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CHOLINOMIMETIC DRUGSRHS - 366
CholinomimeticDrugs(Parasympathomimetic Drug
Parasympathetic nerves use ACh as a neurotransmitter.
Cholinomimetic drugs mimic the action of ACh at its receptors. Knowledge of distribution of receptor subtypes (muscarinic or nicotinic)
helps in predicting drug response.
Cholinergic site Receptor subtype
Neuroeffector
junctionsMuscarinic
Ganglionic synapses Nicotinic
Classification of Cholinomimetics:
. Direct-acting (receptor agonists)
Muscarinic receptors
Nicotinic receptors
. Indirect-acting (cholinesterase inhibitors)
Reversible
Irreversible
http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-309/ANS/Cholinergic_Agonists/cholinergic_agonists.html#Direct%23Directhttp://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-309/ANS/Cholinergic_Agonists/cholinergic_agonists.html#Indirect%23Indirecthttp://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-309/ANS/Cholinergic_Agonists/cholinergic_agonists.html#Direct%23Directhttp://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-309/ANS/Cholinergic_Agonists/cholinergic_agonists.html#Indirect%23Indirect7/28/2019 RHS 366
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Direct-acting Cholinergic Receptor Agonists:
A) Muscarinic receptor agonists:
Drugs that mimic ACh at neuroeffector junctions of PNS
Mechanisms:
Cholinergic receptors are coupled to G proteins (in tramembrane transducers that
egulate second messengers):
Agonist ----> increase in cGMP ----> activation of IP3, DAG cascade
DAG opens smooth muscle Ca2+ channels
IP3 ----> release of Ca2+
from sarcoplasmic reticulum Agonist selectivity is determined by muscarinic receptor subtype and G
protein in cell.
Types of direct acting muscarinic receptor agonists:
A) Esters of choline (eg. acetylcholine, pilocarpine, carbachol, bethanechol chlorid
Poorly absorbed Susceptibility to hydrolysis by cholinesterase affects duration of action
) Alkaloids (eg. muscarine)
Well absorbed, not used clinically
Mushroom poisoning (Amanita muscaria)
. Acetylcholine
Highly susceptible to hydrolysis IV bolus lasts 5-20 seconds
Limited use in topical application in ophthalmology
. Pilocarpine
Acts on smooth muscles of eye to constrict the pupil
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(miosis).
Used to treat glaucoma.
Contracts ciliary muscles by stimulating muscarinic
Receptors.
Penetration (15-30 min) and long duration (8 hrs). Increased aqueous outflow.
. Carbachol
Carbamyl ester of choline.
Used mainly in ophthalmology for cataract surgery
(causes rapid miosis).
Decreases intraocular pressure by opening drainage
angle of anterior chamber of eye. Used in glaucoma (when resistant to pilocarpine or
physostigmine).
. Bethanechol Chloride
Choline ester
Persistent effects because it is resistant to cholinesterases
Selectively stimulates urinary and gastrointestinal tracts
Facilitates emptying of neurogenic bladder in patients after surgery orparturition or with spinal cord injury.
B) Nicotinic receptor agonist
Natural alkaloid found in tobacco which mimics the effects of ACh at
nicotinic receptors at
Autonomic ganglionic synapses (both SNS & PNS)
Skeletal neuromuscular junctions Nicotine still used in some insecticides
Mechanism:
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Activates nicotinic receptor (transmembrane polypeptide comprised of
cation-selective ion channel subunits
Nicotinic agonists
Conformational change in receptor
Opens cation channels
Na+/K+ diffusion into cell
Depolarization of nerve cell or neuromuscular endplate
Clinical use:
No therapeutic action but important for its toxicity
Available as a transdermal patch or as chewing gum
Used as an aid in cessation of smoking
Toxicity:
Both stimulant and depressant (affects both SNS & PNS ganglia).
Stimulates nicotinic receptors in CNS ----> mild alerting action. Also acts centrally ----> tremor & convulsions.
Can increase or decrease HR.
Increased respiratory rate.
Vomiting due to activation of chemoreceptor trigger zone.
Larger doses ----> CNS and respiratory depression by muscle endplate
depolarization blockade
Indirect-acting Cholinomimetic DrugsCharacteristics:
Anticholinesterase drugs ie. inhibitors of ACh metabolism.
Similar effects to direct-acting cholinomimetics.
Mechanism:
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Normally ACh is rapidly degraded in cholinergic synapse.
(T1/2=40ms)
Acting cholinomimetics block the enzymatic hydrolysis of acetylcholine --
increases local concentrations of Ach consequently effect of ACh is
amplified, leading to muscarinic or nicotinic effects, depending on the
organ.
Effect can be therapeutic or life threatening
Classification
A)
Reversible Inhibitors
All are poorly absorbed from conjunctiva, skin & lungs except physostigm
which is well absorbed from all sites. Used topically in eye.
More commonly used clinically than organophosphates.
Quaternary alcohols
Bind reversibly to active site of ACh esterase and prevents access by Ach.
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No covalent bond between enzyme inhibitor complex , so short T1/2 (2-10
min), eg. Edrophonium.
Carbamate esters
Two step hydrolysis like Ach. But the covalent bond of carbamylated enzyme is more resistant to hydrat
(T1/2=30-60 min)
eg. neostigmine, physostigmine
Clinical use:
Primary target organs of anticholinesterase drugs:
eye
Skeletal muscle Neuromuscular junctions
Gastrointestinal tract
Urinary tract
Respiratory tract
Heart
Effects are similar to direct acting cholinergic agonists
Major uses in treatment of: Glaucoma
Myasthenia gravis
Stimulation of gastrointestinal and urinary tract motility (eg. neostigmine)
-same effects as with agonists.
Reversal of neuromuscular blockade.
Atropine poisoning
A) Glaucoma:
An ocular disease caused by increased intraocular pressure due toinadequate drainage of aqueous humour at filtration angle ----> damage to
the retina & optic nerve.
Intraocular pressure is determined by the balance between fluid input &
drainage out of the globe.
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Aqueous humour produced by ciliary epithelium and drained at the filtrat
angle of the anterior chamber.
Therapy:
Objective: increase outflow & decrease production of aqueous humour by
local treatment with:
. Muscarinic cholinomimetics
Direct-acting: pilocarpine, carbachol
Indirect-acting: physostigmine ----> contracting the smooth muscle of irissphincter (contraction of pupil) ----> contraction of ciliary muscle ----> iris
pulled from angle of anterior chamber ----> widening the filtration angle a
opening the trabecular network ----> increased outflow of aqueous humou
----> decreased intraocular pressure.
. Adrenoceptor agonists: eg. Epinephrine
----> contraction of dilator muscle of iris ----> increased aqueous outflow.
Used mainly for treatment of closed angle glaucoma along with surgery.
. B- adrenoceptor blockers: eg. Timolol
----> decreased production of aqueous humour by ciliary epithelium
B) Myasthenia gravis
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Autoimmune disease resulting in destruction of nicotinic receptors ---->
progressive weakness, fatigue, difficulty speaking & swallowing
Resembles neuromuscular block by curare.
Treated with indirect acting cholinesterase inhibitors (eg neostigmine) ---->
increased strength of contraction of muscles
) Reversal of neuromuscular blockade
Short-acting cholinesterase inhibitors (eg. neostigmine, edrophonium Cl)
----> increased ACh concentration which then competes with neuromuscul
blocker for nicotinic receptors.
B) Irreversible Inhibitors
Organophosphates (Parathion, malathion).
Mechanism:
Act by covalently phosphorylating the hydroxyl group of serine on
cholinesterase.
A few organophosphate pesticides are selective in toxicity to insects e.g.
malathion is rapidly metabolized by plasma esterases .: safer
Aging occurs when an alkyl or alkoxy group is lost
----> increased strength of phosphorus-enzyme bond
----> stable enzyme-inhibitor complex which is difficult to split
Before aging occurs patients can be treated with strong nucleophiles eg.
pralidoxime which breaks the phosphorus-enzyme complex and regenerat
the enzyme.
igns of Toxicity:A) Mild exposure:
Pupillary constriction.
Tightness of the chest.
Watery discharge from the nose.
Wheezing
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B) Severe exposure (see DUMBELS):
More intensified symptoms
Visual disturbances
Muscle fasciculation Bronchoconstriction & pulmonary edema
Pronounced muscle weakness
Shallow respiration
Vomiting and diarrhea
CNS effects, anxiety, headache, tremor, seizures, depression.
Death
DUMBELS:
Treatment: Muscarinic blocking drugs, e.g. atropine
D DIARRHEA
U URINATION
M MIOSIS
BBRONCHOCONSTRICTIO
N
EEXCITATION (skel. musc.
& CNS)
L LACRIMATION
S SALIVATION, SWEATING
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Overview of Therapeutic Applications of Cholinomimetic Drugs
Tissue Effect Use/drug
Muscarinic agonists
Eye
GI tract
Urinary
bladder
contraction of ciliary
m./sphincter m. of iris
increased peristalsis,
sphincter relaxation
increased contraction of
detrusor m./sphincter
relaxation
Glaucoma
(pilocarpine)
Paralytic ileus
(bethanechol Cl)
Urinary retention
(bethanechol Cl)
ACh esterase inhibitors
Skeletal
m.
