adrenergic drugs

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ADRENERGIC DRUGSADRENERGIC DRUGS

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Basic plan of the mammalian autonomicBasic plan of the mammalian autonomic
nervous systemnervous system

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Synthesis, action and fate ofSynthesis, action and fate of
norepinephrinenorepinephrine
 TyrosineTyrosine is transported into the axoplasmis transported into the axoplasm
(A) and is converted to(A) and is converted to DOPADOPA and then toand then to
dopaminedopamine (DA). DA is transported into the(DA). DA is transported into the
vesicles of the varicosity, where thevesicles of the varicosity, where the
synthesis and the storage ofsynthesis and the storage of
norepinephrinenorepinephrine (NE) take place (C).(NE) take place (C).
 An action potential causes an influx of CaAn action potential causes an influx of Ca2+2+
into the nerve terminal (not shown) withinto the nerve terminal (not shown) with
subsequent exocytosis of NE (D).subsequent exocytosis of NE (D).
 The NE activatesThe NE activates αα-- andand ββ-adrenergic-adrenergic
receptorsreceptors in the membrane of thein the membrane of the
postsynaptic cell (E). NE that penetratespostsynaptic cell (E). NE that penetrates
into these cells (into these cells (uptake 2uptake 2 ) probably is) probably is
rapidly inactivated byrapidly inactivated by catechol-O-catechol-O-
methyltransferasemethyltransferase (COMT)(COMT) toto
normetanephrine (NMN). The mostnormetanephrine (NMN). The most
important mechanism for termination of theimportant mechanism for termination of the
action of NE in the junctional space isaction of NE in the junctional space is
active reuptake (active reuptake (80%80%) into the nerve) into the nerve
((uptake 1uptake 1 ) and the storage vesicles (F).) and the storage 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
α1
Postsynaptic effector cells, especially smooth
muscles
α2,
Presynaptic adrenergic nerve terminals,
platelets, lipocytes, smooth muscle
β1
Postsynaptic effector cells, especially heart;
lypocytes, brain, juxtaglomerular cells of the
kidney
β2
Presynaptic noradrenergic nerve terminals,
Postsynaptic effector cells, especially smooth
muscle, cardiac muscle
β3
Postsynaptic effector cells, especially lypocytes
α-adreoreceptor’s subtypes:
α1A, α1B, α1D and α2A, α2B, α2C

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G proteinG protein--coupled receptor – molecularcoupled receptor – molecular
modelmodel
NE
↓
β-AR
+↓
α2
-AR
+↓
α1
-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 α1
,α2,
constrict
22 Vessels of skeletal muscles,
liver, and coronary vessels
β2
dilation
33 Veins α1А
constriction
44 Heart β1
increase of rate
and force of
contraction
55 Bronchi α1
β2
constriction
dilation
66 Iris (radial musscle) α1
contract ⇒
midriasis
77 GI
- smooth musscle
- sphincters
α1
,α2,
β2
α1
relaxation
contraction

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## Tissue and organ Receptor Effect
88 Uterus
- myometrium
- sphincters
β2
α1
relaxation
contraction
99 Bladder sphincter α1А
contraction
1010 Juxtaglomerular cells of the
kidney
β1
β2
increase of rennin
secretion
1111 Splin capsule α1
contract
1212 Pancreatic islets α2
decrease of insulin
secretion
1313 Platelets α2
aggregation
1414 Liver α1,
β2
glycogenolysis
1515 Fat β3
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 α-adrenorecetrors leads
to an increase of the effectors function
(except for the intestine)
 The stimulation of β-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. α,β- adrenomimics
- epinephrine (α1
,α2
,β1
,β2
)
- norepinephrine (α1
,α2
,β1
)
2. α- adrenomimics
- methoxamine (α1
,α2
)
- phenylephrine (α1
)
- clonidine (α2
)
- sanorin (α2
)
3. β- adrenomimics
- isoprenaline (β1
,β2
)
- dobutamine (β1
)
- salbutamol, terbutaline,
- tyramine
- amphetamine
- ephedrine

