Adrenergic Drugs

Adrenergic receptors are divided into two major types according to drug potency on the receptors

Alpha-(-) adrenergic receptors, when activated, generally produce excitatory responses

Beta-(-) adrenergic receptors, when activated, generally produce inhibitory responses

Mechanism: Norepinephrine

Release and Recycling

Figure 11-9: Norepinephrine release at a varicosity of a

sympathetic neuron

-Adrenergic Receptors 1 2

Type Vascular Presynaptic

Distribution Blood vessels, GIT, sphincters,

iris radial, liver

Autonomic nerve terminals, blood

vessels, pancreatic islets, platelets

Receptor -

Transduction

GqPCR, linked to activation of

PLC-DAG-IP3

GiPCR, linked to inhibition of

adenyl cyclase-c.AMP

Agonist

Profile

E=NE>>>ISOP E=NE>>> ISOP

Selective

Agonists

Phenylephrine & methoxamine Clonidine, -MeDOPA

Selective

Antagonists

Prazocin Yohimbine

-Adrenergic Receptors

1 2 3

Type Heart Smooth M Fat

Distribution Heart, salivary glands Blood vessel, GIT,

uterus, Skeletal

muscle, Liver,

Fat tissues

Receptor -

Transduction

Gs-PCR, linked to activation of adenyl cyclase-c.AMP-PKA cascade

Agonist

Profile

ISOP >E=NE ISOP>E>>NE ISOP=NE>E

Selective

Agonists

Dobutamine Salbutamol,

terbutaline

BRL 37344

Selective

Antagonists

Atenolol Butoxamine

Direct-acting Adrenergic AgonistsA. Catecholamines

Catecholamines, adrenergic neurotransmitters; L-norepinephrine (NE), L-epinephrine (E), & L-dopamine (DA) in addition to the synthetic analog isoproterenol

They have the following characteristics:

High potency

Rapid enzymatic inactivation by MAO & COMT as well as neuronal & non-neuronal uptake

Therefore they have short duration when given parenterally and are inactive orally

Poor ability to pass the CNS

Direct-acting Adrenergic Agonists

B. Non-catecholamines

Non-catecholamines are adrenergic agonists lacking the catechol hydroxyl groups

Therefore they are of longer duration, can be

given orally and they are not inactivated by

COMT

They include agents like phenylephrine and

ephedrine

General Mode of Action of Adrenergic Agonists

Direct-acting agonists that act directly by binding to the adrenergic receptors, include NE,

E, DA, phenylephrine & isoproterenol

Indirect-acting agonists that cause the release of NE from intra-neuronal storage vesicles by

the virtue of being taken up by the pre-synaptic

adrenergic neurons

o They include agents like amphetamine and

tyramine

Mixed-action agonists, ephedrine

Catechalomines: Activity

Stimulates the fight or flight reaction

Increased plasma glucose levels

Increased cardiovascular function

Increased metabolic function

Decreased gastrointestinal and genitourinary

function

Pharmacological Actions

A. Nonselective Direct-acting

Adrenergic Agonists

1- Cardiac Effects Increased force of contraction (positive inotropic effect)

Enhanced automaticity of latent pacemaker cells that may lead to arrhythmias

Acceleration of impulse conduction velocity(conductivity) between the atria and ventricles via shortening of the refractory period of the A-V node

Increased stroke volume and cardiac output but with accompanied rise in oxygen consumption

The heart efficiency (performance) is decreased in terms of lower cardiac work in relation to oxygen consumed

Reflex bradycardia, NE, (and E in high doses only) (blocked by ATROPINE)

2) Vascular Smooth Muscle Effects

NE constricts all blood vessels except the

coronary vascular bed (>2)

E has mixed effects according to the vascular bed

(2> ), dilation in skeletal muscles, liver & coronaries

Isoprenaline has purely vasodilatotory effects

(2>>> )

Effects of I.V. infusion of Epinephrine,

Norepinephrine & Isoprenaline in

Humans

Dopamine has a complex pharmacology. It can activate at least 4 different receptors: the beta1,

dopamine1 (DA1), alpha1 and alpha2.