Eye
increased muscle activity
similar to agonists
Myasthenia
gravis
(neostigmine)
Glaucoma
(physostigmine)
ADRENERGIC RECEPTORS
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RHS-366
1.Alpha adrenoceptors
Alpha1: postsynaptic, mediate mainly vasoconstriction
Alpha2: presynaptic or postsynaptic
Presynaptic: mediate negative feedback on NE release
Postsynaptic: central or peripheral
Central tractus solitarius : stimulation causes reduction in central sympathetic
discharge and fall of blood pressure
Peripheral postsynaptic receptors mediate inhibition of adenyl cyclase in platelets
and lipocytes
2.Beta adrenoceptors: postsynaptic
B1: present mainly in the heart causing its stimulation
B2: causes bronchodilatation, uterine relaxation, skeletal and coronary
vasodilatation
Presynaptic B1: facilitate NE release
Alpha adrenoceptor agonists
Alpha1 + Alpha2: epinephrine, norepinephrine
Alpha1: phenylephrine, methoxamine
Alpha2: clonidine, alpha-methyl NE
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Alpha adrenoceptor antagonists
Alpha1 + Alpha2: phentolamine
Alpha1: prazosin
Alpha2: yohimbine
B- adrenoceptor agonists
B1 + B2: isoproterenol, epinephrine
B1: NE, dobutamine, pronalterol
B2: salbutamol, terbutaline, albuterol
Beta adrenoceptor antagonists
B1 + B2: propranolol, timolol, nadolol.
B1: atenolol, metoprolol, acebutolol.B2: butoxamine
N.B. labetalol blocks both alpha and beta-adrenoceptors
Steps of synthesis of catecholamines and drugs affecting them
1-henylalanine by phenylalanine hydroxylase to tyrosine
2-Tyrosine by tyrosine hydroxylase to Dopa. This step is inhibited by alpha-methylyrosine and 3-iodotyrosine
-Dopa by aromatic L-amino acid decarboxylase to dopamine. This step is inhibited by
alpha-methyldopa, carbidopa and benserazide
4-Dopamine by dopamine B-hydroxylase to norepinephrine. This step is inhibited by
disulfiram
5-Norepinephrine by N-methyl transferase to epinephrine. This step is inhibited byglucocorticoids
Fate of catecholamines
Enzymatic catabolism of circulating CAs
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1-Norepinephrine by COMT to normetanephrine
2-Epinephrine by COMT to metanephrine
-Both normetanephrine and metanephrine by MAO to 3-methoxy 4-hydroxy mandelic
aldehyde
4-3-methoxy 4-hydroxy mandelic aldehyde to vanillyl mandelic acid (VMA) and 3-
methoxy, 4-hydroxy phenylglycol (MOPEG
Enzymatic catabolism of neuronal CAs
1-Both norepinephrine and epinephrine by MAO to 3,4-dihydroxy mandelc aldehyde
3,4-ihydroxy mandelc aldehyde is converted to 3,4-dihydroxy mandelic acid (DOMA)
and then by COMT to vanillyl mandelic acid (VMA(
3,4-ihydroxy mandelc aldehyde is converted to 3,4-dihydroxy phenylglycol (DOPEG)
and then by COMT to 3-methoxy, 4-hydroxy phenylglycol (MOPEG(
Uptake of catecholamines
1-Neuronal uptake (uptake I): prevented by cocaine
2-Granular uptake: prevented by reserpine
-Non-neuronal uptake (uptake II) prevented by glucocorticoids anf phenoxybenzamine
Types of MAO isoenzymes
1-MAO-A: in peripheral tissues, inhibited selectively by clorgyline
2-MAO-B: in brain, inhibited selectively by deprenyl3-Non-selective MAOIs include hydrazines (e.g. iproniazid) and non-hydrazines
(tranylcypromine
Molecular mechanism of action of CAs
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1-B-receptor stimulation results in activation of adenyl cyclase with increased
ntracellular c-AMP
2-Alpha1-receptor activation increases intracellular calcium through activation of
hospholipase-C
Alpha2-receptor activation inhibits adenylate cyclase and decreases intracellular c-AMP
Functions of alpha1-adrenoceptors:
1-Vasoconstriction
2-Mydriasis
3-Decrease gut motility
4-Contraction of pregnant uterus
5-Ejaculation
Functions of B-adrenoceptors
B1: stimulation of all properties of the heart, increase lipolysis and rennin release
B2: Coronary and skeletal vasodilatation, bronchodilatation, relaxation of pregnant uter
decrease gut motility, inhibition of of mast cell degranulation
Metabolic actions of CAs
1-Alpha1: increase hepatic glycogenolysis, hyperkalemia
2-Alpha2: decrease lipolysis, rennin secretion, insulin release
3-B1: increase lipolysis and rennin secretion
4-B2: increase hepatic glycogenolysis and insulin release, hypokalemia
Reversal effect of epinephrine on blood pressure
VI of epinephrine leads to rapid rise of blood pressure (alpha1-action). When an alphadrenoceptor blocker is given the vasodilator effect (B2-action) of epinephrine is
nmasked resulting in a drop of blood pressure. This reversal effect does not occur with
pure alpha-agonists
Epinephrine, norepinephrine and isoproterenol on HR
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Epinephrine and isoproterenol increase HR (positive chronotropic) due to B1-action
Norepinephrine causes reflex bradycardia secondary to increase in mean arterial BP
Main therapeutic uses of epinephrine
1.Anaphylactic shock2.Cardiac arrest
3.Acute bronchial asthma
4.with local anesthetics
5.Topical hemostatic
Selective B2 agonists
Advantages
1.Less toxic effects on the heart2.Effective orally and by inhalation
3.Longer duration of action
Therapeutic uses
1.Bronchial asthma as salbutamol and terbutaline
2-remature labor as retodrine
3.eripheral vascular disease as isoxsuprine
Adverse reactions
1.keletal muscle tremors 2.Nervousness and weakness
3.Tachyphylaxis and hypoxemia may occur with excessive use
Compare between Dopamine and Dobutamine
Dobutamine
1.Selective B1-agonist.
DOPAMINE
1.Agonist to dopamine receptors, B1 and alpha
adrenoceptors
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2.Does not release NE
3.Much less
4.Given by IV infusion
2.Causes release of NE
3.Chronotropic and arrhythmogenic
4.Given by IV infusion.
Adverse reactions of ephedrine and amphetamine
Amphetamine1.CNS stimulation and
excitement, acute psychosis
2.Dependence, anorexia
3.Weight loss
4.Palpitation, tachycardia
.Arrhythmias, hypertension
and hyperpyrexia.
Ephedrine1.CNS stimulation
2.Palpitation and tachycardia
3.Urinary retention
4.Tachyphylaxis
Cardiovascular uses of sympathomimetics 1.hock states following AMI as Dopamine or dobutamine
2.hock state following sympathectomy as alpha agonists
3.Complete heart block and cardiac arrest as isoproterenol or epinephrine
4.Congestive heart failure as dobutamine, prenalterol
5.Nasal decongestants as naphazoline, xylometazoline
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6.Local haemostatic as epinephrine
7.Peripheral vascular disease as isoxsuprine, nylidrin
Classification of B-adrenoceptor blockers
Cardioselective B-blockers1.Atenolol, Acebutolol and Metoprolol
2.Less liable to cause bronchospasm or Raynaud's phenomenon
3.with minimal effects upon renal plasma flow or metabolic responses to hypoglycemia
B-blockers with intrinsic sympathomimetic activity
1.indolol, Oxprenolol, alprenolol
.They have limited effect on HR, A-V conduction, myocardial contractility, peripheral
lood flow, bronchomotor tone and plasma lipids
Lipophilic B-blockers1.Propranolol, Timolol, Alprenolol
2.Well absorbed from the GIT
3.Extensive hepatic metabolism
4.Shorter half-life (3-5 hour
4.Cross Blood Brain Barrier
Hydrophilic B-blockers
1.Nadolol, Atenolol
2.Less well absorbed 3.Elimination primarily by the kidney
4.Longer half life (7-14 hours
5.Do not cross BBB
Beta blockers as antihypertensives
1.Negative inotropic and chronotropic action
2.nhibition of rennin secretion by the kidney
3.Reconditioning of baroreceptors
4.Decrease central sympathetic outflow5.Decrease NE release
6.Formation of vasodilator PG
Beneficial effects of B-blockers in angina pectoris
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1.Reduction of myocardial oxygen demand by decrease in heart rate, systolic BP and
contractility. Decrease lipolysis and free fatty acid utilization
ncrease of oxygen supply by prolongation of diastolic coronary perfusion time, shift of
subepicardial to subendocardial coronary blood flow and inhibition of platelet aggregat
Therapeutic uses of B-adrenoceptor blockers
1.Hypertension
2.Ischemic heart disease (angina pectoris and acute phase of myocardial infarction(
3.Arrhythmias
4.Hypertrophic obstructive cardiomyopathy
5.Migraine prophylaxis
6.Open angle glaucoma
7.Hyperthyroidism8.Pheochromocytoma (+ alpha blocker
9.GI bleeding in hepatic cirrhosis
Adverse reactions of B-adrenoceptor blockers
B1-mediated
1.Cardiac failure
2.Bradycardia
3.A-V block 4.Hypotension
B2-mediated
1.Bronchospasm
2.rolongation of insulin hypoglycemia
3.ntermittent claudication
4.Cold extremeties
5.atigue
6.Reduced blood flow to liver and kidneyAbrupt cessation after prolonged therapy can lead to dysrhythmias, hypertension, and
worsening of angina
Other side effects: night mares, mental depression, increase in plasma triglycerides and
ecrease HDL
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Characteristic features and uses of Labetalol
1.elective alpha1 blocker and non-selective B-blocker
2.Has a rapid antihypertensive effect
Used for emergency control of severe hypertension, pheochromocytoma, hypertensiveresponse during abrupt withdrawal of clonidine
General therapeutic uses of alpha-adrenergic blockers
1.Essential hypertension
2.heochromocytoma
3.eripheral vascular disease
4.hock associated with severe vasospasm
5.Toxicity of alpha-agonists6.Urinary obstruction
razosin
1.elective postsynaptic alpha-1 adrenoceptor blocker
2.Used in essential hypertension, severe CHF, and Raynaud's vasospasm
Adverse reactions include dose-related postural hypotension (first-dose phenomenon),
izziness, sodium and water retention on chronic use, tachycardia occurs much less than
with the non-selective alpha blockers
Therapeutic uses of ergot alkaloids
1.Migraine attack as ergotamine and dihydroergotamine
2.Migraine prophylaxis as methysergide
3.ostpartum hemorrhage (ergonovine and methylergonovine
4.Senile cerebral insufficiency (dihydroergotoxine
. Bromocriptine is used to suppress lactation, amenorrhoea-galactorr
ALPHA AND BETA ADRENERGIC
RECEPTOR AGONISTS
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RHS-366
ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS
History:
A. Finklemann in 1930 stimulated the sympathetic input to rabbit intestine and
ound a decrease in spontaneous movements. Perfusate did the same thing to a 2nd
iece of intestine. Effects mimicked by "adrenaline".
