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Transcript of Adrenergic Drugs Adrenergic receptors are divided into two major types according to drug potency on...
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
-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
-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
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
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
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
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
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)
Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in
Humans
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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