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

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Adrenergic Drugs Adrenergic receptors are divided into two major types according to drug potency on the receptors Alpha-(α-) adrenergic receptors, when activated, generally produce excitatory responses Beta-(β-) adrenergic receptors, when activated, generally produce inhibitory responses

Transcript of Adrenergic Drugs Adrenergic receptors are divided into two major types according to drug potency on...

Page 1: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Adrenergic Drugs

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

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

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

Page 2: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

-Adrenergic Receptors

α1 α2 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, α-MeDOPA

Selective Antagonists

Prazocin Yohimbine

Page 3: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

-Adrenergic Receptors

β1 β2 β3 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

Page 4: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Direct-acting Adrenergic Agonists

A. 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

Page 5: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

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, ephedrine and amphetamine

Page 6: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

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

Page 7: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Pharmacological ActionsA. 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 but in high doses

Page 8: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

2) Vascular Smooth Muscle Effects

NE constricts all blood vessels except the coronary vascular bed (α>β2)

E has mixed effects according to the vascular bed (β2> α), dilation in skeletal muscles, liver & coronaries

Isoprenaline has purely vasodilatotory effects

(β2>>> α)

Page 9: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in

Humans

Page 10: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

3- Effects on Gastrointestinal Tract Relaxation of GIT smooth muscle through

Inhibition of the release of ACh from cholinergic neurons via activation of α2-adrenoceptors on cholinergic nerve terminals

Stimulation of β2-receptors, activates adenyl cyclase-c.AMP- PKA cascade leading phophorylating inactivation of myosin-light chain kinase enzyme

Stimulation of α1-adrenoceptors causes increased potassium channel activity resulting in increased K+ conductance & hyperpolarization

Page 11: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

4- Effects on Respiratory System

β2-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 β2-adrenoceptors stimulation (Asthma)

α1-Adrenoceptors activation results in vasoconstriction of the upper respiratory tract mucous membranes and hence lowering congestion (Nasal decogestant)

Page 12: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

5- Effects on the 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 β2-adrenoceptors agonists to delay premature labor

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6- Effects on the Eye

Stimulation of α1-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

α1-adrenoceptors stimulation results in vasoconstriction that in turn causes inhibition of the formation of aqueous humor & lowering of IOP

This latter effect usually predominates

Page 14: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

7- Metabolic Effects

Lipolysis is stimulated leading to increased breakage of triglcerides into free fatty acids and glycerol through activation of lipase enzymatic activity (β1/ β3-adrenergic receptor stimulation-increased c.AMP-PKA activation -phosphoryaltion of lipase)

Hepatic & Skeletal Muscle Glycogenolysis are stimulated resulting in hyperglycemia & increased plasma glucose & lactic acid (β2-adrenergic receptor stimulation with subsequent activation of adenyl cyclase-c.AMP-PKA cascade-Activated PKA phosphorylates phosphorylase kinase - activates phosphorylase)

Calorigenic action where oxygen consumption is increased in response to catecholamines mainly due to increased oxidisable substrate from increased lipolysis in adipose tissues

Page 15: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Selective α1-Adrenergic Agonists

Phenylephrine & methoxamineo elevated systolic & diastolic BP o increased total peripheral resistanceo 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

Page 16: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Therapeutic Uses of α1-Adrenergic Agonists

Local nasal decongestant to produce vasoconstriction of nasal mucosal vasculature

Treatment of supraventricular tachycardia arising 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

Page 17: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

α2 -Adrenergic Agonists

Clonidine & α-methyldopa activate α2-Adrenergic receptors in the lower brain stem (nucleus of tractus solitaries) leading to decreased central outflow of the sympathetic nervous system

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

IV injection raises BP by direct stimulation of postsynaptic α1- & α2-Adrenergic receptors

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

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β1-Adrenergic Agonists

Dobutamine is a synthetic dopamine analog. It is a selective β1-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

It produces renal and mesenteric vasodilation (D1-receptors) similar to dopamine

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

Page 19: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

β2 adrenergic receptor agonists

Terbutaline, albuterol (salbutamol), & ritodrine are selective β2 adrenergic receptor agonists with little effect on β1 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 and long

duration of action and possess no CNS stimulation Therapeutic uses of β2 adrenergic receptor agonistso Treatment of bronchial asthma and bronchospasm

associated with bronchitis and emphysemao Delay delivery in premature labor and in threatened

abortion; ritodrine is frequently used for this purpose

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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 β2 as well as α- and β1-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 β2 agonists Tyramine in cheese, fermented sausage & wineso It enters synaptic vesicle and causes displacement &

release of NE & normally degraded by MAOo MAO inhibitors in conjunction with tyramine-

containing foods may lead to rapid release of NE & severe hypertension

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Indirect- & Mixed-Acting Adrenergic Receptor Agonists

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 β2 agonist activity, limited CNS stimulation

Phenylpropanolamine also used to relieve upper respiratory conditions associated with common cold

Page 22: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Clinical uses of α- & β-Adrenergic Agonists

Nasal decongestant: Vasoconstriction in nasal mucous membranes by α1-agonists like phenylephrine, pseudoephedrine & xylometazoline

Treatment of hypotensiono Selective α1-agonists like phenylephrine, methoxamine

& mephentermine are administered parenteraly to elevate blood pressure in hypotension accompanying spinal anesthesia. They cause prompt vasoconstriction increasing total peripheral resistance and hence raising diastolic and systolic pressures

o In hypovolemic shock use of α1-agonists has the potential to cause further impairment of microcirculation already affected by high level of catecholamine release

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Clinical uses of α- & β-Adrenergic Agonists

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 β1-adrenergic receptors

Page 24: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Clinical uses of α- & β-Adrenergic Agonists

Anaphylactic Shock: Epinephrine is of choice given by SC route to reverse the histamine-induced broncho-constriction & hypotension

Opthalmic Uses:o Mydriatics: phenylephrine & ephedrine may be

used for eye examinationo Glaucoma: phenylephrine or epinephrine may be

used locally to decrease IOP

Page 25: Adrenergic Drugs  Adrenergic receptors are divided into two major types according to drug potency on the receptors  Alpha-(α-) adrenergic receptors,

Clinical uses of α- & β-Adrenergic Agonists

5- Respiratory uses:o Treatment of asthma using the selective β2 adrenergic

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, α1 agonists such as phenylephrine, pseudoephedrine & phenylpropanolamine can be used orally to produce vasoconstriction of mucous membrane vasculature

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Clinical uses of α- & β-Adrenergic Agonists

As Vasoconstrictors with Local Anesthetics: Epinephrine and phenylephrine may be used to produce localized vasoconstriction which inhibits systemic absorption and lower bleeding

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

Cardiac arrest; Epinephrine or isoprenaline may be used by IV roué or by intra-cardiac injection

o They may be used in complete heart block