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ADRENERGIC DRUGSADRENERGIC DRUGS

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Basic plan of the mammalian Basic plan of the mammalian autonomic nervous systemautonomic nervous system

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Synthesis, action and fate of Synthesis, action and fate of norepinephrinenorepinephrine

TyrosineTyrosine is transported into the is transported into the axoplasm (A) and is converted to axoplasm (A) and is converted to DOPADOPA and then to and then to dopaminedopamine (DA). DA is transported into the (DA). DA is transported into the vesicles of the varicosity, where vesicles of the varicosity, where the synthesis and the storage of the synthesis and the storage of norepinephrinenorepinephrine (NE) take place (NE) take place (C). (C).

An action potential causes an An action potential causes an influx of Cainflux of Ca2+2+ into the nerve into the nerve terminal (not shown) with terminal (not shown) with subsequent exocytosis of NE (D). subsequent exocytosis of NE (D).

The NE activates The NE activates - - and and --adrenergic receptorsadrenergic receptors in the in the membrane of the postsynaptic cell membrane of the postsynaptic cell (E). NE that penetrates into these (E). NE that penetrates into these cells (cells (uptake 2uptake 2) probably is rapidly ) probably is rapidly inactivated by inactivated by catechol-O-catechol-O-methyltransferasemethyltransferase (COMT) (COMT) to to normetanephrine (NMN). The most normetanephrine (NMN). The most important mechanism for important mechanism for termination of the action of NE in termination of the action of NE in the junctional space is active the junctional space is active reuptake (reuptake (80%80%) into the nerve ) into the nerve ((uptake 1uptake 1) and the storage ) and the storage vesicles (F).vesicles (F).

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Byosynthesis of catecholaminesByosynthesis of catecholamines

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Types of adrenergic receptorsTypes of adrenergic receptors

Receptor Typical location

1 Postsynaptic effector cells, especially smooth muscles

2, Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle

1 Postsynaptic effector cells, especially heart; lypocytes, brain, juxtaglomerular cells of the kidney

2 Presynaptic noradrenergic nerve terminals,

Postsynaptic effector cells, especially smooth muscle, cardiac muscle

3 Postsynaptic effector cells, especially lypocytes

-adreoreceptor’s subtypes:1A, 1B, 1D and 2A, 2B, 2C

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G proteinG protein--coupled receptor – molecular coupled receptor – molecular modelmodel

NE

-AR+

2-AR+

1-AR+

Gs-protein+

Gi- protein-

Gq- protein+

Adenylyl cyclase

Adenylyl cyclase

Phospholypase C

cAMP cAMP

IP3 DAG

Protein kynases

Interaction between epinephrine and the β2-adrenoceptor

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Characteristics ofCharacteristics of adrenoreceptorsadrenoreceptors

## Tissue and organ Receptor Effect

11 Skin, kidney vessels 1,2, constrict

22 Vessels of skeletal muscles, liver, and coronary vessels

2 dilation

33 Veins 1А constriction

44 Heart 1 increase of rate and force of contraction

55 Bronchi 1

2

constrictiondilation

66 Iris (radial musscle) 1 contract midriasis

77 GI- smooth musscle- sphincters

1,2,2

1

relaxationcontraction

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## Tissue and organ Receptor Effect

88 Uterus- myometrium- sphincters

2

1

relaxationcontraction

99 Bladder sphincter 1А contraction

1010 Juxtaglomerular cells of the kidney

1 2 increase of rennin secretion

1111 Splin capsule 1 contract

1212 Pancreatic islets 2 decrease of insulin secretion

1313 Platelets 2 aggregation

1414 Liver 1, 2 glycogenolysis

1515 Fat 3 lipolysis

Characteristics ofCharacteristics of adrenoreceptorsadrenoreceptors

Effect of adrenoreceptors stimulation The stimulation of certain postsynaptic

adrenoreceptors is associated with effects that are typical for their activation

The stimulation of -adrenorecetrors leads to an increase of the effectors function (except for the intestine)

