sympathomimetics 30 31

7/28/2019 Sympathomimetics 30 31

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Sympathomimetics

Dr Attia & dr Razza

1430-1431

2009-2010


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Autonomic Nervous System


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ANS is divided into

Sympathetic Parasympathetic

Origin From all thoracic andupper 3 lumber

segments

From cranial 3,7,9,10

and Sacral 2,3,4

segments

Character Short preganglionic

and long postganglionicfibres

Long preganglionic and

short postganglionic


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Autonomic Nervous System


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ANS Stimulation - Response

Structure Sympathetic

Stimulation

Parasympathetic

StimulationFight & fright or flight Rest & digest

HeartHR

AV conduction

VentricularBlood Vessels

Tachycardia

Vasoconstriction &

Dilatation

Bradycardia

No effectVasodilation of some vessels

Smooth muscleEye

BronchiGIT

Urinary Bladder

Mydriasis

BronchodilationRelax wall, Contract Sphincters

Urine retention

Miosis

Bronchospasm(Contract)Contact Wall & Relax sphincters

Micturation

SecretionsSalivary

Sweat

Thick viscid ()

(Perfuse watery)NO effect

Sex Organs Ejaculation Erection


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Adrenergic receptors

Receptor Location Effect1 Postsynaptic in smooth

Muscle of

Blood vessels

GIT & Urinary

sphincters

Vasoconstriction

contraction

2 Presynaptic NA release

1 Heart

Kidney

Rate and Contraction Renin release

2 Sm. Muscle ofBlood vessels

Bronchi

Intestine

Urinary

liver

Relaxation

Relaxation

Relaxation

Relaxation

glycogenolysis

3 Adipose tissue Lipolysis


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Alpha-1 receptors Sites; mainly post-synaptic on effector organs

Actions:= Contractions

1. Smooth m of BVVC (skin, MM, renal)TPR

hypertension

2. Spasm of GIT & urinarysphincters

3. Contraction of DPMmydriasis

4. Ejaculation & contraction of prostatic capsule

5. Contraction of pregnant uterus

6.

Viscid salivation7. Facilitate neuromuscular transmission

8. Pilomotor smooth muscleerection of hair

Specific agonists: Phenylephrine

Specific antagonists:Prazocin


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Alpha-2 receptors1. Sites:1. CNS 2. Presynaptic 3. postsynaptic (some

organs)

2. Actions: Inhibition Except1. CNSsedation sympathetic centers

2. Presynaptic (autoreceptors)

1. Release of NA

2. Release of Ach in enteric gangliarelax of wall GIT

3. Kidneyrelease of renin

4. Pancreas release of insulin

5. Fat cellsLipolysis

6. Eye:aqueous humor formation

7. Platelets aggregation & Some vascular BV

3. Selective agonist: Clonidine

4. Selective anta onist:Yohimbine


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Beta- receptorsB1

Heart

B2

Bronchi (SM)

B3

Fat cellsPresynaptic release of Noradrenaline

Postsynaptic CNS

Anxiety

BV vasodilation

sk m BV

Fat cells

Lipolysis

HeartCOP

BronchodilationRelax GIT, UB, uterus

thermogenesis

Kidney

renin

Glycogenolysis

Liver, muscle

Fat cells

Lipolysis

FFA

Release of insulin

K uptake by Sk m

SK M tremors

Selective agonist Dobutamine Salbutamol Octopamine

Selectiveantagonist

Atenolol Butoxamine??


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General notes on

Sympathetic receptors

1. Alpha + beta relax wall of GIT

2. Alpha-1 contraction of pregnant uterus +

VC while B-2 the opposite

3. Alpha-2 lipolysis While Beta1 + beta-3

lipolysis

4. Alpha-2 Renin While beta1 renin

5. Alpha-2 Insulin while Beta 2Insulin6. Dopamine D1 receptors (on renal and

splanchnic, coronary BVVasodilatation


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Noradrenaline (Norepinephrine; NA)

Synthesis

Tyrosine +OH DOPA (+MAO)(-CO2)Dopamine (+OH) Noradrenaline (Inside granules)

In adrenal medulla & some areas in bra`

NA is the chemical transmitter at postganglionicsympathetic (Exception Sweat glands/ BV) andinside CNS.