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Classification of adrenergic drugsClassification of adrenergic drugs
ADRENORECEPTOR ANTAGONISTS
Direct acting
(receptor antagonists)
Indirect acting
(Sympatholytics)
1. α-adrenoblockers
- phentolamine,
phenoxybenzamine (α1
,α2
)
- prazosin (α1
)
- tamsulosin (α1A
)
- yohimbine (α2
)
2. β- adrenoblockers
- propranolol (β1
,β2
)
- metoprolol, atenolol, (β1
)
3. α,
β- adrenoblockers
- labetalol (α1
,β1
,β2
)
- reserpine
- guanethidine (octadine)

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Pharmacologic action of epinephrinePharmacologic action of epinephrine
β1
β2
vessels
α1
vagus
1. is due to β1 AR activation
(cause ventricular contraction)
2. is due to vagal discharge
3. is due to α1 AR stimulation
(cause vasoconstriction)
4. is due to β2 (vasodilator)-
receptors activation
Effects on the heart produced by epinephrine include:
Slight initial increase in heart rate (β1-receptors)
Increased stroke volume
Increased cardiac output
A propensity toward arrhythmias
Effects on smooth muscle include:
Bronchiolar smooth muscle relaxes (β2).
Gastrointestinal smooth muscle relaxes (α2- and β-receptor stimulation)
Sphincter contraction (α- stimulation),
Metabolic effects of epinephrine include:
Hyperglycemia via liver and muscle glycogenolysis
Inhibition of insulin secretion (α1)
An increase in free fatty acids

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Clinical application of epinephrineClinical application of epinephrine
 It’s used only parenterally (S.C., I.M., rarely I.V.) andIt’s used only parenterally (S.C., I.M., rarely I.V.) and
local I.V. effect lasts forlocal 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 forsevere bronchospasm, anaphylaxis (primary treatment for
anaphylactic shock)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 withto 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 work)cardiac work)
 arrhythmiasarrhythmias

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Clinical application ofClinical application of
norepinephrinenorepinephrine
 Clinical usageClinical usage
 septic shockseptic shock
 Unwanted effectsUnwanted effects
 can precipitate angina, myocardialcan precipitate angina, myocardial
infarction (infarction (↑↑ cardiac work)cardiac work)
 If extravasates, can cause tissueIf extravasates, can cause tissue
necrosisnecrosis

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Clinical application ofClinical application of
sympathomimeticssympathomimetics
 Ephedrine is used:Ephedrine is used:
 In the treatment of bronchialIn the treatment of bronchial
asthmaasthma
 As a nasal decongestantAs a nasal decongestant
 As a pressor agent in spinalAs a pressor agent in spinal
anesthesiaanesthesia
 As a mydriaticAs a mydriatic
 Adverse effectsAdverse effects
 These are similar to the adverseThese are similar to the adverse
effects seen with epinephrine.effects seen with epinephrine.
 In addition, CNS effects mayIn addition, CNS effects may
occur.occur.


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αα11 -stimulating drugs-stimulating drugs
 Phenylephrine (mesatone)Phenylephrine (mesatone) ((αα11 ))
 to prolong the duration of anesthesia in conjunctionto prolong the duration of anesthesia in conjunction
with local anestheticwith local anesthetic
 open-angle glaucomaopen-angle glaucoma
 Naphazoline (naphtizine)Naphazoline (naphtizine) ,, xylometazolinexylometazoline ((αα22 ))
 oral cavity surgeryoral cavity surgery

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ββ11 -stimulating bronchodilators-stimulating bronchodilators
 Dobutamine is usedDobutamine is used
 to improve myocardial function in congestive heartto improve myocardial function in congestive heart
failure (it causes minimal changes in heartfailure (it causes minimal changes in heart rate andrate and
systolic pressure).systolic pressure).
 Adverse effectsAdverse effects
 Dobutamine increases atrioventricular conduction andDobutamine increases atrioventricular conduction and
must, therefore, be used with caution in atrialmust, therefore, be used with caution in atrial
fibrillation.fibrillation.
 Other adverse effects are similar to those of otherOther adverse effects are similar to those of other
catecholamines.catecholamines.

