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Sympathetic (Adrenergic) Drugs (Sympathomimetic Agents)

Catecholamines, the transmitters in sympathetic POSTganglionic neurons and the adrenal medulla.

OH (para)

OH (meta)

C

C

N

Catechol

Ethylamine

The transmitter in all adrenergic neurons is Norepinephrine (NE)

When NE and Epinephrine (Epi) interact with an adrenoceptor, in some tissues the response is excitatory while in other tissues it is inhibitory

• Two Families:

– Alpha () and Beta () – Based on affinity to

adrenergic agonists

- affinity: • Epi≥ NE>> isoproteranol

- affinity: • Isoproteranol> Epi> NE

CH

OH

NH

HO

HO

CH

OH

NH2HO

HO

CH

OH

NH

HO

HO

Epi NE Isoprenaline

Epinephrine Norepinephrine Isoproteranol

Epinephrine Norepinephrine Isoproteranol

Adrenergic Receptors

Adrenergic receptors locate on smooth muscle, cardiac muscle, exocrine glands, endocrine glands and on nerve terminals.

-Adrenoceptor

H-Bonding

region

H-Bonding

region

H-Bonding

region Van der Waals

bonding region

Ionic

bonding

region

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ADRENALINE

-Adrenoceptor

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-Adrenoceptor

ADRENALINE

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- excitatory in most tissues

(except - intestinal smooth muscle)

- inhibitory in most tissues

(except – heart)

• Generally

1 ---Contraction of smooth muscle

2 ---Relaxation of smooth muscle

1 ---Stimulation in heart

2 ---Inhibition, for GI tract ---Relaxation

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SUMMARY OF ADRENERGIC RECEPTOR ACTION

RECEPTOR

LOCATION

AGONIST

ANTAGONIST

1

blood vessels

vasoconstriction (treat hypotension)

vasodilation (treat hypertension)

2

blood vessels pre-synaptic membranes in adrenergic nerves

Mixed effect vasoconstriction

(treat hypotension) inhibits NE release

Decreases sympathetic outflow (vasodilation) (treat hypertension

vasodilation (treat hypertension)

vasodilates and prevent reflex tachycardia

(treat hypertension)

1

heart

increases heart rate (treat heart failure)

slows heart rate (treat hypertentsion, angina, arrhythmia)

2

bronchiole smooth muscle arterioles

bronchodilation (treat asthma etc...) vasodilation

bronchoconstriction

vasoconstriction

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CATECHOLAMINE BIOSYNTHESIS

tyrosine

dopamine

norepinephrine

epinephrine

tyrosine

hydroxylase*

dopamine

hydroxylase

Phenyl-N-methyl-

transferase

Dopa Aromatic

amino acid

decarboxylase

* rate limiting step

dopamine

Synthesis of catecholamines

• The regulatory step in catecholamine synthesis is the conversion of tyrosine by tyrosine hydroxylase into the catecholamine, deoxyphenylalanine (i.e. DOPA). A catecholamine is a substance with two hydroxyl moieties (-OH) connected to an aromatic ring.

• DOPA decarboxylase removes the carboxylic acid from the side chain carbon with the amino group to form dopamine.

• Dopamine is taken up into the vesicle and converted into norepinephrine by dopamine β-hydroxylase. This conversion occurs within the neurotranmitter vesicle.

• In the adrenal medulla there is a fourth enzyme, phenylethanolamine N-methyltransferase (or PNMT). PNMT converts norepinephrine to epinephrine by adding a methyl (-CH3) group to the terminal carbon.

Once synthesized, these neurotransmitters are sequestered in synaptic vesicles and released up neuronal activation.

CATECHOLAMINE INACTIVATION

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NE

EPI

EPI EPI

NE

NE

DA

DA

DA

NET= NorEpinephrine Transporter

DAT = Dopamine Transporter

NE NET

DAT DA

DA

NE NE

NE

NE

NE

NE

NE

Inactive

metabolites

NE NE

Inactive

metabolites

Catechol-O-Methyl-

Transferase (COMT)

*

*

* = most important!