B. Von Euler 1946 demonstrated that NE, not EPI is the main endogenous
atecholamine in sympathetically innervated tissue.
C. The study of the sympathetic nervous system is important from a clinical
erspective. The SNS is involved in controlling heart rate, contractility, blood
ressure, vasomotor tone, carbohydrate and fatty acid metabolism etc. Stimulation
he SNS occurs in response to physical activity, psychological stress, allergies etc.
Drugs influencing the SNS are used in treatment of hypertension, shock, cardiac
ailure and arrhythmias, asthma and emphysema, allergies and anaphylaxis.
D. There are three major catecholamines: NE, EPI, and DA naturally found in the
ody. EPI and NE mediate the response of the sympathoadrenal system to activati
nd are also found in the CNS. DA is primarily a CNS neurotransmitter.
. Sympathomimetic amines have 7 major classes of action
A. A peripheral excitatory action: i.e. on smooth muscles of blood vessels supplying ski
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B. A peripheral inhibitory action: i.e. on smooth muscles of gut, bronchioles, and blood
essels supplying skeletal muscle.
C. A cardiac excitatory action: i.e. positive chronotropic, dromotropic, and inotropic
ffects.
D. Metabolic actions: i.e. enhanced glycogenolysis and lipolysis.
E. Endocrine actions: i.e. modulation of secretion of insulin
. CNS actions: i.e. increased wakefulness and inhibition of appetite.
G. Presynaptic actions: i.e. inhibition of release of NE, NPY, and ACh at autonomic ner
erminals by activation of alpha 2 receptors.
Enhanced release of ACh by activation of presynaptic alpha 2 receptors on somatic mo
eurons. Enhanced release of NE, and NPY by activation of Beta 2 receptors.
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Classification of adrenergic receptor agonists (sympathomimetic amines) or
drugs that produce sympathomimetic-like effects.
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I. Pharmacology of Epinephrine
A. Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1, 2, & 3) receptorherefore, its effects on target organs are complex.
B. Effects of EPI on blood pressure are dose dependent.
1. When given in large doses intravenously, EPI gives a rapid increase in blood pressur
As the response wanes, the mean pressure falls below normal before returning to contro
evels. The pressor effects are due to A) the positive inotropic effect of EPI, B) the posihronotropic effect, and C) vasoconstriction in many vascular beds. The depressor effec
ue to the activation of vasodilator beta 2 receptors in the vasculature perfusing skeletal
muscle. This effect is not seen initially because it is overwhelmed by the vasoconstrictiv
ffect of alpha 1 receptors on vascular smooth muscle at other sites, however
asoconstriction is lost as the concentration of EPI goes down, but the beta 2 mediated
asodilatory effect is retained. If you pretreat a person with an alpha adrenergic recepto
locker, one sees the so-called epinephrine reversal effect i.e. the unopposed effect of th
eta 2 receptors causes a pronounced decrease in total peripheral resistance, and meanslood pressure falls in response to EPI.
. When given in small doses, there is little or no effect on the mean blood pressure
ecause the increase in blood pressure resulting from increased heart rate and contractil
s counteracted by the decrease in total peripheral resistance due to vasodilation in blood
essels perfusing skeletal muscle. You will recall that these beta 2 receptors have a low
hreshold to activation than alpha 1 receptors, therefore the net effect oflow doses of EPs vasodilation.
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. When EPI causes an increase in mean arterial pressure (High doses); it activates a
ompensatory vagal baroreceptor mediated bradycardia which also helps to return blood
ressure toward normal.
C. Effects of EPI on vascular smooth muscle are variable, resulting in a substantial
edistribution of blood flow. That is, EPI causes a marked reduction of blood flow throu
he skin by activating its alpha 1 receptors, while simultaneously redistributing flow
hrough the muscles by causing vasodilation there through the activation of Beta 2
eceptors. This has obvious utility in survival of the organism by preparing it for fight o
light. EPI can reduce renal blood flow by 40% in doses that do not affect mean blood
ressure. Effects of EPI on Cerebral Circulation. No significant constrictor action onerebral blood vessels. If you think about it, it is a lucky thing that the blood flow to the
rain is not restricted during responses to stressors.
D. Effects of EPI on Cardiac Muscle are mediated primarily by beta 1 receptors, althou
Beta 2 and alpha receptors are also present in the heart. As indicated before, EPI has a
owerful chronotropic and inotropic effect. EPI reduces the time for systole and makes
more powerful without decreasing the duration of diastole. The latter effect occursecause EPI also increases the rate of relaxation of ventricular muscle. Cardiac output
nhanced and the work of the heart and its oxygen consumption are markedly increased
Cardiac efficiency (work done relative to oxygen consumption) is lessened! The
hronotropic action of EPI is due to its ability to accelerate the slow depolarization of
acemaker cells of the SA node that takes place during diastole. Large doses may provo
ardiac arrhythmias. Large doses of EPI, or long term elevation of plasma catecholamin
amages the myocardium. This may in part explain the beneficial effects of beta blocke
n heart failure.
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E. Effects of EPI on Other Smooth Muscles. In general GI muscle is relaxed and restin
one and peristaltic movements are reduced. This is due to the inhibitory effect of beta 2
eceptors, and possibly also due to inhibition of release of ACh by activation of inhibito
resynaptic alpha 2 receptors on cholinergic nerve terminals. The response of the uterus
ariable depending on phase of the sexual cycle, state of gestation, and dose of the drugDuring the last month of pregnancy, EPI inhibits uterine tone and contractions, by
ctivating beta 2 receptors. As a result, selective beta 2 agonists are used to delay the on
f premature labor. Bronchial smooth muscle is powerfully relaxed by EPI via activatio
f Beta 2 receptors. Selective beta 2 agonists are used in the treatment of asthma. Epi
elaxes the detrusor muscle of the bladder by activating beta receptors, and contracts the
rigone and sphincter muscles due to alpha agonist effects. The result is urinary retentio
. Metabolic effects of EPI:
. Glycogenolysis via activation of beta 2 receptors, results in an increase in blood
lucose.
. Lipolysis via activation of beta 3 receptors, results in an increase in the concentration
ree fatty acids in blood.
. Insulin secretion is inhibited by alpha 2 receptors, and increased by beta 2 receptors,
nhibition predominates in man.
. EPI promotes a fall in plasma K due to enhanced uptake of K into skeletal muscle vi
n action on Beta 2 receptors. This action has been exploited in the management of
yperkalemia.
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G. Absorption and fate of EPI
. Absorption of EPI as well as other catecholamines from GI tract is negligible due to
apid conjugation and oxidation in the intestinal mucosa of the GI tract and liver.
ubcutaneous absorption slows due to vasoconstriction. Inhaled effects largely restricteo the respiratory tract in low doses. Larger doses can give systemic effects, including
rrhythmias. The liver which is rich in both COMT and MAO destroys most circulating
EPI.
H. Toxicity and contraindications
. EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness, headach
remor, weakness, dizziness, etc. Hyperthyroid and hypertensive patients are particularl
usceptible.
. More serious reactions include cardiac arrhythmias, including fatal ventricular
rrhythmias when EPI is given to a patient anesthetized with halogenated hydrocarbon
nesthetics such as halothane. Also cerebral hemorrhage due to severe hypertension has
ccurred. Use of EPI in patients receiving nonselective Beta blockers is contraindicated
ecause the unopposed actions of EPI on vascular alpha 1 receptors can lead to severe
ypertension and cerebral hemorrhage.
Therapeutic uses of EPI
. Relief of bronchospasm
. Relief of hypersensitivity reactions and anaphylaxis
. To prolong the duration of action of local anesthetics.
. As a topical haemostatic to control superficial bleeding from skin and mucosa
. To restore cardiac rhythm in patients with cardiac arrest.
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II. Pharmacology of Norepinephrine
A. Cardiovascular effects of NE
. NE is a potent agonist at alpha and Beta 1 receptors, and has little action on beta 2
eceptors, therefore when given by intravenous infusion of low doses; NE causes a
ronounced increase in total peripheral resistance (i.e. because there is no opposing Bet
mediated vasodilation). This is combined with its direct inotropic effect on the heart to
ause a substantial increase in mean blood pressure, and a reflex mediated bradycardia.
ontrast to EPI, pretreatment with an alpha 1 antagonist will block the pressor effects of
NE, but will not cause reversal to a depressor effect. Since the effects of NE are mainly
lpha and Beta 1 receptors, indirectly acting sympathomimetics which act by releasing N
ave predominantly alpha mediated and cardiac effects.