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ββ22 -stimulating bronchodilators-stimulating bronchodilators
 such as salbutamol, terbutaline,such as salbutamol, terbutaline,
fenoterol, salmeterol, albuterolfenoterol, salmeterol, albuterol
 are used therapeutically for theare used therapeutically for the
treatment of bronchial asthmatreatment of bronchial asthma
or bronchospasmor bronchospasm
 they are chiefly used as aerosolthey are chiefly used as aerosol
inhalantsinhalants

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Clinical application of antiadrenergicClinical application of antiadrenergic
agentsagents
 αα-ADRENOBLOCKERS-ADRENOBLOCKERS
 Phentolamine (Phentolamine (αα11 ,, αα22 ))
 has been used to control acute hypertensive episodeshas been used to control acute hypertensive episodes
caused by use of sympathomimetics.caused by use of sympathomimetics.
 Tolazoline (Tolazoline ( αα11 ,, αα22 ))
 can be used in the treatment of neonates withcan be used in the treatment of neonates with
persistent pulmonary hypertension, despite use ofpersistent pulmonary hypertension, despite use of
oxygen therapy and mechanical ventilation.oxygen therapy and mechanical ventilation.
 has been used experimentally to relieve vasospasmhas been used experimentally to relieve vasospasm
and in the treatment of Raynaud's phenomenon.and in the treatment of Raynaud's phenomenon.

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agentsagents
 αα-ADRENOBLOCKERS-ADRENOBLOCKERS
 Prazosin (Minipress) (Prazosin (Minipress) ( αα11 ))
 HypertensionHypertension
 PheochromocytomaPheochromocytoma
 Benign prostatic hyperplasiaBenign prostatic hyperplasia
 Treatment of Raynoud’s phenomenonTreatment of Raynoud’s phenomenon
(vasospasm(vasospasm→→digital ischemia)digital ischemia)
 Terazosin (Hytrin) and Doxazosin (Cardura) (Terazosin (Hytrin) and Doxazosin (Cardura) ( αα11 ))
 Tamsulosin (Omnik, Flomax) (Tamsulosin (Omnik, Flomax) ( αα1A1A ))

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agentsagents
 ββ-ADRENOBLOCKERS-ADRENOBLOCKERS
 Propranolol (Inderal, Anaprilin) (Propranolol (Inderal, Anaprilin) ( ββ11 ,, ββ22 ))
 ischemic heart diseaseischemic heart disease
 hypertensionhypertension
 Aortic dissectionAortic dissection
 portal hypertensionportal hypertension
 migrane preventionmigrane prevention
 Side effectsSide effects
 sinus bradicardiasinus bradicardia
 AV blockAV block
 hypotensionhypotension
 fatique, depressionfatique, depression
 impotence,impotence, ↓↓ libidolibido
 may precipitate bronchospasmmay precipitate bronchospasm

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agentsagents
 ββ-ADRENOBLOCKERS-ADRENOBLOCKERS
 Metoprolol (Lopressor) (Metoprolol (Lopressor) ( ββ11 ))
 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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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 theIt acts via catecholamine depletion. It inhibits the
uptake of norepinephrine into vesicles, anduptake of norepinephrine into vesicles, and
intraneuronal degradation of norepinephrine by MAOintraneuronal degradation of norepinephrine by MAO
then occurs. This action takes place both centrally andthen occurs. This action takes place both centrally and
peripherally.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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agentsagents
 Guanethidine (Octadine)Guanethidine (Octadine)
 acts presynaptically. It inhibits the release of NE fromacts presynaptically. It inhibits the release of NE from
peripheral adrenergic neurons.peripheral adrenergic neurons.
 It displaces norepinephrine from intraneuronal storageIt displaces norepinephrine from intraneuronal storage
granules.granules.
 Much of the norepinephrine released from theMuch of the norepinephrine released from the
adrenergic nerve terminals is deaminated byadrenergic nerve terminals is deaminated by
intraneuronal MAO.intraneuronal MAO.
 Therapeutic useTherapeutic use
 as a potent, long-acting antihypertensive agentas 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 takingGuanethidine is contraindicated in patients taking
MAO inhibitors.MAO inhibitors.

NEXT LECTURENEXT LECTURE
The CNS affecting drugs:The CNS affecting drugs:
Introduction, targets for drug’s action.Introduction, targets for drug’s action.
Antiepileptics. Drugs for treatment ofAntiepileptics. Drugs for treatment of
Parkinson’s disease.Parkinson’s disease.
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