MonoAmine

Oxidase (MAO)

DA

DA

NE NE

NE

NE

NE

NE

DA

DA

NE NE

NE

NE

NE

NE

DA

DA

NE NE

NE

NE

NE

NE

DA

DA

NE NE

NE

NE

NE

NE

DA

DA

NE NE

NE

NE

NE

NE

The catecholamines are metabolized by two enzymes: Monoamine oxidase (MAO) and Catechol-O-methyl transferase (COMT). MAO is largely associated with mitochondria in the neuron, and so can alter the amount of monoamine in the nerve terminal. COMT is located extracellularly on membranes.

Metabolic Inactivation of NE and Epi

CHCH2 NHRHO

HO

OH

MAOCHCHOHO

HO

OH

Aldehyde dehydrogenase

CHCOOHHO

HO

OHCOMT

CHCOOHHO

H3CO

OH

Vanilyl mandelic acid

If R= H, NoradrenalineR= CH3, Adrenaline

CHCH2 NHRHO

HO

OH

MAO

CHCHOHO

H3CO

OHAldehydedehydrogenase

COMT

CHCOOHHO

H3CO

OH

Vanilyl mandelic acid

If R= H, NoradrenalineR= CH3, Adrenaline

CHCH2 NHRHO

H3CO

OH

• By chemistry – Catecholamines –Non-catecholamines

• By mode of action –Direct acting – Indirect acting –Dual/Mixed acting

• By selectivity (to types of receptor)

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Classification of Sympathomimetics

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1. Direct-acting agonists

• bind to and activate 1, 2, 1 and 2 receptors.

• Naturally-occurring molecules which bind to these receptors include:

• NE (binds to 1, 2 and 1 receptors),

• Epi (a hormone produced in and secreted from the adrenal medulla which binds to 1, 2, 1 and 2 receptors -- Epi is a non-selective adrenergic agonist)

• Dopamine (DA; also a neurotransmitter which binds to DA receptors as well as 1, 2 and 1 receptors ).

2. Indirect-acting adrenergic agonists produce NE-like actions by stimulating NE release and preventing its re-uptake and thus its inactivation. By preventing NE inactivation, these drugs allow NE to linger in adrenergic synpases. (e.g. amphetamines and cocaine)

3. Dual-acting adrenergic agonists act as a direct- and an indirect-adrenergic agonists (hence dual-acting) - they bind to adrenergic receptors and stimulate NE release. (e.g. ephedrine)

NH

OH

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1. Direct-acting Sympathomimetics

They are phenethylamine derivatives that contain the appropriate substitution to impart direct receptor-activating capabilities.

Epinephrine (Adrenaline)

CH

OH

NH

HO

HO

*

(-)-1-(3,4-Dihydroxyphenyl)-2-methylaminoethanol

The levorotatory isomer of Epi has about 12 times the activity of dextro-form & 15 times the racemic mixture

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Synthesis

HO

HO

ClCH2COCl

POCl3 or ZnCl2

C

O

HO

HO

CH2Cl1. CH3NH2

2. Al/Hg or H2/PtEpi

The racemic mixture resolved by preparing the (+) tartaric acid salts then the diasteroisomeric salts separated by fractional crystallization.

Assay:

1. Non Aq. Titration

Catechol

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Epinephryl borate

CH

OH

NH

O

O

BONa

Used topically for treatment of glaucoma.

Dipivefrine.HCl

CH

OH

NH

O

O

O

O

Pivalic acid ester of Epi, prodrug, more lipophilic with enhanced eye penetration. Used topically for treatment of glaucoma.

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Norepinephrine (Noradrenaline)

CH

OH

NH2HO

HO

(-) 2-Amino-1-(3,4-dihydroxyphenyl)ethanol

Assay:

1. Non Aq. Titration

It is used as a bitartrate salt principally to support blood pressure in various acute hypotensive state specially in myocardial shock.