DA1 receptors exist in the renal vascular bed.

Activation of these receptors produces a decrease in

renal vascular resistance and an increase in renal

blood flow.

Activation of the beta1 receptor selectively increases

the force of myocardial contraction. without a

significant effect on heart rate.

However, high doses of dopamine,, can induce

rhythm disturbances

low doses: the DA1 receptors will be activated

moderate doses:the beta1 receptors will be activated

high doses:- the alpha receptors will be activated

3- Effects on

Gastrointestinal Tract

Relaxation of GIT smooth muscle through

Inhibition of the release of ACh from cholinergic neurons via activation of 2-adrenoceptors on cholinergic nerve terminals

Stimulation of 2-receptors, activates adenyl cyclase-c.AMP- PKA cascade leading phophorylating

inactivation of myosin-light chain kinase enzyme

Stimulation of 1-adrenoceptors causes increased potassium channel activity resulting in increased K+

conductance & hyperpolarization

4- Effects on Respiratory System

2-Adrenoceptors stimulation leads to relaxation (inhibition) of bronchiolar smooth muscle and

bronchodilation, and hence lowering airway

resistance (Asthma)

Inhibition of antigen-mediated production of

inflammatory mediators of asthma via 2-adrenoceptors stimulation (Asthma)

1-Adrenoceptors activation results in vasoconstriction of the upper respiratory tract

mucous membranes and hence lowering

congestion (Nasal decogestant)

5- Effects on the genitourinary system

o Uterus

They are dependent on the uterine status

Norepinephrine increases the rate of contraction of

pregnant human uterus

Epinephrine inhibits uterine tone and contractions

during the last month of pregnancy as well as at

parturition

This observation is the basis for the use of 2-adrenoceptors agonists to delay premature labor

5- Effects on the genitourinary system

o Urinary Bladder

1-adrenoceptors show

High density in smooth muscle of urethera &

prostate

Selective 1-adrenoceptor antagonists are

used for treatment of urinary retention in

benign prostatic hypertrophy

6- Effects on the Eye

Stimulation of 1-adrenoceptors on the radial smooth muscle of the iris leads to pupil dilation (mydriasis), theoretically result in blocking of drainage of aqueous humor and increase of IOP

1-adrenoceptors stimulation results in vasoconstriction that in turn causes inhibition of the formation of aqueous humor & lowering of IOP (no cycloplegia)

-blockers (timolol) decrease the formation of aqueous humor & used topically in glaucoma treatment

Metabolic activity of Epinephrine

7- Metabolic Effects

Lipolysis & thermogenesis are stimulated leading to increased breakage of triglycerides into free fatty acids and glycerol through activation of lipase enzymatic activity (1/ 3-adrenergic receptor)

Hepatic & Skeletal Muscle Glycogenolysis are stimulated resulting in hyperglycemia & increased plasma glucose & lactic acid (2-adrenergic receptor stimulation)

Gluconeogenesis is stimulated as well

Calorigenic action :oxygen consumption is increased in response to catecholamines mainly via increased oxidisable substrate from increased lipolysis

8.Endocrine Glands

Insulin release is stimulated via 2-adrenoceptors

& inhibited by -receptors

Insulin R activity is decreased by 1-receptors

through decreased GLUT4 translocation

Glucagon secretion is increased by sympathetic

stimulation

Renin release from juxtaglomerular appartatus is

stimulated via 1-adrenoceptors

9.Central Nervous System (CNS)

Catecholamines are powerful CNS stimulants

Cocaine & amphetamine euphoric effects are mediated via increase CA brain levels due to

uptake blockade /enhanced release respectively

Side effects of adrenergic agonists may include

anxiety, nervousness, & tremors while antagonist

may enhance depression

10.Skeletal Muscles

1-agonists (E & dobutamine) facilitate Ach

release from motor neurons, hence increase

muscle activity (myasthenia gravis)