B. Other responses to NE are not prominent in Man.
C. Toxicity
. The toxic effects of NE are like those of EPI, except they are less pronounced and les
requently seen i.e. anxiety, headache, palpitations, etc. In toxic doses, can get severeypertension. NE, like EPI is contraindicated in anesthesia with drugs that sensitize the
eart to the arrhythmic effects of catecholamines such as halothane. Accidental
xtravasation of NE during attempted intravenous infusion can cause local anoxic necro
nd impaired circulation through the limb. In pregnant females, NE should not be used
ecause it stimulates alpha 1 receptors in the uterus that cause contraction.
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D. Therapeutic uses
Currently very little therapeutic use. Sometimes used as a cardiac stimulant in cardiogen
r septicemic shock.
V. Pharmacology of Dopamine
A. Cardiovascular effects
. At low doses DA activate D 1 receptors in renal, mesenteric, and coronary vascular
eds. This leads to vasodilation. Increased flow through renal blood vessels is useful in
ardiogenic and septicemic shock when perfusion of vital organs is compromised. DA
ctivates Beta 1 receptors at higher concentrations leading to a positive inotropic effect.
Total peripheral resistance is usually unchanged, although at higher concentrations DA
ause activation of alpha 1 receptors mediating vasoconstriction.
B. Toxicity
. Toxicity of high doses of DA is similar to that noted above for NE. Since the drug ha
n extremely short half life in plasma, DA toxicity usually disappear quickly if the
dministration is terminated.
C. Therapeutic uses
. Useful in treatment of severe congestive heart failure, particularly in patients with
liguria or impaired renal function. DA is also useful in the treatment of cardiogenic an
eptic shock in patients with reduced renal function.C. DA Agonists
1. Fenoldopam is a rapidly acting vasodilator which is used for acute control of
evere hypertension. It is a D1 receptor agonist as well as an alpha 2 agonist. It does n
ffect alpha 1 or beta receptors. The half life of fenoldopam is 10 minutes.
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V. Pharmacology of Isoproterenol
A. Cardiovascular effects
. ISO is primarily a beta receptor agonist, therefore intravenous infusion of ISO leads tubstantial reduction of total peripheral resistance. Simultaneously, ISO causes a direct
notropic and chronotropic effect on the heart. The net result is a reduction in mean
ressure.
B. Actions on other smooth muscles.
. ISO relaxes almost all varieties of smooth muscle, but particularly bronchial and GI
mooth muscle. Its effectiveness in asthma may also be due to inhibition of the release o
istamine by activation of Beta 2 receptors.
C. Metabolic effects
. ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also strongly
eleases insulin by activating Beta 2 receptors.
D. Metabolism
. Primarily by COMT, not MAO. Mainly in the liver.
E. Toxicity
. Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily.
. Therapeutic uses
. Used in emergencies to stimulate heart rate in patients with bradycardia or heart bloc
ts use in asthma and shock has been discontinued due to development of more selective
ympathomimetics.
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VI. Pharmacology of Dobutamine
A. The mechanisms of action of dobutamine are complex. It is given as the racemic
mixture. The l-isomer is a potent agonist at alpha 1 receptors, while the d-isomer is aotent alpha 1 antagonist. Both isomers are beta receptor agonists with greater selectivit
or Beta 1 than beta 2 receptors. The net result of administration of the racemic mixture
more or less selective Beta agonist effects.
B. Cardiovascular effects
. Total peripheral resistance is not much affected, presumably by the counterbalancing
ffects of beta 2 agonist mediated vasodilation, and alpha 1 agonist mediated
asoconstriction. Dobutamine has a prominent inotropic effect on the heart, withoutmuch of a chronotropic effect. The explanation for this is unclear. Like other inotropic
gents, dobutamine may potentially increase the size of a myocardial infarct by increasi
xygen demand.
C. Toxicity is like isoproterenol, esp. arrhythmias
D. Not effective orally. Given by I.V. route, however its half life in plasma is two minu
herefore it must be given by a continuous infusion. After a few days, tolerance develop
o its effects. This has led to short term use repeated intermittently.
E. Therapeutic Uses
. Used in the short term treatment of congestive heart failure or acute myocardial
nfarctions, because of its inotropic effect, and because it does not increase heart rate an
as minimal effects on blood pressure. These effects minimize the increased oxygen
emands on the failing heart muscle.
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VII Pharmacology of Selective Beta 2 Agonists
A. These compounds are mainly utilized for treatment of asthma. Their advantage over
on-selective beta agonists is that they do not cause undesired cardiovascular effects bytimulating beta 1 receptors of the heart.
B. Metaproterenol, Terbutaline, Albuterol, Pirbuterol are structural analogues of the
atecholamines which have been modified so that they are not substrates of COMT and
oor substrates for MAO. These results in a longer duration of action compared to
atecholamines and vary from 3 to 6 hours when administered by inhalation.
C. Formoterol is a selective Beta 2 agonist with similarities to the above agents, howe
t has the advantages a rapid onset of action (minutes) and a long duration (12 hours).
D. Salmeterol is another long acting Beta 2 agonist however it has a slow onset of acti
herefore it is not useful for acute asthmatic attacks. It may also have anti-inflammatory
ctivity.
D. Ritodrine is a selective Beta 2 agonist which was developed as a uterine relaxant. It
sed to delay the onset of premature labor. Other beta 2 agonists have been used for the
ame purpose in Europe. While these drugs can delay the onset of birth, they may not h
ny significant effect in reducing perinatal mortality and may increase maternal morbid
Nifedepine ( a calcium channel blocker: NOT a beta 2 blocker) caused longer
ostponement of delivery, fewer maternal side effects, and fewer admissions to the
eonatal intensive care unit.
E. Adverse effects of Beta 2 agonists
. Skeletal muscle tremor is the most common adverse side effect. This may be due to th
resence of Beta 2 receptors in skeletal muscle, which when activated, cause twitches aremor. Tolerance generally develops to this side effect.
. Restlessness, apprehension, anxiety
. Tachycardia may occur possibly secondary to beta 2 receptor mediated vasodilation.
atients with heart disease particularly, can see arrhythmias.
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. Increased glycogenolysis
. Some recent epidemiological studies suggest that regular use of Beta 2 agonists may
ctually cause increased bronchial hyper reactivity and deterioration in the control
sthma. In patients requiring regular use of these drugs, strong consideration should beiven to the use of additional or alternative therapies, such as use of inhaled
lucocorticoids.
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VIII. Pharmacology of Alpha 1 Agonists
A. Phenylephrine and Methoxamine
. Primarily directly acting vasoconstrictors by activating alpha 1 receptors. The resultin
ypertension results in a prominent reflex bradycardia. They are used in the treatment o
trial tachycardia to terminate the arrhythmia by causing a reflex bradycardia.
henylephrine is also used as a nasal decongestant and mydriatic. They are not
metabolized by COMT, therefore they also have a longer duration of action than the
atecholamines.
B. Mephentermine and Metaraminol
. These drugs have two effects: a) They are directly acting alpha 1 agonists, and b) they
re indirectly acting sympathomimetics i.e. they cause the release of endogenous
orepinephrine. The direct effect on alpha 1 receptors mediates vasoconstriction and an
ncreased blood pressure. The indirect effect of released NE on the heart is a positive
notropic and chronotropic action that also increases blood pressure. This results in a ref
radycardia. Both drugs are administered intravenously. Adverse effects are due to CNS
timulation, excessive increases in blood pressure, and arrhythmias. They are used in th
reatment of the hypotension which is frequently associated with spinal anesthesia.
Metaraminol is also used in the termination of paroxysmal atrial tachycardia, particularl
n patients with existing hypotension.
C. Midodrine
. It is an orally effective alpha 1 agonist which is a prodrug. Its activity is due tometabolism to desglymidodrine. Sometimes used in patients with autonomic insufficien
nd postural hypotension.
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X. Pharmacology of Alpha 2 Agonists
A. Introduction
. Selective alpha 2 agonists are used primarily for the treatment ofhypertension. Thei
fficacy is somewhat surprising since many blood vessels, especially those of the skin a
mucosa, contain post-synaptic alpha 2 receptors that mediate vasoconstriction. Indeed
lonidine, the prototype alpha 2 agonist drug which we will consider was originally
eveloped as a nasal decongestant because of its ability to cause vasoconstriction of blo
essels in the nasal mucosa. The capacity of alpha 2 agonists to lower blood pressure
esults from their CNS effect, possibly from the activation of alpha 2 receptors in the
medulla that diminish centrally mediated sympathetic outflow.
B. Pharmacology of Clonidine
. Pharmacological effects
. Intravenous clonidine can cause a transient rise in blood pressure due to its ability to
ause vasoconstriction via an alpha 2 agonist effect on vascular smooth muscle of skin a
mucosa. This is followed by a decreased blood pressure due presumably to activation ofCNS alpha 2 receptors, resulting in a decreased central outflow of impulses in the
ympathetic nervous system, although this is an area of intense current research interest
nd some evidence suggests that different mechanisms may be more important. Some o
he antihypertensive effect of clonidine may also be due to diminished release of NE at
ympathetic postganglionic nerve terminals due to activation of presynaptic alpha 2
eceptors. Clonidine also stimulates parasympathetic outflow and causes slowing of the
eart.
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. Pharmacokinetics
. Clonidine is well absorbed orally, and is nearly 100% bioavailability. The mean half
f the drug in plasma is about 12 hours. It is excreted in an unchanged form by the kidn
nd its half life can increase dramatically in the presence of impaired renal function. Aransdermal delivery system is available in which the drug is released at a constant rate
bout a week. Three or four days are required to achieve steady state concentrations.
. Adverse effects
. The major adverse effects of clonidine are dry mouth, and sedation. Other effects
nclude bradycardia, and sexual dysfunction. About 20% of patients develop a contactermatitis to the transdermal delivery system. In patients with long term therapy with
lonidine, abrupt discontinuation is associated with development of a withdrawal
yndrome and potentially life threatening hypertension.