CH

OH

NH

HO

HO

Isoprenaline Sulfate (Isoproterenol Sulfate)

1-(3,4-Dihydroxyphenyl)-2-isopropylaminoethanol sulfate

It has strong β1- and β2-agonist activities but lacks α-activity

Used mainly in bronchial asthma by sublingual, parenteral or inhalation routs

Metabolized by COMT and slowly metabolized by MAO

Non-Selective β Agonists

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Isoxsuprine (X = O) Nylidrin (X = CH2)

CH

OH

NH

HO X

They are direct acting slightly selective β2 agonists with less pronounced effect on the heart.

Nylidrin improves peripheral circulation so it is used in peripheral vascular diseases (In PVD there is a

narrowing of veins and arteries that supply the arms, legs, and organs

located below your stomach because of arteriosclerosis).

Isoxsuprine is used to relax the uterus in dysmenorrhea.

Selective β2 Agonists

Metaproterenol

CH

OH

NH

HO

HO

(±)-1-(3,5-Dihydroxyphenyl)-2-isopropylaminoethanol

More effective orally with longer duration of action compared to isoproterenol

Not Metabolized by COMT but slowly metabolized by MAO

Used orally or inhalation for treatment of bronchial asthma.

Terbutaline (Bricanyl)

CH

OH

NH

HO

HO

It is a selective β2 agonist indicated as a bronchodilator for bronchial asthma & to relieve bronchospasms associated with bronchitis.

Not Metabolized by COMT but slowly metabolized by MAO

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Albuterol (Salbutamol, Ventolin®)

CH

OH

NH

HO

HO

It is used to relieve bronchospasms associated with bronchitis and a bronchodilator for bronchial asthma.

Not Metabolized by COMT but slowly metabolized by MAO. So, It has a long duration of action

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-Adrenoceptor

H-Bonding

region

H-Bonding

region

H-Bonding

region Van der Waals

bonding region

Ionic

bonding

region

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ADRENALINE

-Adrenoceptor

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-Adrenoceptor

ADRENALINE

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SALBUTAMOL

-Adrenoceptor

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-Adrenoceptor

SALBUTAMOL

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SALBUTAMOL

-Adrenoceptor

Isoetharine

CH

OH

NH

HO

HO

Metabolized by COMT but slowly metabolized by MAO.

It is a short duration selective β2 agonist. It relaxes uterine and bronchiolar smooth muscles.

Ritodrine

HO

HN

OH

OH

It is a selective β2 agonist.

It relaxes uterine and bronchiolar smooth muscles.

It is used to control premature labor and to reverse fetal distress caused by excessive uterine activity.

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Salmeterol

HO

HO

HN

OH

O

It is a more recently developed selective β2

agonist with an extended duration of action.

It is used to relieve bronchospasms associated with bronchitis and a bronchodilator for bronchial asthma.

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Selective -Agonists

Phenylepherine NHCH3

OH

OH

H

It is the prototypical selective direct-acting 1

agonist. It is potent vasoconstrictor and is active orally with a duration of action twice that of Epi.

It is used as mydriatic, in spinal anesthesia and in treatment of severe hypotension due to shock or drug administration.

OCH3

OCH3

NH2

OH

CH3

Methoxamine

It is selective direct-acting 1 agonist.

It has no stimulating effect on the heart or CNS.

It is less potent than phenylephrine as a vasoconstrictor.

It is used during surgery to maintain adequate arterial blood pressure especially in conjugation with spinal anesthesia.

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Imidazoline Derivatives

They are partial agonists at both 1- and α2-receptors.

They are used for their vasoconstrictive effects as nasal decongestant.

They have limited access to the CNS as they exist in an ionized form at physiological pH . They have the following general structure:

NH

N

R

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Naphazoline HCl

NH

N

2-(1-Naphthylmethyl)-2-imidazoline

Tetrahydrozoline HCl

2-(1,2,3,4-Tetrahydro-1-naphthyl)-2-imidazoline HCl

Used as nasal decongestant.