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Adrenergic SystemTermination of

(nor)epinephrine action:1. Reuptake into presynaptic nerve

ending; 80%

Predominant mechanism

active transport; inhibited byCocaine & TCA

2. Catechol-O-methyltransferase (COMT)

In the cytoplasm of post-junctional

cells

3. Monoamino-oxidase (MAO)

In mitochondria of nerve and post-

junctional cells

4. Presynaptic a2-receptors Negative feedback that inhibits

norepinephrine release


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Sympathomimetics (Adrenergic Agonists)

Classification


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I. Catecholamines

A. Epinephrine (Adrenaline) Direct ( 1,2, 1, 2, 3)Pharmacological Actions:

1. CVSCardiac stimulation (1) actionHR, contractility,Vasoconstriction, BP2. Smooth muscle:Stimulation of 2 receptors in GIT and Bronchi

Relaxation

3. Eye: Mydriasis (1)

4. Metabolic: Hyperglycemia & Lipolysis

Therapeutic Uses:1. Cardiac arrest (intracardiac injection)2. Anaphylaxis It is antidote to histamine. (In anaphylactic shock histamine release vasodilation severe hypotension antagonized by Epinephrine Inj. 1:1000Dilution)

3. Prolongation of action of local anesthetics-Epistaxis

4. Acute bronchial asthma

Side effects: 1, 1, 2,1. CVS: hypertension, cerebral hemorrhage, cardiac arrhythmia, tachycardia,palpitation, Angina, MI

2. CNS: Nervousness, tremors

Contraindications:

Hypertension, hyperthyroidism, Diabetes mellitus, coronary arterydisease, CHF, old patients


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I. Catecholamines Contd

1. B. Norepinephrine (NA) (1, 2, 1, 3) Effects are predominantly on

1

, has stimulant effect on 1

receptorsof heart, No 2 action.

Used in

1. Shock, weaker metabolic effects than epinephrine.2. Why norarenal ine can cause abor tion bu t Ad .no t?

3. What is the ef fec t o f alpha b locker on Ad & Norad?

4. What is the effect on Noradrenaline on HR?

C. Dopamine (D1, B1, 1) Precursor of epinephrine and norepinephrine, Low conc. Of Dopamine

stimulate D1 receptors in renal vessels, mesentryvasodilatation,renal blood flowuseful in cardiogenic & hypovolemic shock

At high Conc. Stimulate 1receptors in the heart+ve inotropicand contractlity & higher concentration1-receptorsBloodpressure

USES:

Various shock (Cardiogenic shock & Septic shock, &

Refractory heart failure & acute renal dysfunction


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I. Catecholamines Contd

D. Isoprenaline (Isoproterenol); Beta only (B1,B2)1. Powerful action on

1

& 2

receptors, no effect on receptors

2. Used in emergency to HR (1 effect) in bradycardia &

3. heart block & Bronchial asthma

4. Expect its adverse effects? Contraindicaons?

5. In a table form compare between adr, noradr., isopren.?

As regards (Receptors-BP-pulse pressure-HR-uses)

E. Dobutamine: Selective 1 Selective 1 action contractility > than HR t very short (2min), given by IV route

Used to treat cardiogenic shock (improves contractility, O2consumption)

1. Resistant heart failure& heart block

2. myocardial infarction

3. After cardiac surgery


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II. Selective 2 agonist

Salbutamol: Selective 2 Stimulates 2 receptors selectively located in

bronchi Bronchodilatation.

Used in bronchial asthma

by inhalation or Orally.

Ritodrine

Selective stimulant for2

receptors in uterusuterine relaxation.

Used as prophylactic in repetitive abortion or

premature labor.


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III. Selective 1 agonist

Phenylephrine: Stimulates 1 receptors inBV vasoconstriction it activates receptors only at much higher conc.

uses1.Hypotension by

intravenous infusion.