. Therapeutic uses
. The major use of clonidine is in the treatment of hypertension.
. Clonidine is useful in the management of withdrawal symptoms seen in addicts after
withdrawal from opiates, alcohol, and tobacco. This may be due to its ability to suppres
ympathomimetic symptoms of withdrawal.
. Clonidine is useful in the diagnosis of hypertension due to pheochromocytoma. In
rimary hypertension, clonidine causes a marked reduction in circulating levels of
orepinephrine. This is not seen if the cause of hypertension is pheochromocytoma.
. Apraclonidine and Brimonidine are structural analogues of clonidine (i.e. alpha 2
gonists) which are used topically in the treatment of glaucoma by decreasing the rate o
ynthesis of aqueous humor. Brimonidine also acts by enhancing the outflow of aqueou
umor. Its efficacy in reducing intraocular pressure is equivalent to timolol.
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C. Pharmacology of Guanfacine and Guanabenz
. Guanfacine and guanabenz are alpha 2 receptor agonists which are also believed to
ower blood pressure by activation of central sites. Their pharmacological effects and siffects are quite similar to clonidine. Guanfacine has a longer mean half life in plasma
han clonidine (12-24 hrs).
X. Miscellaneous Adrenergic Agonist Drugs
A. Amphetamine
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. Amphetamine is an indirectly acting sympathomimetic which causes release of NE fr
drenergic nerve endings, and also blocks its reuptake into the cytoplasm of the nerve
erminal. As such it has potent peripheral effects on alpha 1 & 2 receptors, and Beta 1, b
ot beta 2 receptors. It is also a potent CNS stimulant which is orally effective.
. Cardiovascular effects of amphetamine include increased blood pressure, and reflex
radycardia. In larger doses see cardiac arrhythmias.
. Other smooth muscles respond to amphetamine as they do to previously described
ympathomimetics. The contractile effect on the sphincter of the urinary bladder is
articularly pronounced and has been used for the treatment of incontinence.
. Amphetamine is one of the most potent sympathomimetic amines in stimulating the
CNS. The d-isomer is 3 to 4 times more potent than the l-isomer. CNS effects includencreased wakefulness and alertness; decreased sense of fatigue; elevation of mood, wit
ncreased initiative, self-confidence, and ability to concentrate; elation and euphoria;
epressed appetite; physical performance in athletes is improved; performance of simpl
mental tasks is improved, however although more work is accomplished, the number of
rrors increases. The most striking improvement with amphetamine occurs when
erformance is reduced by fatigue and lack of sleep. The behavioral effects of
mphetamine depend both on the dose and the mental state or personality of the
ndividual. Prolonged use or high doses are nearly always followed by depression andatigue. Tolerance develops to the appetite suppressant effects rapidly. Amphetamine
timulates the respiratory center. When respiration is depressed by centrally acting drug
mphetamine can stimulate respiration.
. Toxicity includes: restlessness, dizziness, tremor, irritability, insomnia, confusion,
ssaultiveness, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or
omicidal tendencies. The psychotic effects of amphetamine, including vivid hallucinat
nd paranoid delusions, which are often mistaken for schizophrenia is the most common
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erious effect, and can be elicited in any individual taking sufficient quantities of
mphetamine for a long period of time. Cardiovascular effects are common and include
ardiac arrhythmias, hypertension or hypotension, and circulatory collapse. GI symptom
nclude dry mouth, nausea, vomiting, and diarrhea. Fatal poisoning usually terminates in
onvulsions, stroke, and coma. Repeated use leads to the development of tolerance andsychological dependence.
. Therapeutic uses include treatment of narcolepsy, obesity, and attention-deficit
yperactivity disorder.
. Methamphetamine, in low doses, has prominent CNS effects like amphetamine,
without significant peripheral actions. It has a high potential for abuse. It is used
rincipally for its central effects which are more pronounced than amphetamine.
Methylphenidate is a mild CNS stimulant whose pharmacological properties is
ssentially the same as amphetamine but which may not lead to as much motor activatio
Pemoline is another CNS stimulant which has minimal cardiovascular effects. It is used
he treatment of attention-deficit hyperactivity disorder and is given once daily due to it
ong half-life.
B. Ephedrine
. Ephedrine is an alkaloid isolated from the plant Ephedrine sinica. Extracts of this pla
ave been used in Chinese herbal medicine for at least 2000 years. Ephedrine has both
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irectly- and indirectly- mediated sympathomimetic effects. That is, it stimulates both
lpha and beta receptors, and it causes release of NE. Ephedrine was the first
ympathomimetic drug which was effective orally. Its spectrum of effects is similar to
EPI, another sympathomimetic with both alpha and beta agonist effects, however it has
onger duration of effect. In addition it has CNS effects similar to amphetamine, but lesntense. In the past it was used as a CNS stimulant for treatment of narcolepsy, and as a
ronchodilator in asthma. More selective agents have replaced ephedrine.
C. Ethylnorepinephrine
. It is primarily a beta agonist with some alpha agonist effects. It is administered IM or
C to cause bronchiolar dilation as well as vasoconstriction in the bronchioles, which
educes bronchial congestion.
D. Oral sympathomimetics used primarily for relief of nasal congestion include
henylephrine, pseudoephedrine, and phenylpropanolamine.
E. Topical sympathomimetics used primarily as nasal decongestants or mydriatics inclu
aphazoline, tetrahydrozoline, and oxymetazoline. and xylometazoline
XI. A Summary of Therapeutic Uses of Sympathomimetics
A. Uses that relate to vascular effects of sympathomimetics
. Control of superficial hemorrhage, i.e. in facial, oropharyngeal, and nasopharyngeal
urgery. EPI
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. Decongestion of mucous membranes.
. Usually get temporary relief, but it is often followed by a rebound swelling.
. To prolong the duration of action of local anesthetics: EPI
. in the treatment of hypotension and shock.
. Use controversial because autoregulatory phenomena usually cause intense sympathe
ctivation and sympathomimetics may compromise perfusion of vital organs. DA!
B. Uses that relate to CNS effects of sympathomimetics
. Narcolepsy (amphetamines)
. Weight Reduction (amphetamines)
. Attention deficit-hyperactivity disorder (amphetamines, methylphenidate)
C. Uses for cardiac effects
. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia.
. Epinephrine used in emergency treatment of cardiac arrest.
. DA is useful in the treatment of cardiogenic or septicemic shock especially in patien
with compromised renal function.
D. Uses in allergic reactions
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. Epinephrine is the drug of choice to reverse the manifestations of serious acute
ypersensitivity reactions due both to its cardiovascular effects and its ability to suppres
elease of histamine.
. Asthma is preferentially treated with selective beta 2 agonists (Metaproterenol,erbutaline, albuterol).
E. Uses in ophthalmology
. Sympathomimetics cause mydriasis i.e. phenylephrine and epi. These two drugs also
ause a reduction in intraocular pressure in wide angle glaucoma.
. Uses in obstetrics
. Beta 2 agonist (Ritodrine) blocks onset of premature labor by inhibiting contractility
terus
G. Nasal decongestion
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Uptake of catecholamines:
1) Neuronal Uptake:
Adrenergic neurons have a high capacity of actively taking up noradrenaline from thextracellular fluid to the cytoplasm resulting in a fall of the transmitter concentration
the receptor sites. This neuronal uptake process or Uptake 1 is both stereo- and struct
selective. It has a higher affinity for L-than for D-forms, and for noradrenaline twice
much as for adrenaline.
Uptake1 is probably the most important mechanism in terminating the action of
neuronally released noradrenaline. Drugs that inhibit uptake-1 potentiate the respons
sympathetic stimulation and to exogenously administered noradrenaline and adrenaliSuch drugs include cocaine, guanethidine and tricyclic antidepressants as desipramin
2) Granular uptake:
The noradrenaline taken up into the cytoplasmic pool may also be actively transporte
into the storage vesicles or granules, a process described as granular uptake. Inhibitor
of uptake1, have little effect on this process whereas resepine has little effect on
uptake1 but is a potent inhibitor of granular uptake
3) Extraneuronal uptake:
Some peripheral tissues as cardiac muscle and smooth muscle of the intestine and blo
vessels may also take up circulating catecholamines especially when their concentrat
becomes relatively high. This extraneuronal uptake or uptake2 has different
characteristics from uptake1 and is suggested to play a role in inactivating circulating
catecholamines
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ADRENOCEPTOR ANTAGONISTS
RHS-366
General Pharmacology
These drugs block the effect of sympathetic
erves on blood vessels by binding to alpha-
drenoceptors located on the vascular smooth muscle. Most of these drugs acts as
ompetitive antagonists to the binding of norepinephrine that is released by sympathetic
erves synapsing on smooth muscle. Therefore, sometimes these drugs are referred to a
ympatholytics because they antagonize sympathetic activity. Some alpha-blockers are
on-competitive (e.g., phenoxybenzamine), which greatly prolongs their action.
Vascular smooth muscle has two primary types of alpha-adrenoceptors: alpha1 (a1) and
lpha2 (a2). The a1-adrenoceptors are located on the vascular smooth muscle. In contras
2-adrenoceptors are located on the sympathetic nerve terminals as well as on vascular
mooth muscle. Smooth muscle (postjunctional) a1 and a2-adrenoceptors are linked to a
Gq-protein, which activates smooth muscle contraction through the IP3 signal transduct
athway. Prejunctional a2-adrenoceptors located on the sympathetic nerve terminals ser
s a negative feedback mechanism for norepinephrine release.
1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrin
o the smooth muscle receptors. Non-selective a1 and a2-adrenoceptor antagonists block
ostjunctional a1 and a2-adrenoceptors, which causes vasodilation; however, the blockin
f prejunctional a2-adrenoceptors leads to increased release of norepinephrine, which
ttenuates the effectiveness of the a1 and a2-postjunctional adrenoceptor blockade.