Used as nasal decongestant.

Xylometazoline HCl

NH

N

2-(4-tert-Butyl-2,6-dimethylbenzyl)-2-imidazoline HCl

Its duration of action is 4-6 hrs. Used as nasal decongestant.

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Clonidine HCl NH

HN

N

Cl

Cl

It is a (phenylimino)imidazolidine derivative that possesses selectivity for 2-adrenergic receptor. It produces vasodilation by inhibiting the release of noradrenaline.

It is used mainly in treatment of hypertension.

Selecte 2-agonist

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Methyldopa

A phenethylamine derivative (-methylnorepinephrine) that shows selectivity toward the 2 receptor.

CH2

CO2H .1.5 H2O

HO

HO

H2N

CH3

The presence of an -methyl group in correct configuration on the phenethylamine moiety results in enhanced selectivity toward the 2 receptor. -Methylnorepinephrine is not given as a drug, it is the metabolic product of the drug Methyldopa.

Selecte 2-agonist

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CH2

CO2H

HO

HO

H2N

CH3

CH2

CO2Et

HO

HO

H3N

CH3

Cl

Methyldopate

Esterases

Methyldopa

L-Aromatic AminoAcid Decarboxylase

CH2

H

HO

HO

H2N

CH3

-Methyldopamine

Dopamine-Hydroxylase

C

HHO

HO

H3C

NH2

OH

H

1R,2S) -Methylnorepinephrine

1

2

Methyldopa is used only by oral administration since its zwitterionic character limits its solubility. However, the ester HCl salt was developed as highly water soluble salt. -Methylnorepinephrine acts on 2 receptors in the CNS by the same manner as clonidine to decrease sympathetic outflow and lower pressure (BP).

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2. Indirect-acting Sympathomimetics

They act indirectly by releasing NE. They enter the nerve ending by way of the active uptake process and displace NE from its storage granules.

Amphetamine NH2

(±)-α-Methylphenethylamine

It is used mainly as CNS stimulant.

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Hydroxyamphetamine NH2

HO

(±)-2-(4-Hydroxyphenyl)isopropylamine

– Elimination of one phenolic OH group leads to a significant decrease in activity which is more pronounced on β – than α– receptors.

– It is used as ophthalmic adrenergic drug in combination with atropine (mydriatic).

– It has no action on CNS & used to correct the hypotension associated with spinal anaesthesia.

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Pseudoephedrine

– It is the (S,S)-diastereoisomer of Ephedrine (threo- diastereomer).

NHCH3

OH

– Pseudoephedrine is much less potent than ephedrine due to the way of interaction with the receptor site.

– It is used as nasal decongestants .

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Propylhexedrine

HN

(±)-N,α-Dimethylcyclohexaneethanamine

– It is the cyclohexyl analogue of amphetamine.

– It has ½ the pressor effect of amphetamine, devoid of central excitatory effect and addiction liability. – Its major use by inhalation is for a local vasoconstrictive effect on nasal mucosa for symptomatic relief of nasal congestion.

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3. Dual-Acting Sympathomimetics

– They are phenylethylamine derivatives and usually have no hydroxyls on the aromatic ring but do have a β-hydroxyl gr.

– They act as a direct- and an indirect-adrenergic agonists.

Ephedrine

Erythro (-)-2-methylamino-1-phenyl propan-1-ol

[R-(R*,S*)]-α-[1-(methylamino)ethyl]benzenemethanol

(R)

(S) NHCH3

OH

– Its pressor action and local vasoconstrictive effects are of greater duration than Epi

– It has a pronounced CNS stimulation and is effective orally and systematically

– It is used for asthma, urticaria, low BP and narcolepsy

People with narcolepsy experience excessive

daytime sleepiness and intermittent,

uncontrollable episodes of falling asleep during

the daytime. These sudden sleep attacks may

occur during any type of activity at any time of

the day.