2-agonists (E & salbutamol) cause muscle

tremors possibly via hypokalemia &

increased muscle activity

Selective 1-Adrenergic Agonists

Phenylephrine & methoxamine,

metaraminol, mephentermine

o elevated systolic & diastolic BP

o increased total peripheral resistance

o barororeceptor mediated reflex decrease

in heart rate via enhancement of vagal activity

They are less potent but longer acting than

norepinephrine, being non susceptible to

metabolism with COMT

Therapeutic Uses of 1-Adrenergic Agonists

Local nasal decongestant to produce vasoconstriction of nasal mucosal vasculature

Treatment of supraventricular tachycardiaarising in AV node and atria

They elevate blood pressure & stimulate vagal

activity via baroreceptor-mediated reflex action

To overcome hypotension induced by some general anesthetic agent

2 -Adrenergic Agonists

Clonidine & -methyldopa activate 2-Adrenergic receptors in the lower brain stem (nucleus of tractus solitaries) leading to decreased central outflow of the

sympathetic nervous system

Peripherally, they decrease NE release by stimulation of

presynaptic 2-Adrenergic receptors

Oral intake produces a prolonged hypotensive response (Treatment of Hypertension)

IV injection raises BP by direct stimulation of postsynaptic 1- & 2-Adrenergic receptors

In addition, -methyldopa is taken up by adrenergic neurons and synthesized into -methylnorepinephrine which is a false adrenergic transmitter

Norepinephrine acts at presynaptic alpha2 receptors to inhibit its own release.

2 -Adrenergic Agonists

They are used in management of hypertension

Clonidine does not induce postural hypotension

Clonidine can cause rebound hypertension upon sudden stop,

Small doses of clonidine are effective as prophylactic therapy of migraine

Dry mouth & constipation are most frequent side effects (inhibition of cholinergic neuronal activity)

Apraclonidine is used as adjuvant therapy for glaucoma via decrease of aqueous humor formatiom

1-Adrenergic Agonists

Dobutamine is a synthetic dopamine analog. It is a selective 1-adrenergic agonist. On the heart, it produces a more pronounced positive inotropic effect than its chronotropic effect when compared to dopamine. There is no defined reason for such differential action

Therapeutic use of dobutamine is based on its ability to increase cardiac output via the positive inotropy with little effect on heart rate and myocardial oxygen consumption

o Hence, it is used in cardiogenic shock and decompensated heart failure

2 adrenergic receptor agonists

Terbutaline, albuterol (salbutamol), pirbuterol

& ritodrine are selective 2 adrenergic receptor agonists with little effect on 1 cardiac receptors

Hence, they have the advantage of producing

bronchodilation without cardiac stimulation

They produce uterine relaxation

They are given orally, IV or by inhalation & have

no CNS stimulation

Salmeterol & formoterol are long-acting agonists

Fenoterol is an intermediate-acting (8 hrs)

2-Adrenergic Receptor Agonists

Orciprenaline (metaprotrenol, Alupent R) is relatively a selective agonist used both by oral & inhalation

Therapeutic uses of 2 adrenergic receptor agonists

o Treatment of bronchial asthma and bronchospasm associated with bronchitis and emphysema

o Delay delivery in premature labor and in threatened abortion; ritodrine is frequently used for this purpose

Indirect- & Mixed-Acting

Adrenergic Receptor Agonists

Ephedrine: Chemically related to EP and stimulates release of NE

It is not a substrate for COMT or MAO & hence has long duration of action

It activates 2 as well as - and 1-aderenergic receptors It is used to treat mild cases of asthma

It crosses BBB giving rise to CNS stimulant action

It is now replaced by more selective 2 agonists

Tyramine in cheese, fermented sausage & wines

o It enters synaptic vesicle and causes displacement & release of NE & normally degraded by MAO

o MAO inhibitors in conjunction with tyramine-containing foods may lead to rapid release of NE & severe hypertension

Indirect: 1.Amphetamine: Promotes the release of monoamines from nerve

endings from the terminal cytoplasm..