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urthermore, blocking a2-prejunctional adrenoceptors in the heart can lead to increases
eart rate and contractility due to the enhanced release of norepinephrine that binds to
eta1-adrenoceptors.
Alpha-blockers dilate both arteries and veins because both vessel types are innervated bympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in th
rterial resistance vessels. Because most blood vessels have some degree of sympatheti
one under basal conditions, these drugs are effective dilators. They are even more
ffective under conditions of elevated sympathetic activity (e.g., during stress) or during
athologic increases in circulating catecholamines caused by an adrenal gland tumor
pheochromocytoma).
Therapeutic Uses
Alpha-blockers, especially a1-adrenoceptor antagonists, are useful in the treatment of
rimary hypertension, although their use is not as widespread as other antihypertensive
rugs. The non-selective antagonists are usually reserve for use in hypertensive
mergencies caused by a pheochromocytoma. This hypertensive condition, which is mo
ommonly caused by an adrenal gland tumor that secretes large amounts of
atecholamines, can be managed by non-selective alpha-blockers (in conjunction with
eta-blockade to blunt the reflex tachycardia) until the tumor can be surgically removed
pecific Drugs
Newer alpha-blockers used in treating hypertension are relatively selective a1-adrenocep
ntagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older dru
re non-selective antagonists (e.g., phentolamine, phenoxybenzamine). (Go to
www.rxlist.com for specific drug information)
ide Effects and Contraindications
The most common side effects are related directly to alpha-adrenoceptor blockade. The
ide effects include dizziness, orthostatic hypotension (due to loss of reflex
asoconstriction upon standing), nasal congestion (due to dilation of nasal mucosal
rterioles), headache, and reflex tachycardia (especially with non-selective alpha-
lockers). Fluid retention is also a problem that can be rectified by use of a diuretic in
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onjunction with the alpha-blocker. Alpha blockers have not been shown to be benefici
n heart failure orangina, and should not be used in these conditions.
BETA ADRENOCEPTOR ANTAGONISTS
Pharmacology
Beta blockers block the action ofendogenouscatecholamines (epinephrine (adrenaline)
nd norepinephrine (noradrenaline) in particular), on -adrenergic receptors, part of the
ympathetic nervous system which mediates the "fight or flight" response.
There are three known types of beta receptor, designated 1, 2 and 3. 1-Adrenergic
eceptors are located mainly in the heart and in the kidneys. 2-Adrenergic receptors are
ocated mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle,
nd skeletal muscle. 3-receptors are located in fat cells.
-Receptor antagonism
timulation of 1 receptors by epinephrine induces a positive chronotropic and inotropic
ffect on the heart and increases cardiac conduction velocity and automaticity. Stimulatf 1 receptors on the kidney causes renin release. Stimulation of 2 receptors induces
mooth muscle relaxation (resulting in vasodilation andbronchodilation amongst other
ctions), induces tremor in skeletal muscle, and increases glycogenolysis in the liveran
keletal muscle. Stimulation of 3 receptors induces lipolysis.
Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have
minimal effect on resting subjects. That is, they reduce the effect of excitement/physica
xertion on heart rate and force of contraction, dilation of blood vessels and opening ofronchi, and also reduce tremor and breakdown ofglycogen.
t is therefore expected that non-selective beta blockers have an antihypertensive effect.
The antihypertensive mechanism appears to involve: reduction in cardiac output (due to
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egative chronotropic and inotropic effects), reduction in renin release from the kidneys
nd a central nervous system effect to reduce sympathetic activity.
Antianginal effects result from negative chronotropic and inotropic effects, which decre
ardiac workload and oxygen demand.
The antiarrhythmic effects of beta blockers arise from sympathetic nervous system
lockade resulting in depression ofsinus node function and atrioventricular node
onduction, and prolonged atrialrefractory periods. Sotalol, in particular, has additional
ntiarrhythmic properties and prolongs action potential duration throughpotassium
hannel blockade.
Blockade of the sympathetic nervous system on renin release leads to reduced aldostero
ia the renin angiotensin aldosterone system with a resultant decrease in blood pressureue to decreased sodium and water retention.
ntrinsic sympathomimetic activity
ome beta blockers (e.g. oxprenolol andpindolol) exhibit intrinsic sympathomimetic
ctivity (ISA). These agents are capable of exerting low level agonist activity at the -
drenergic receptor while simultaneously acting as a receptor site antagonist. These
gents, therefore, may be useful in individuals exhibiting excessivebradycardia with
ustained beta blocker therapy.
Agents with ISA are not used in post-myocardial infarction as they have not been
emonstrated to be beneficial. They may also be less effective than other beta blockers
he management ofangina and tachyarrhythmia.[3]
1-Receptor antagonism
ome beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both -
1-adrenergic receptors, which provides additional arteriolarvasodilating action.
Other effects
Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep
isturbance caused by some agents.[4] Beta blockers protect against social anxiety:
http://en.wikipedia.org/wiki/Reninhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Chronotropichttp://en.wikipedia.org/wiki/Inotropichttp://en.wikipedia.org/wiki/Sinus_nodehttp://en.wikipedia.org/wiki/Atrioventricular_nodehttp://en.wikipedia.org/wiki/Atrium_(anatomy)http://en.wikipedia.org/wiki/Refractory_period_(cardiac)http://en.wikipedia.org/wiki/Sotalolhttp://en.wikipedia.org/wiki/Action_potentialhttp://en.wikipedia.org/wiki/Potassium_channelhttp://en.wikipedia.org/wiki/Potassium_channelhttp://en.wikipedia.org/wiki/Renin-angiotensin_systemhttp://en.wikipedia.org/wiki/Oxprenololhttp://en.wikipedia.org/wiki/Pindololhttp://en.wikipedia.org/wiki/Receptor_agonisthttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Bradycardiahttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Angina_pectorishttp://en.wikipedia.org/wiki/Tachyarrhythmiahttp://en.wikipedia.org/wiki/Beta_blocker#_note-Rossi%23_note-Rossihttp://en.wikipedia.org/wiki/Labetalolhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Arteriolehttp://en.wikipedia.org/wiki/Melatoninhttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid10335905%23_note-pmid10335905http://en.wikipedia.org/wiki/Reninhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Chronotropichttp://en.wikipedia.org/wiki/Inotropichttp://en.wikipedia.org/wiki/Sinus_nodehttp://en.wikipedia.org/wiki/Atrioventricular_nodehttp://en.wikipedia.org/wiki/Atrium_(anatomy)http://en.wikipedia.org/wiki/Refractory_period_(cardiac)http://en.wikipedia.org/wiki/Sotalolhttp://en.wikipedia.org/wiki/Action_potentialhttp://en.wikipedia.org/wiki/Potassium_channelhttp://en.wikipedia.org/wiki/Potassium_channelhttp://en.wikipedia.org/wiki/Renin-angiotensin_systemhttp://en.wikipedia.org/wiki/Oxprenololhttp://en.wikipedia.org/wiki/Pindololhttp://en.wikipedia.org/wiki/Receptor_agonisthttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Bradycardiahttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Angina_pectorishttp://en.wikipedia.org/wiki/Tachyarrhythmiahttp://en.wikipedia.org/wiki/Beta_blocker#_note-Rossi%23_note-Rossihttp://en.wikipedia.org/wiki/Labetalolhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Arteriolehttp://en.wikipedia.org/wiki/Melatoninhttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid10335905%23_note-pmid103359057/28/2019 RHS 366
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Improvement of physical symptoms has been demonstrated with beta-blockers such as
ropranolol; however, these effects are limited to the social anxiety experienced in
erformance situations." [5] Beta blockers can impair the relaxation of bronchial muscle
mediated by beta-2) and so should be avoided by asthmatics.
Clinical use
Large differences exist in the pharmacology of agents within the class, thus not all beta
lockers are used for all indications listed below.
ndications for beta blockers include:
Hypertension
Angina Mitral valve prolapse
Cardiac arrhythmia
Congestive heart failure
Myocardial infarction
Glaucoma
Migraineprophylaxis
Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
Essential tremor Phaeochromocytoma, in conjunction with -blocker
Congestive heart failure
Although beta blockers were once contraindicated in congestive heart failure, as they ha
he potential to worsen the condition, studies in the late 1990s showed their positive
ffects on morbidity and mortality in congestive heart failure.[6][7][8]Bisoprolol, carvedi
nd sustained-release metoprolol are specifically indicated as adjuncts to standard ACE
nhibitorand diuretic therapy in congestive heart failure.