The stimulation of -adrenorecetrors usually leads to a decrease in the innervated organ function (except for the heart)

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Classification of adrenergic drugsClassification of adrenergic drugs

ADRENORECEPTOR STIMULANTS

Direct acting(receptor agonists)

Indirect acting(sympathomimetics)

1. ,- adrenomimics - epinephrine (1,2,1,2)

- norepinephrine (1,2,1)

2. - adrenomimics- methoxamine (1,2)

- phenylephrine (1)

- clonidine (2)

- sanorin (2)

3. - adrenomimics- isoprenaline (1,2)

- dobutamine (1)- salbutamol, terbutaline,

fenoterol, salmeterol (2)

- tyramine- amphetamine- ephedrine

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Classification of adrenergic drugsClassification of adrenergic drugs

ADRENORECEPTOR ANTAGONISTS

Direct acting

(receptor antagonists)

Indirect acting

(Sympatholytics)

1. -adrenoblockers - phentolamine,

phenoxybenzamine (1,2)

- prazosin (1)

- tamsulosin (1A)

- yohimbine (2)

2. - adrenoblockers- propranolol (1,2)

- metoprolol, atenolol, (1)

3. ,- adrenoblockers

- labetalol (1,1,2)

- reserpine- guanethidine (octadine)

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Pharmacologic action of epinephrinePharmacologic action of epinephrine

1

2

vessels

1

vagus1. is due to 1 AR activation

(cause ventricular contraction)

2. is due to vagal discharge3. is due to 1 AR stimulation

(cause vasoconstriction)4. is due to 2 (vasodilator)-

receptors activation

Effects on the heart produced by epinephrine include:Slight initial increase in heart rate (1-receptors)Increased stroke volumeIncreased cardiac outputA propensity toward arrhythmias

Effects on smooth muscle include:Bronchiolar smooth muscle relaxes (2).Gastrointestinal smooth muscle relaxes (2- and -receptor

stimulation)Sphincter contraction (- stimulation),

Metabolic effects of epinephrine include: Hyperglycemia via liver and muscle glycogenolysisInhibition of insulin secretion (1)An increase in free fatty acids

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Clinical application of epinephrine Clinical application of epinephrine

It’s used only parenterally (S.C., I.M., rarely I.V.) and It’s used only parenterally (S.C., I.M., rarely I.V.) and local I.V. effect lasts for local I.V. effect lasts for 5` whereas S.C. – up to 30` 5` whereas S.C. – up to 30`

Clinical usageClinical usage severe bronchospasm, anaphylaxis (primary treatment severe bronchospasm, anaphylaxis (primary treatment

for anaphylactic shock)for anaphylactic shock) severe hypotensionsevere hypotension cardiogenic shockcardiogenic shock AV block and cardiac arrestAV block and cardiac arrest nasal decongestantnasal decongestant ophthalmic vasoconstrictor and mydriaticophthalmic vasoconstrictor and mydriatic chronic open-angle glaucomachronic open-angle glaucoma to prolong the duration of anesthesia in conjunction with to prolong the duration of anesthesia in conjunction with

local anestheticlocal anesthetic Unwanted effectsUnwanted effects

anxiety, headacheanxiety, headache can precipitate angina, myocardial infarction (can precipitate angina, myocardial infarction ( cardiac cardiac

work)work) arrhythmiasarrhythmias

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Clinical application of Clinical application of norepinephrinenorepinephrine Clinical usageClinical usage

severe hypotensionsevere hypotension septic shockseptic shock

Unwanted effectsUnwanted effects can precipitate angina, can precipitate angina,

myocardial infarction (myocardial infarction ( cardiac cardiac work)work)

arrhythmiasarrhythmias If extravasates, can cause tissue If extravasates, can cause tissue

necrosisnecrosis

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Clinical application of Clinical application of sympathomimeticssympathomimetics Ephedrine is used:Ephedrine is used:

In the treatment of bronchial In the treatment of bronchial asthmaasthma

As a nasal decongestantAs a nasal decongestant As a pressor agent in spinal As a pressor agent in spinal

anesthesiaanesthesia As a mydriaticAs a mydriatic

Adverse effectsAdverse effects These are similar to the These are similar to the

adverse effects seen with adverse effects seen with epinephrine.epinephrine.