Amphetamine also blocks the reuptake

of monoamines.

Several structural analogs of

amphetamine and "amphetamine like"

agents are available for clinical use.

These include:

Dexamphetamine (the resolved and more

potent d-isomer of amphetamine)

Hydroxyamphetamine,

Methamphetamine

Methylphenidate

Clinical Therapeutics of CNS Stimulants

1) Because of its local anesthetic activity,

cocaine has some limited uses as a oral, nasal

and ophthalmic local anesthetic.

2) Appetite suppression - amphetamine and

analogs

3) Narcolepsy - methylphenidate, amphetamine

analogs

4) Attention deficient hyperactivity disorder with

(ADHD) - methylphenidate, amphetamine and

analogs

Indirect- & Mixed-Acting

Adrenergic Receptor Agonists

2.Pseudoephedrine & Phenylpropanolamine

They stimulate the release of NE

They are used as over-the-counter (OTC) nasal decongestants for symptomatic relief of hay fever and rhinitis

Pseudoephedrine has little 2 agonist activity, limited CNS stimulation

Phenylpropanolamine also used to relieve

upper respiratory conditions associated with

common cold

Clinical uses of - & -Adrenergic Agonists

1.Nasal decongestant: Vasoconstriction in nasal mucous membranes by 1-agonists like phenylephrine, pseudoephedrine & xylometazoline

2.Treatment of hypotension

o Selective 1-agonists like phenylephrine, methoxamine & mephentermine are administered parenteraly to elevate blood pressure in hypotension accompanying spinal anesthesia. vasoconstriction TPR and hence raising diastolic and systolic pressures

o In hypovolemic shock use of 1-agonists has the potential to cause further impairment of microcirculation already affected by high level of catecholamine release

Clinical uses of - & -Adrenergic Agonists

3.Cardiogenic shock (MI), NE, dobutamine or DA

NE is given by ONLY IV infusion at doses that raise BP, and increase cardiac contractility without serious vasoconstriction

Dopamine is advantageous in producing splanchnic and renal vasodilation (D receptors), increasing glomerular filtration and urine production

Dobutamine is more or less similar to dopamine being more selective on cardiac 1-adrenergic receptors

Clinical uses of - & -Adrenergic Agonists

4. Anaphylactic Shock: Epinephrine is of

choice given by SC route to reverse the

histamine-induced broncho-constriction &

hypotension

5.Ophthalmic Uses:

o Mydriatics: phenylephrine & ephedrine may be

used for eye examination

o Glaucoma: phenylephrine or epinephrine may

be used locally to decrease IOP {Dipivefrin}

Clinical uses of - & -Adrenergic Agonists

6- Respiratory uses:

o Treatment of asthma using the selective 2adrenergic receptor agonists including terbutaline,

albuterol and orciprenaline by oral route or by

inhalation. They have fewer cardiovascular stimulant

effects

o Relieve of congestion of upper respiratory tract in hey

fever and rhinitis. For this purpose, 1 agonists such as phenylephrine, pseudoephedrine & phenylpropanolamine can be used orally to produce vasoconstriction of mucous membrane vasculature

Clinical uses of - & -Adrenergic Agonists

7.As Vasoconstrictors with Local Anesthetics: Epinephrine and phenylepherine {1} produce localized vasoconstriction which inhibits systemic absorption and lower bleeding

8.Epistaxis; Epinephrine (1:100,000 dilution) or -agonists may be used to stop bleeding from nasal mucosa

9.Cardiac arrest; Epinephrine or isoprenalinemay be used by IV route or by intra-cardiac injection

o They may be used in complete heart block

Contraindications to use of adrenergic

Cardiac dysrhythmias, angina pectoris

Hypertension

Hyperthyroidism

Cerebrovascular disease

Distal areas with a single blood supply

such as fingers, toes, nose and ears

Renal impairment use caution