The beta blockers are a benefit due to the reduction of the heart rate which will lower th
myocardial energy expenditure. This is turns prolongs the diastolic filling and lengthens
oronary perfusion.[9] Beta blockers have also been a benefit to improving the ejection
raction of the heart despite an initial reduction in it.
http://en.wikipedia.org/wiki/Beta_blocker#_note-anxiety%23_note-anxietyhttp://en.wikipedia.org/wiki/Hypertensionhttp://en.wikipedia.org/wiki/Angina_pectorishttp://en.wikipedia.org/wiki/Mitral_valve_prolapsehttp://en.wikipedia.org/wiki/Cardiac_arrhythmiahttp://en.wikipedia.org/wiki/Congestive_heart_failurehttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Glaucomahttp://en.wikipedia.org/wiki/Migrainehttp://en.wikipedia.org/wiki/Prophylaxishttp://en.wikipedia.org/wiki/Tachycardiahttp://en.wikipedia.org/wiki/Tremorhttp://en.wikipedia.org/wiki/Anxietyhttp://en.wikipedia.org/wiki/Hyperthyroidismhttp://en.wikipedia.org/wiki/Essential_tremorhttp://en.wikipedia.org/wiki/Phaeochromocytomahttp://en.wikipedia.org/wiki/Phaeochromocytomahttp://en.wikipedia.org/wiki/Phaeochromocytomahttp://en.wikipedia.org/wiki/Alpha_blockerhttp://en.wikipedia.org/wiki/Congestive_heart_failurehttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid10714728%23_note-pmid10714728http://en.wikipedia.org/wiki/Beta_blocker#_note-pmid11835035%23_note-pmid11835035http://en.wikipedia.org/wiki/Beta_blocker#_note-pmid12390947%23_note-pmid12390947http://en.wikipedia.org/wiki/Bisoprololhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/ACE_inhibitorhttp://en.wikipedia.org/wiki/ACE_inhibitorhttp://en.wikipedia.org/wiki/Diuretichttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid12173717%23_note-pmid12173717http://en.wikipedia.org/wiki/Beta_blocker#_note-anxiety%23_note-anxietyhttp://en.wikipedia.org/wiki/Hypertensionhttp://en.wikipedia.org/wiki/Angina_pectorishttp://en.wikipedia.org/wiki/Mitral_valve_prolapsehttp://en.wikipedia.org/wiki/Cardiac_arrhythmiahttp://en.wikipedia.org/wiki/Congestive_heart_failurehttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Glaucomahttp://en.wikipedia.org/wiki/Migrainehttp://en.wikipedia.org/wiki/Prophylaxishttp://en.wikipedia.org/wiki/Tachycardiahttp://en.wikipedia.org/wiki/Tremorhttp://en.wikipedia.org/wiki/Anxietyhttp://en.wikipedia.org/wiki/Hyperthyroidismhttp://en.wikipedia.org/wiki/Essential_tremorhttp://en.wikipedia.org/wiki/Phaeochromocytomahttp://en.wikipedia.org/wiki/Alpha_blockerhttp://en.wikipedia.org/wiki/Congestive_heart_failurehttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid10714728%23_note-pmid10714728http://en.wikipedia.org/wiki/Beta_blocker#_note-pmid11835035%23_note-pmid11835035http://en.wikipedia.org/wiki/Beta_blocker#_note-pmid12390947%23_note-pmid12390947http://en.wikipedia.org/wiki/Bisoprololhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/ACE_inhibitorhttp://en.wikipedia.org/wiki/ACE_inhibitorhttp://en.wikipedia.org/wiki/Diuretichttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid12173717%23_note-pmid121737177/28/2019 RHS 366
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Trials have shown that Beta blockers reduce the absolute risk of death by 4.5% over a 1
month period. As well as reducing the risk of mortality, the number of hospital visits an
ospitalizations were also reduced in the trials.
Anxiety and performance enhancement
ome people, particularly musicians, use beta blockers to avoid stage fright and tremor
uring public performance and auditions. The physiological symptoms of the fight/fligh
esponse associated withperformance anxiety andpanic (pounding heart, cold/clammy
ands, increased respiration, sweating, etc.) are significantly reduced, thus enabling
nxious individuals to concentrate on the task at hand. Officially, beta blockers are not
pproved foranxiolytic use by the U.S. Food and Drug Administration. [10]
ince they lower heart rate and reduce tremor, beta blockers have been used by someOlympicmarksmen to enhance performance, though beta blockers are banned by the
nternational Olympic Committee (IOC).[11] Although they have no recognisable benefit
most sports, it is acknowledged that they are beneficial to sports such as archery and
hooting.
Adverse effects
Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea
iarrhea,bronchospasm, dyspnea, cold extremities, exacerbation ofRaynaud's syndrom
radycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision,
ecreased concentration, hallucinations, insomnia, nightmares, clinical depression, sexu
ysfunction, erectile dysfunction and/or alteration ofglucose and lipidmetabolism. Mix
1/-antagonist therapy is also commonly associated with orthostatic hypotension.
Carvedilol therapy is commonly associated with edema.[3]
Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares,
epression) are more common in agents with greater lipid solubility, which are able toross theblood-brain barrierinto the CNS. Similarly, CNS adverse effects are less
ommon in agents with greater aqueous solubility.
Adverse effects associated with 2-adrenergic receptor antagonist activity (bronchospas
eripheral vasoconstriction, alteration of glucose and lipid metabolism) are less commo
http://en.wikipedia.org/wiki/Musicianshttp://en.wikipedia.org/wiki/Stage_frighthttp://en.wikipedia.org/wiki/Audition_(performing_arts)http://en.wikipedia.org/wiki/Stage_frighthttp://en.wikipedia.org/wiki/Panichttp://en.wikipedia.org/wiki/Anxiolytichttp://en.wikipedia.org/wiki/Food_and_Drug_Administrationhttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid16957148%23_note-pmid16957148http://en.wikipedia.org/wiki/Olympic_Gameshttp://en.wikipedia.org/wiki/Marksmanhttp://en.wikipedia.org/wiki/International_Olympic_Committeehttp://en.wikipedia.org/wiki/Beta_blocker#_note-ref4%23_note-ref4http://en.wikipedia.org/wiki/Adverse_drug_reactionhttp://en.wikipedia.org/wiki/Nauseahttp://en.wikipedia.org/wiki/Diarrheahttp://en.wikipedia.org/wiki/Bronchospasmhttp://en.wikipedia.org/wiki/Dyspneahttp://en.wikipedia.org/wiki/Raynaud's_syndromehttp://en.wikipedia.org/wiki/Bradycardiahttp://en.wikipedia.org/wiki/Hypotensionhttp://en.wikipedia.org/wiki/Heart_failurehttp://en.wikipedia.org/wiki/Heart_blockhttp://en.wikipedia.org/wiki/Fatigue_(medical)http://en.wikipedia.org/wiki/Dizzinesshttp://en.wikipedia.org/wiki/Hallucinationshttp://en.wikipedia.org/wiki/Insomniahttp://en.wikipedia.org/wiki/Clinical_depressionhttp://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Erectile_dysfunctionhttp://en.wikipedia.org/wiki/Glucosehttp://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Metabolismhttp://en.wikipedia.org/wiki/Orthostatic_hypotensionhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Edemahttp://en.wikipedia.org/wiki/Beta_blocker#_note-Rossi%23_note-Rossihttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Blood-brain_barrierhttp://en.wikipedia.org/wiki/Musicianshttp://en.wikipedia.org/wiki/Stage_frighthttp://en.wikipedia.org/wiki/Audition_(performing_arts)http://en.wikipedia.org/wiki/Stage_frighthttp://en.wikipedia.org/wiki/Panichttp://en.wikipedia.org/wiki/Anxiolytichttp://en.wikipedia.org/wiki/Food_and_Drug_Administrationhttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid16957148%23_note-pmid16957148http://en.wikipedia.org/wiki/Olympic_Gameshttp://en.wikipedia.org/wiki/Marksmanhttp://en.wikipedia.org/wiki/International_Olympic_Committeehttp://en.wikipedia.org/wiki/Beta_blocker#_note-ref4%23_note-ref4http://en.wikipedia.org/wiki/Adverse_drug_reactionhttp://en.wikipedia.org/wiki/Nauseahttp://en.wikipedia.org/wiki/Diarrheahttp://en.wikipedia.org/wiki/Bronchospasmhttp://en.wikipedia.org/wiki/Dyspneahttp://en.wikipedia.org/wiki/Raynaud's_syndromehttp://en.wikipedia.org/wiki/Bradycardiahttp://en.wikipedia.org/wiki/Hypotensionhttp://en.wikipedia.org/wiki/Heart_failurehttp://en.wikipedia.org/wiki/Heart_blockhttp://en.wikipedia.org/wiki/Fatigue_(medical)http://en.wikipedia.org/wiki/Dizzinesshttp://en.wikipedia.org/wiki/Hallucinationshttp://en.wikipedia.org/wiki/Insomniahttp://en.wikipedia.org/wiki/Clinical_depressionhttp://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Erectile_dysfunctionhttp://en.wikipedia.org/wiki/Glucosehttp://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Metabolismhttp://en.wikipedia.org/wiki/Orthostatic_hypotensionhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Edemahttp://en.wikipedia.org/wiki/Beta_blocker#_note-Rossi%23_note-Rossihttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Blood-brain_barrier7/28/2019 RHS 366
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with 1-selective (often termed "cardioselective") agents, however receptor selectivity
iminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macu
ensa inhibits renin release, thus decreasing the release of aldosterone. This causes
yponatremia and hyperkalemia.
A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a
atient's risk of developing diabetes whilst ACE inhibitors and Angiotensin II receptor
ntagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.[12]
Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuret
nd beta-blockers as first-line treatment of hypertension due to the risk of diabetes.[13]
Beta blockers must not be used in the treatment ofcocaine, amphetamine, or other alpha
drenergic stimulantoverdose. The blockade of only beta receptors increases
ypertension, reduces coronary blood flow, left ventricular function, and cardiac output
nd tissue perfusion by means of leaving the alpha adrenergic system stimulation
nopposed. [14] The appropriate antihypertensive drugs to administer during hypertensiv
risis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like
urosemide and alpha blockers likephentolamine.
Examples of beta blockers
Dichloroisoprenaline, the first beta blocker.