In addition, CNS effects may In addition, CNS effects may occur.occur.

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11-stimulating drugs-stimulating drugs

Phenylephrine (mesatone) Phenylephrine (mesatone) ((11))

severe hypotensionsevere hypotension nasal decongestantnasal decongestant to prolong the duration of anesthesia in to prolong the duration of anesthesia in

conjunction with local anestheticconjunction with local anesthetic open-angle glaucomaopen-angle glaucoma

Naphazoline (naphtizine)Naphazoline (naphtizine), , xylometazolinexylometazoline ( (22))

nasal decongestantnasal decongestant oral cavity surgeryoral cavity surgery

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11-stimulating bronchodilators-stimulating bronchodilators

Dobutamine is used Dobutamine is used to improve myocardial function in congestive heart to improve myocardial function in congestive heart

failure (it causes minimal changes in heart failure (it causes minimal changes in heart rate rate

and systolic pressure).and systolic pressure).

Adverse effectsAdverse effects Dobutamine increases atrioventricular conduction Dobutamine increases atrioventricular conduction

and must, therefore, be used with caution in atrial and must, therefore, be used with caution in atrial

fibrillation.fibrillation. Other adverse effects are similar to those of other Other adverse effects are similar to those of other

catecholamines.catecholamines.

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22-stimulating bronchodilators-stimulating bronchodilators

such as salbutamol, terbutaline, such as salbutamol, terbutaline,

fenoterol, salmeterol, albuterolfenoterol, salmeterol, albuterol

are used therapeutically for are used therapeutically for

the treatment of bronchial the treatment of bronchial

asthma or bronchospasmasthma or bronchospasm

they are chiefly used as they are chiefly used as

aerosol inhalantsaerosol inhalants

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Clinical application of antiadrenergic Clinical application of antiadrenergic agentsagents -ADRENOBLOCKERS-ADRENOBLOCKERS

Phentolamine (Phentolamine (11, , 22)) has been used to control acute hypertensive has been used to control acute hypertensive

episodes caused by use of sympathomimetics.episodes caused by use of sympathomimetics.

Tolazoline (Tolazoline (11, , 22)) can be used in the treatment of neonates with can be used in the treatment of neonates with

persistent pulmonary hypertension, despite use of persistent pulmonary hypertension, despite use of

oxygen therapy and mechanical ventilation.oxygen therapy and mechanical ventilation. has been used experimentally to relieve has been used experimentally to relieve

vasospasm and in the treatment of Raynaud's vasospasm and in the treatment of Raynaud's

phenomenon.phenomenon.

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Clinical application of antiadrenergic Clinical application of antiadrenergic agentsagents -ADRENOBLOCKERS-ADRENOBLOCKERS Prazosin (Minipress) (Prazosin (Minipress) (11))

HypertensionHypertension PheochromocytomaPheochromocytoma Benign prostatic hyperplasiaBenign prostatic hyperplasia Treatment of Raynoud’s phenomenon Treatment of Raynoud’s phenomenon

(vasospasm(vasospasmdigital ischemia)digital ischemia)

Terazosin (Hytrin) and Doxazosin (Cardura) Terazosin (Hytrin) and Doxazosin (Cardura) ((11)) Benign prostatic hyperplasiaBenign prostatic hyperplasia

Tamsulosin (Omnik, Flomax) (Tamsulosin (Omnik, Flomax) (1A1A)) Benign prostatic hyperplasiaBenign prostatic hyperplasia

