obat simpatomimetik
DESCRIPTION
re-upload not mineTRANSCRIPT
-
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