2. Nasal decongestant3. Mydriatic in various

ophthalmic formulations


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IV. Selective 2 agonistClonidine & -methyldopa (Aldomet)

Clonidine & -methyldopa (Aldomet) C-2,P-2,R-2) They act on presynaptic 2 receptorsstimulationrelease NE in CNSCsympathetic discharge fromCNSVasodilatation/BP (& HR) + (I1-receptor)

Clonidine is used to treat

1. Hypertension (renal patients)2. Autonomic neuropathy in diabetics, migraine, IT analgesic

3. Withdrawal symptoms in addicts (Tobacco-morphine), menopause

4. Can you use them in glucoma? Why?

Side effects: Hypertension, Stop rebound, sedation,

bradycardia, constipation, and sexual dysfunction

-methyldopa (Aldomet) is used to treat (C-2,P-2,R-2)

hypertension during pregnancy & renal impairment. Why?

Side effects: Sedation, depression, postural hypotension,edema, hemolytic anemia (Allergic), impotence


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V. Indirect acting agonistsAmphetamine, Ephedrine act by releasing noradrenaline at sympathetic

nerve endings, they have marked effects on CNS

AmphetaminePharmacological actions

A. Indirect: Stimulation of -adrenergic receptors BP (like NA but weaker,slower, longer, with tachyphylaxis)

b. CNS: Strong CNS stimulant effect:1. Small dose: alertness, wakefulness, mental activity, delays mental fatigue, improves

physical performance Euphoria But followed by Fatigue, depression.

2. Moderate dose: Anxiety, nervous tension, tremors.3. Large dose: Abnormal behaviour (Parania like syndrome), hyperthermia, convulsion

4. Appetite suppressant

5. Medullary centers & Spinal reflexes

Therapeutic Uses: Produces addiction (Obsolete)1. Attention deficit disorder in children (No addiction) (methyphenidate)

2. Narcolepsy (No Addiction)3. Obesity, psychic depression

Side Effects

1. CNS: irritability, tremors, restlessness, hallucination, paranoia, suicide

2. CVS: palpitation, hypertension, arrhythmia

3. Tolerance, addiction


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V. Indirect acting agonists

Ephedrine: Like adrenaline But1. Dual action: Mainly indirect (weaker, slower, longer & tachyphylaxis

2. CNS stimulant: < amphetamine

Actions: Found in many dietary supplements: Energy-Boosters, Dietpills (Metabolife) etc.

A. local1. Nose decongestion

2. Eye: decongestion + mydriasisB. Systemic:1. CNS stimulant: Insomnia, anxiety, Medullary C, Spinal reflexes

2. CVS: Heart, BP

3. Smooth muscles like adrenaline

4. Skeletal muscle stimulant

Uses:1. Analeptic2. ADHD-Bronchial asthma

3. Mydriatic-nasal decongestant-Nocturnal enuresis

4. Prevent hypotension in spinal anesthesia

Adverse effects; Contraindications1. CNS

2. CVS retention of urine in old age3. Tolerance & tachyphylaxis but not addiction


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Sympathomimetics Clinical uses


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Questions for Revision of sympathomimetics?A. Classify sympathomimetics according to their nature?

B. Classify them accordring o their chemistry?

C. Classify them according to mechanism of action?D. Classify them according to their selectivity complete;

1. Selective alpha-1 agonist like

2. Selective Alpha2 agonist like.

3. Non selective Alpha1 + alpha 2 like.

4. Selective B1 agonist like.

5. Selective B2 agonist like.6. Non selective B1 + B2 like..

7. Alpha1+ Alpha2 + B1+B2+B3 like

8. Alpha1 + Alpha2 + B1 +B3 like

9. D + B1 + Alpha1 like

10. Vasopressor like

11. Nasal decongestant like12. Added to local anesthetic like

13. Cardiac stimulant.

14. Vasodilator like.

15. Uterine relaxant like.

16. Anorexigenic like.

17. CNS stimulant like..

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