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Clinical application of antiadrenergic Clinical application of antiadrenergic agentsagents -ADRENOBLOCKERS-ADRENOBLOCKERS Propranolol (Inderal, Anaprilin) (Propranolol (Inderal, Anaprilin) (11, , 22))

ischemic heart diseaseischemic heart disease hypertensionhypertension Aortic dissectionAortic dissection arrhythmiasarrhythmias portal hypertension portal hypertension migrane preventionmigrane prevention

Side effectsSide effects sinus bradicardiasinus bradicardia AV blockAV block hypotensionhypotension fatique, depressionfatique, depression impotence, impotence, libido libido may precipitate bronchospasmmay precipitate bronchospasm

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Clinical application of antiadrenergic Clinical application of antiadrenergic agentsagents -ADRENOBLOCKERS-ADRENOBLOCKERS Metoprolol (Lopressor) (Metoprolol (Lopressor) (11))

Ischemic heart diseaseIschemic heart disease HypertensionHypertension Aortic dissectionAortic dissection ArrhythmiasArrhythmias Hypertrophic cardiomyopathyHypertrophic cardiomyopathy

Side effectsSide effects are similar to those of propranololare similar to those of propranolol

Drugs affecting NE synthesis and releaseDrugs affecting NE synthesis and release

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Clinical application of antiadrenergic Clinical application of antiadrenergic agentsagents Drugs affecting NE synthesis and releaseDrugs affecting NE synthesis and release Reserpine (a rauwolfia alkaloid)Reserpine (a rauwolfia alkaloid)

It acts via catecholamine depletion. It inhibits the It acts via catecholamine depletion. It inhibits the uptake of norepinephrine into vesicles, and uptake of norepinephrine into vesicles, and intraneuronal degradation of norepinephrine by intraneuronal degradation of norepinephrine by MAO then occurs. This action takes place both MAO then occurs. This action takes place both centrally and peripherally.centrally and peripherally.

Therapeutic use of reserpine is in:Therapeutic use of reserpine is in: the treatment of hypertensionthe treatment of hypertension

Adverse effects include:Adverse effects include: SedationSedation Psychic depression that may result in suicidePsychic depression that may result in suicide Abdominal cramps and diarrheaAbdominal cramps and diarrhea Gastrointestinal ulcerationGastrointestinal ulceration Possible increased incidence of breast carcinomaPossible increased incidence of breast carcinoma

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Clinical application of antiadrenergic Clinical application of antiadrenergic agentsagents Guanethidine (Octadine)Guanethidine (Octadine)

acts presynaptically. It inhibits the release of NE acts presynaptically. It inhibits the release of NE from peripheral adrenergic neurons.from peripheral adrenergic neurons.

It displaces norepinephrine from intraneuronal It displaces norepinephrine from intraneuronal storage granules. storage granules.

Much of the norepinephrine released from the Much of the norepinephrine released from the adrenergic nerve terminals is deaminated by adrenergic nerve terminals is deaminated by intraneuronal MAO. intraneuronal MAO.

Therapeutic useTherapeutic use as a potent, long-acting antihypertensive agent as a potent, long-acting antihypertensive agent

Adverse effects include:Adverse effects include: Postural hypotensionPostural hypotension Syncope, especially with strenuous exerciseSyncope, especially with strenuous exercise DiarrheaDiarrhea EdemaEdema

Guanethidine is contraindicated in patients Guanethidine is contraindicated in patients taking MAO inhibitors.taking MAO inhibitors.

NEXT LECTURENEXT LECTURE

The CNS affecting drugs:The CNS affecting drugs:

Introduction, targets for drug’s Introduction, targets for drug’s

action. Antiepileptics. Drugs for action. Antiepileptics. Drugs for

treatment of Parkinson’s disease.treatment of Parkinson’s disease.

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