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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%23Indirect

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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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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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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.

http://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htm

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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

http://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/angina.htmhttp://en.wikipedia.org/wiki/Endogenoushttp://en.wikipedia.org/wiki/Catecholaminehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Adrenergic_receptorhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Fight_or_flighthttp://en.wikipedia.org/wiki/Chronotropichttp://en.wikipedia.org/wiki/Inotropichttp://en.wikipedia.org/wiki/Smooth_musclehttp://en.wikipedia.org/wiki/Vasodilationhttp://en.wikipedia.org/wiki/Bronchodilationhttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Glycogenolysishttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Lipolysishttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Glycogenhttp://en.wikipedia.org/wiki/Antihypertensivehttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/angina.htmhttp://en.wikipedia.org/wiki/Endogenoushttp://en.wikipedia.org/wiki/Catecholaminehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Adrenergic_receptorhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Fight_or_flighthttp://en.wikipedia.org/wiki/Chronotropichttp://en.wikipedia.org/wiki/Inotropichttp://en.wikipedia.org/wiki/Smooth_musclehttp://en.wikipedia.org/wiki/Vasodilationhttp://en.wikipedia.org/wiki/Bronchodilationhttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Glycogenolysishttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Lipolysishttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Glycogenhttp://en.wikipedia.org/wiki/Antihypertensive

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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-pmid10335905

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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-pmid12173717

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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_barrier

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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/Nadolol

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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/Butaxamine

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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/Propranolol

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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