CH

OH

HC

NH

CH3

CH3

Ph

HC OH

HC

CH3

NHCH3

Ph

CHHO

CH

CH3

H3CHN

Ph

CH

HC

CH3

NHCH3

HO

Ph

HC

CH

CH3

H3CHN

OH

Ephedrine

D(-) Ephedrine L(+) Ephedrine

D(-) Pseudoephedrine L(+) Pseudoephedrine

(mp = 40oC, []D = -6o)

(mp = 76oC, []D = -50o)

Isomer Relative Activity

D (-) Pseudoephedrine

DL Pseudoephedrine

L (+) Pseudoephedrine

L (+) Ephedrine

DL Ephedrine

D (-) Ephedrine

1

4

7

11

26

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– Enantiomers: Optical isomers which are mirror images

– Diastereoisomers: Optical isomers which are not mirror images

– Racemates: Mixture of equal parts of enantiomers

Pressor activities of ephedrines

C

H2C

N+

H3C

H

H

H

OH

OH

OH

XAnionicsite

FlatArea

Receptor

(-)-Epinephrine - more active- Ephedrine (more active)

Stereochemistry

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Phenyl propanolamine HCl (Norephedrine)

NH2

OH

(±) Norephedrine

It is the 1o amine corresponding to ephedrine.

It has a slightly higher vasoconstrictive effect with lower toxicity.

It is used as prolonged nasal decongestive agent.

-phentolamine

12

3

4 5

6

R1 R2 R3

CH CH NH

R4 R5

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

CH3

CH3

CH3

CH3

ISOPROPYL

CH3

CH3

NOREPINEPHRINE

EPINEPHRINE

ISOPROTERENOL

DOPAMINE

PHENYLEPHRINE

METARAMINOL

EPHEDRINE

OCTOPAMINE

TYRAMINE

AMPHETAMINE

D

I

R

E

C

T

M

I

X

E

D

I

N

D

I

R

E

C

T

Catechol (orto-dihydroxybenzene) + an amino group on the side chain

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Adrenergic Receptors Antagonists

α-Blockers

– They are either competitive or noncompetitive.

– They are used in peripheral vascular diseases.

– They are classified into the following categories:

1. Ergot and ergot alkaloids. 2. Yohimbine. 3. β-Haloalkylamines (Noncompetitive) 4. Imidazoline derivatives

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β-Haloalkylamines – They produce a slowly developing, prolonged adrenergic blockade that is not overcome by massive doses of Epi or NE.

Phenoxybenzamine

– Its action is described as a “Chemical Sympathectomy”.

– It has a slow onset of action but its effect may last 3-4 days till the formation of new receptors that replace those that have been irreversibly inhibited.

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– It is used for preoperative management of pheochromocytoma (pheochromocytoma is a tumor of the adrenal medulla gland, that secretes high amounts of catecholamines, mostly norepinephrine that cause persistent or episodic high blood pressure.).

N+

CH3

O

Alpha receptor

N Cl

CH3

O

N

CH3

O

alpha rec.

• Mode of action:

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Imidazoline derivatives

Tolazoline HCl

N

HN

4,5-Dihydro-2-(phenylmethyl)-1H-imidazole

– It is used as:

1. A vasodilator (histamine like activity) in treatment of peripheral vascular disorders.

2. Diagnosis of pheochromocytoma

3. In persistent pulmonary hypertension of the new born

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Phentolamine Mesylate

N

HN

NHO

It is a potent adrenergic blocking agent. Uses:

1. Pheochromocytoma. Acute hypertensive crisis.

2.Treat necrosis due to vasoconstrictors

Synthesis of Phentolamine:

3-(4-methylanilino)phenol

2-chloromethylimidazoline

Phentolamine

Selective 1-Blockers

N

NH3CO

H3CO

N

N R

O

NH2

Quinazoline ring

Piprazine ring

Acyl moiety

R Gen. Name

O

Prazosin

O

Terazosin

O

O

Doxazosin

Furan

Tetrahydrofuran

Benzo-1,4-dioxane

Clinical Uses:

