• Clonidine is an α2 agonist that is used in
essential hypertension to lower blood
pressure partly by inhibition of noradrenaline
release and partly by central action inhibition
of sympathetic vasomotor centers, decreasing
sympathetic outflow to the
periphery.
 Norepinephrine (Levarterenol®, Levophed®)
α1=α2; β1>>β2
• Pharmacological Effects - Mainly alpha effects when
given therapeutically which is contrary to the expected
outcome since it is the endogenous adrenergic
neurotransmitter
– Peripheral Vasoconstriction, Increase in systolic and diastolic
BP
– Reflex bradycardia
• Indications - Some hypotensive states such as shock
but because it restricts blood flow to the kidney, other
medications like dopamine are better first line agents

01/04/2023
 Epinephrine (Adrenaline)
α1=α2; β1=β2

• Catecholamine
• Synthesized in the Adrenal Medulla and
released in the blood stream
• Pharmacological effects - acts as an agonist
at both alpha and beta receptors
• Vascular effect - Dose specific - Low dose
beta stimulated vasodilation and high dose
yields alpha stimulated vasoconstriction

01/04/2023
 Cardiac effects - beta1 - increased
contractility (inotropic) and rate
(chronotropic)
– Increased systolic blood pressure and decrease
diastolic due to decreased peripheral resistance
caused by low dose beta 2 effect
Respiratory - Bronchodilation due to beta 2
response
– Will relieve allergic or histamine induced
constriction
Hyperglycemia - due to glycogenolysis in liver
and increase release of glucagon (Beta 2) and
decrease release of insulin (alpha 2)
01/04/2023
 Indications - Broncospasm, glaucoma
(side effect is mydriasis), anaphylactic
shock, prolong local anesthetics due to
vasoconstriction, cardiac arrest

Pharmacokinetics - Rapid onset, brief

duration, destroyed by COMT/MOA and
metabolites excreted in urine

01/04/2023
 Isoproterenol (Isuprel®)
β1=β2 >>> α

• Synthetic Catecholamine which is nonselective for beta

receptors but little alpha effects
– Cardiac - increase rate and contraction
– Decrease peripheral resistance
• Result is decreased diastolic and little effect on systolic pressure
– Bronchodilation
• Indications
– Heart stimulation to increase rate and force in emergency
situations
• Pharmacokinetics
– Stable against MAO and only a marginal substrate for COMT

01/04/2023
 Dopamine (Intropin®)

• Natural precursor to Norepinephrine

• Can activate alpha and beta adrenergic receptors and D1 and
D2 dopaminergic receptors (beta and dopamine effects at
normal doses; alpha effects at higher doses)
– Dopamine causes vasodilatation in the renal vascular beds
increasing blood flow to the kidney
• Pharmacological Actions – are dose dependent
alpha 1 alpha 2 B1 B2 DA
1-3mcg/kg/min - - 1 - 4
3-10mcg/kg/min 0/1 0 4 2 4
>10-20mcg/kg/min 3 0 4 1 0
01/04/2023
 Cardiovascular – Positive inotropic and
chronotropic effects due to Beta 1 activation
(except at high doses where it produces
vasculature vasoconstriction due to Alpha
stimulation
 Indications - Shock
 Adverse Effects – Sympathetic stimulation

01/04/2023
 Dobutamine (Dobutrex®)
β1>β2 >>>α

• Mechanism of Action – Primarily a beta 1 agonist.

Increases heart rate and output with few vascular
effects
• Considered a Beta 1 selective agent
• Less likely to cause tachycardia than a nonselective
agent like isoproterenol (because of vasodilation)
• Indication – Decompensated HF by increasing
output without increasing oxygen demand

01/04/2023
 ß2 Selective Adrenergic Agonists metaproterenol ,
terbutaline ,albuterol (Ventolin), Ritodrine
 Effects:
 Activation of pulmonary ß2 adrenergic receptors
result in smooth-muscle relaxation and
bronchodilation.
 ß adrenergic receptor agonists also decrease
histamine and leukotriene release from lung mast
cells. reduction in histamine and leukotriene
release would be beneficial in asthma .
 ß adrenergic receptor agonists enhance
mucociliary activity and diminish microvascular
permeabilty.
• Terbutaline
– Active after oral, subcutaneous, or administration by
inhalation
– Rapid onset of action.
– Used for management of chronic obstructive lung
disease and for treatment of acute bronchospasm
(smooth muscle bronchoconstriction), including status
asthmaticus
• Albuterol [Ventolin]
– ß2 adrenergic receptor-selective
– Effective following inhalation or oral administration.
-Commonly used in chronic and acute asthma
management
• Ritodrine
– ß2 adrenergic receptor-selective: developed as a uterine
relaxant
– May be administered by i.v. in certain patients for
arresting premature labor; if successful, oral therapy
may be started.
 Adverse Effects of ß2 Selective Adrenergic Agonists
• Excessive cardiovascular stimulation
• Skeletal muscle tremor (tolerance develops,
unknown mechanism) due to ß2 adrenergic receptor
activation
• Overusage may be a factor in morbidity and
mortality in asthmatics.
B.Indirectly Acting Sympathomimetics are agents
that elevate the concentration of NE at
neuroeffector junctions, because they either:
1. inhibit re-uptake of NE into noradrenergic neurons,
e.g., cocaine. Therefore, NE is not inactivated and
has a prolonged action on both a and b receptors
2. Facilitate NE release. These drugs (e.g.,
amphetamine) enters noradrenergic neurons and
cause NE release
3. slow NE breakdown by monoamine oxidase (MAO),
such as tranylcypromine
4. or exert all three of these effects (e.g., amphetamine)
Amphetamine:( Indirect acting sympathomimetic )
– CNS stimulant
respiratory center ,mood elevation decreased perception of fatigue
– Other effects: headache, palpitations, dysphoria
• Appetite suppression
• Weight loss due to decrease food intake
• psychological tolerance/dependence
Methylphenidate (Ritalin)
– Mild CNS stimulant, chemically related to amphetamine
– Effects more prevalent on mental than motor activities
– General pharmacological profile similar to amphetamine
– Major Therapeutic Use:
• Narcolepsy
• Attention-deficit hyperactivity disorder
 
C-Mixed-Action Adrenergic Agonists
Mixed-action drugs induce the release of
norepinephrine from presynaptic terminals, and
they activate adrenergic receptors on the
postsynaptic membrane.
Ephedrine and pseudoephedrine
 plant alkaloids drugs mixed-action adrenergic
agents.
 They release stored noradrenaline from nerve
endings and also directly stimulate both αand β -
receptors. Thus, a wide variety of adrenergic actions
that are similar to those of adrenaline, although less
potent.
They have absorbed orally and penetrate into the CNS.
 Pharmacological effects:
 increases heart rate, cardiac output
 usually increases blood pressure
 may cause urinary hesitancy due to stimulation of a
smooth muscle receptors in bladder base.
 bronchodilation: ß adrenergic receptor response
 Limited Clinical Use due to better pharmacological
alternatives (asthma, heart block, CNS stimulation)
Therapeutic uses:
 Symptomatic relief of nasal congestion
 To reverse hypotension that may be produced by
spinal anesthesia