Non-selective agents
Alprenolol
Carteolol
Levobunolol
Mepindolol
Metipranolol
Nadolol
http://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/ACE_inhibitorshttp://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonisthttp://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonisthttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid17240286%23_note-pmid17240286http://en.wikipedia.org/wiki/Beta_blocker#_note-pmid16809680%23_note-pmid16809680http://en.wikipedia.org/wiki/Cocainehttp://en.wikipedia.org/wiki/Amphetaminehttp://en.wikipedia.org/wiki/Stimulanthttp://en.wikipedia.org/wiki/Overdosehttp://en.wikipedia.org/wiki/Hypertensionhttp://en.wikipedia.org/wiki/Ventricular_functionhttp://en.wikipedia.org/wiki/Cardiac_outputhttp://en.wikipedia.org/wiki/Beta_blocker#_note-Toxicity.2CCocaine.3BeMedicine%23_note-Toxicity.2CCocaine.3BeMedicinehttp://en.wikipedia.org/wiki/Antihypertensivehttp://en.wikipedia.org/wiki/Vasodilatorshttp://en.wikipedia.org/wiki/Nitroglycerinhttp://en.wikipedia.org/wiki/Diureticshttp://en.wikipedia.org/wiki/Furosemidehttp://en.wikipedia.org/wiki/Alpha_blockershttp://en.wikipedia.org/wiki/Phentolaminehttp://en.wikipedia.org/wiki/Carteololhttp://en.wikipedia.org/wiki/Levobunololhttp://en.wikipedia.org/w/index.php?title=Mepindolol&action=edithttp://en.wikipedia.org/wiki/Metipranololhttp://en.wikipedia.org/wiki/Nadololhttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/ACE_inhibitorshttp://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonisthttp://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonisthttp://en.wikipedia.org/wiki/Beta_blocker#_note-pmid17240286%23_note-pmid17240286http://en.wikipedia.org/wiki/Beta_blocker#_note-pmid16809680%23_note-pmid16809680http://en.wikipedia.org/wiki/Cocainehttp://en.wikipedia.org/wiki/Amphetaminehttp://en.wikipedia.org/wiki/Stimulanthttp://en.wikipedia.org/wiki/Overdosehttp://en.wikipedia.org/wiki/Hypertensionhttp://en.wikipedia.org/wiki/Ventricular_functionhttp://en.wikipedia.org/wiki/Cardiac_outputhttp://en.wikipedia.org/wiki/Beta_blocker#_note-Toxicity.2CCocaine.3BeMedicine%23_note-Toxicity.2CCocaine.3BeMedicinehttp://en.wikipedia.org/wiki/Antihypertensivehttp://en.wikipedia.org/wiki/Vasodilatorshttp://en.wikipedia.org/wiki/Nitroglycerinhttp://en.wikipedia.org/wiki/Diureticshttp://en.wikipedia.org/wiki/Furosemidehttp://en.wikipedia.org/wiki/Alpha_blockershttp://en.wikipedia.org/wiki/Phentolaminehttp://en.wikipedia.org/wiki/Carteololhttp://en.wikipedia.org/wiki/Levobunololhttp://en.wikipedia.org/w/index.php?title=Mepindolol&action=edithttp://en.wikipedia.org/wiki/Metipranololhttp://en.wikipedia.org/wiki/Nadolol7/28/2019 RHS 366
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Oxprenolol
Penbutolol
Pindolol
Propranolol
Sotalol Timolol
1-Selective agents
Acebutolol
Atenolol
Betaxolol
Bisoprolol[16]
Esmolol
Metoprolol
Nebivolol
Mixed 1/-adrenergic antagonists
Carvedilol
Celiprolol
Labetalol
2-Selective agents
Butaxamine (weak -adrenergic agonist activity
ide Effects / Health Consequences
Low Blood Pressure
Slow Heart Rate
Impaired Circulation
Loss of Sleep
http://en.wikipedia.org/wiki/Oxprenololhttp://en.wikipedia.org/wiki/Penbutololhttp://en.wikipedia.org/wiki/Pindololhttp://en.wikipedia.org/wiki/Propranololhttp://en.wikipedia.org/wiki/Sotalolhttp://en.wikipedia.org/wiki/Timololhttp://en.wikipedia.org/wiki/Acebutololhttp://en.wikipedia.org/wiki/Atenololhttp://en.wikipedia.org/wiki/Betaxololhttp://en.wikipedia.org/wiki/Bisoprololhttp://en.wikipedia.org/wiki/Beta_blocker#_note-bisoprolol%23_note-bisoprololhttp://en.wikipedia.org/wiki/Beta_blocker#_note-bisoprolol%23_note-bisoprololhttp://en.wikipedia.org/wiki/Esmololhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/Nebivololhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/w/index.php?title=Celiprolol&action=edithttp://en.wikipedia.org/wiki/Labetalolhttp://en.wikipedia.org/wiki/Butaxaminehttp://en.wikipedia.org/wiki/Oxprenololhttp://en.wikipedia.org/wiki/Penbutololhttp://en.wikipedia.org/wiki/Pindololhttp://en.wikipedia.org/wiki/Propranololhttp://en.wikipedia.org/wiki/Sotalolhttp://en.wikipedia.org/wiki/Timololhttp://en.wikipedia.org/wiki/Acebutololhttp://en.wikipedia.org/wiki/Atenololhttp://en.wikipedia.org/wiki/Betaxololhttp://en.wikipedia.org/wiki/Bisoprololhttp://en.wikipedia.org/wiki/Beta_blocker#_note-bisoprolol%23_note-bisoprololhttp://en.wikipedia.org/wiki/Esmololhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/Nebivololhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/w/index.php?title=Celiprolol&action=edithttp://en.wikipedia.org/wiki/Labetalolhttp://en.wikipedia.org/wiki/Butaxamine7/28/2019 RHS 366
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Heart Failure
Asthma
Depression
Sexual Dysfunction
Nausea Headaches
Dizziness
Muscle Cramps
Pharmacological differences
Agents with intrinsic sympathomimetic action (ISA)
o Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol
Agents with greater aqueous solubility
o Atenolol, celiprolol, nadolol, sotalol
Agents with membrane stabilising activity
o Acebutolol, betaxolol, pindolol, propranolol
Agents with antioxidant effect
o Carvedilol
o Nebivolol
ndication differences
Agents specifically indicated forcardiac arrhythmia
o Esmolol, sotalol
Agents specifically indicated forcongestive heart failure
o Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol
Agents specifically indicated forglaucoma
o Betaxolol, carteolol, levobunolol, metipranolol, timolol
Agents specifically indicated formyocardial infarction
o Atenolol, metoprolol,propranolol Agents specifically indicated formigraine prophylaxis
o Timolol,propranolol
http://en.wikipedia.org/wiki/Antioxidanthttp://en.wikipedia.org/wiki/Cardiac_arrhythmiahttp://en.wikipedia.org/wiki/Esmololhttp://en.wikipedia.org/wiki/Sotalolhttp://en.wikipedia.org/wiki/Congestive_heart_failurehttp://en.wikipedia.org/wiki/Bisoprololhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/Nebivololhttp://en.wikipedia.org/wiki/Glaucomahttp://en.wikipedia.org/wiki/Betaxololhttp://en.wikipedia.org/wiki/Carteololhttp://en.wikipedia.org/wiki/Levobunololhttp://en.wikipedia.org/wiki/Metipranololhttp://en.wikipedia.org/wiki/Timololhttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Atenololhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/Propranololhttp://en.wikipedia.org/wiki/Migrainehttp://en.wikipedia.org/wiki/Timololhttp://en.wikipedia.org/wiki/Propranololhttp://en.wikipedia.org/wiki/Antioxidanthttp://en.wikipedia.org/wiki/Cardiac_arrhythmiahttp://en.wikipedia.org/wiki/Esmololhttp://en.wikipedia.org/wiki/Sotalolhttp://en.wikipedia.org/wiki/Congestive_heart_failurehttp://en.wikipedia.org/wiki/Bisoprololhttp://en.wikipedia.org/wiki/Carvedilolhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/Nebivololhttp://en.wikipedia.org/wiki/Glaucomahttp://en.wikipedia.org/wiki/Betaxololhttp://en.wikipedia.org/wiki/Carteololhttp://en.wikipedia.org/wiki/Levobunololhttp://en.wikipedia.org/wiki/Metipranololhttp://en.wikipedia.org/wiki/Timololhttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Atenololhttp://en.wikipedia.org/wiki/Metoprololhttp://en.wikipedia.org/wiki/Propranololhttp://en.wikipedia.org/wiki/Migrainehttp://en.wikipedia.org/wiki/Timololhttp://en.wikipedia.org/wiki/Propranolol7/28/2019 RHS 366
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Propranolol is the only agent indicated for control of tremor,portal hypertension and
esophageal variceal bleeding, and used in conjunction with -blocker therapy in
phaeochromocytoma
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromusc
unction, causingparalysis of the affected skeletal muscles. This is accomplished either
ctingpresynaptically via the inhibition ofacetylcholine (ACh) synthesis or release, orcting postsynaptically at the acetylcholine receptor. While there are drugs that
resynaptically (such asbotulin toxin and tetrodotoxin), the clinically-relevant drugs w
ostsynaptically.
Clinically, neuromuscular block is used as an adjunct to anesthesia to induceparalysis
hat surgery, especially intra-abdominal and intra-thoracic surgeries, can be carried
with fewer complications. Because neuromuscular block may paralyze muscles requi
or breathing, mechanical ventilation should be available to maintain adequate respiratio
Classification
These drugs fall into two groups:
Non-depolarizing blocking agents: These agents constitute the majority of the clinica
elevant neuromuscular blockers. They act by blocking the binding of ACh to its recept
nd in some cases, they also directly block the ionotropic activity of the ACh receptors
Depolarizing blocking agents: These agents act by depolarizing theplasma membran
he skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistan
urther stimulation by ACh.
http://en.wikipedia.org/wiki/Propranololhttp://en.wikipedia.org/wiki/Portal_hypertensionhttp://en.wikipedia.org/wiki/Phaeochromocytomahttp://en.wikipedia.org/wiki/Neuromuscular_junctionhttp://en.wik