– Hypertension

– Benign prostatic hypertrophy - reverses smooth muscle contraction –(Benign prostatic hyperplasia (BPH) is an

enlarged prostate gland . The prostate gland surrounds

the urethra, the tube that carries urine from

the bladder out of the body. As the prostate gets bigger,

it may squeeze or partly block the urethra. This often

causes problems with urinating). Prazosin improves urine

flow rates by relaxing smooth muscle. Relaxation is

produced by blocking alpha-1 adrenoreceptors in the

bladder neck and prostate.

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• In the 1950’s , a derivative of isoproterenol in which the catechol hydroxyls had been replaced by chlorines, dichloroisoproterenol (DCI), was discovered to be a - antagonist, although it had no clinical utility.

Receptor Antagonists ( Blockers)

• Replacement of the 3,4,-dichlolor substituents with a carbon bridge gave the drug clinical utility, giving rise to Pronethanol.

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• It was found shortly thereafter that an oxymethylene bridge, OCH2 could be inserted into the arylethanolamine structure of pronethalol to give propranolol, an aryloxypropanolamine and the first clinically successful β-blocker.

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Propranolol

Nonselective Blockers

1-Isopropylamino-3-(1-naphthyloxy)-propan-2-ol

– It is the prototype non-selective competitive antagonist at both 1 and 2 receptors.

– Relatively high lipid solubility allows distribution to the CNS (some drowsiness)

O

NH

HO

OH

O

Cl+

O

O

NH2

Propranolol

-Naphthol Epichlorohydrine

Synthesis:

Major Metabolites:

O

NH

HO

Propranolol 4-hydroxypropranolol

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Clinical Uses

1. Angina pectoris. Reduces cardiac work and O2 consumption.

2. Hypertension.

3. Migraine headache (Prophylactic treatment)

4. Cardiac Arrhythmias

5. Pheochromocytoma

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β Blockers :

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Nonselective antagonists

1-Selective antagonists

Propranolol Metoprolol

Nadolol Atenolol

Timolol Esmolol

Pindolol Acebutalol

Labetolol

Carvedilol

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Selective 1 Blockers (Cardioselective)

Atenolol

NH2

O NH

OH

O

– It is the prototype Selective 1 Blockers

– Its half-life is twice that of propranolol

– It is used in hypertension, angina pectoris associated with coronary atherosclerosis and acute myocardial infarction.

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Esmolol

O NH

OH

O

O

– Very rapid onset & short duration of action – 1-selective – Used as IV infusion for pre-operative tachycardia and hypertension, arrhthymias – Used in electroconvulsive therapy

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Aryloxypropanolamines

SAR

1. The nature of substituents on the aromatic ring determines whether the effect is predominantly activation or blockade 2. Para-substitution on the aromatic ring typically confers β1 selectivity

3. Bulky aliphatic groups (tert-butyl, iso-propyl) on the amino function are requested for antagonistic activity. 2o amine is essential for optimum activity.

O

NH

HO

4. β-blockers have a high degree of stereoselectivity. The configuration of the hydroxy bearing carbon must be (S)- for optimal affinity. (R)-isomer is 100 times less potent than the (S)- one

Reserpine • Reserpine almost irreversibly blocks the uptake (and

storage) of noradrenaline and dopamine into synaptic vesicles by inhibiting the Vesicular Monoamine Transporters (VMAT).

• In so doing, it leaves the noradrenaline in the cytoplasm, where it is destroyed by monamine oxidase (MAO). The end result is the depletion of NE in the sympathetic neuron.

• It was once used to treat hypertension, but has many side effects, including depression, stomach cramps, diarrhoea, etc.

NH

N

O

OOCH3

OCH3

OCH3

CH3O2C

CH3OH

H

H

OCH3