1. SYMPATHETIC NERVOUS SYTEM
SYMPATHETIC NERVOUS SYSTEM : LEARNING OBJECTIVES:
Drugs affecting norepinephrine synthesis, storage, release and metabolism.
Adrenergic receptors types: alpha / beta receptors, locations and cell signaling.
List and describe directly acting adrenergic agonists – on alpha 1, 2, beta 1, 2
List and describe indirectly acting adrenergic agonist – amphetamine and tyramine and mixed agonist - ephedrine
Effects of epinephrine on different tissues – heart, blood vessels, GIT, eye, bladder, bronchus and metabolic actions.
Compare the effects of epinephrine, norepinephrine, phenylephrine and isoproterenol on blood pressure tracings with special emphasis on heart rate and pulse pressure.
Uses of sympathomimetic drugs.
Classification, uses and adverse effects of alpha blockers
Classification of beta blockers.
Effects of beta receptors on different tissues.
Uses of beta blockers.
Drugs used in glaucoma.

2. SYMPATHETIC NERVOUS SYTEM
Norepinephrine is the major transmitter at post-ganglionic sympathetic nerves – except sweat glands.
Acetylcholine is the nerve transmitter at post- ganglionic sympathetic nerves supplying sweat glands (thermoregulatory).
Epinephrine is secreted by the adrenal medulla.
Dopamine is the transmitter in basal ganglia and anterior pituitary; and renal and mesenteric vasculature.

3. CNS Pre-ganglionic Ganglion Post-ganglionic Effectors Cranial
Ach
Ach
Parasympathetic
Cardiac & smooth
muscles, gland cells,
nerve terminals
Cranial
Nicotinic
Muscarinic
Ach
Sympathetic NE
Cardiac & smooth
muscles, gland cells,
nerve terminals
Nicotinic
Adrenergic
(a, b)
Ach
Ach
Sympathetic
Thermoregulatory
Sweat glands
Nicotinic
Muscarinic
Thoracolumbar
Ach
Sympathetic D
Renal vascular
smooth muscle
Nicotinic
Dopaminergic
(D1)
Ach
Sympathetic (adrenal medulla)
Released into
blood
Epi, NE
Nicotinic
Ach
Ach
Parasympathetic
Sacral
Genitourinary and
lower GIT
Nicotinic
Muscarinic
Ach = acetylcholine
D = dopamine
Epi = epinephrine
NE = norepinephrine

4. SYNTHESIS, STORAGE AND RELEASE OF NOREPINEPHRINE (NE)

5. SYMPATHETIC NERVOUS SYTEM
SYNTHESIS, STORAGE AND RELEASE OF NOREPINEPHRINE (NE):
Norepinephrine Transporter (NET) (Uptake-1 )
It is an important mechanism for the termination of the NE.
Cocaine, Imipramine inhibits this NET.
Extra neuronal transporter (Uptake-2)
NET is an efficient mechanism after the release of NE for reuptake of NE into neurons -87%
VMAT-2
UPTAKE 2 (extra neuronal uptake) : CA are taken into other tissues – 5%.
DIFFUSION -7% GoodmanGilman

6. METABOLISM OF CATECHOLAMINES
Catecholamines are metabolized by two enzyme systems – MAO and COMT.
NE after NET (uptake-1) into the axoplasm is acted upon by MAO.
NE which diffuses into the circulation is acted upon by COMT, mainly in the liver.
24hour estimation of urinary metanephrine and VMA is diagnostic in phaeochromocytoma.
COMT plays a major role in the metabolism of catecholamines particularly in liver.
Biochemical Testing
Pheochromocytomas and paragangliomas synthesize and store catecholamines, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. Elevated plasma and urinary levels of catecholamines and the methylated metabolites, metanephrines, are the cornerstone for the diagnosis. The hormonal activity of tumors fluctuates, resulting in considerable variation in serial catecholamine measurements. Thus, there is some value in obtaining tests during or soon after a symptomatic crisis. However, most tumors continuously leak O-methylated metabolites, which are detected by measurements of metanephrines.
Catecholamines and metanephrines can be measured by using different methods (e.g., high-performance liquid chromatography, enzyme-linked immunosorbent assay, and liquid chromatography/mass spectrometry). In a clinical context suspicious for pheochromocytoma, when values are increased three times the upper limit of normal, a pheochromocytoma is highly likely regardless of the assay used. However, as summarized in Table 343-2, the sensitivity and specificity of available biochemical tests vary greatly, and these differences are important in assessing patients with borderline elevations of different compounds. Urinary tests for vanillylmandelic acid (VMA), metanephrines (total or fractionated), and catecholamines are widely available and are used commonly for initial testing. Among these tests, the fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are more convenient and include measurements of catecholamines and metanephrines. Measurements of plasma metanephrine are the most sensitive and are less susceptible to false-positive elevations from stress, including venipuncture. Although the incidence of false-positive test results has been reduced by the introduction of newer assays, physiologic stress responses and medications that increase catecholamines still can confound testing. Because the tumors are relatively rare, borderline elevations are likely to be false positives. In this circumstance, it is important to exclude diet or drug exposure (withdrawal of levodopa, sympathomimetics, diuretics, tricyclic antidepressants, alpha and beta blockers) that might cause false positives and then repeat testing or perform a clonidine suppression test (measurement of plasma metanephrines 3 h after oral administration of 300 g of clonidine). Other pharmacologic tests, such as the phentolamine test and the glucagon provocation test, are of relatively low sensitivity and are not recommended.
The major metabolites of norepinephrine and epinephrine excreted in urine are metanephrine and VMA (vanillyl mandelic acid).

7. SYMPATHETIC NERVOUS SYTEM
Adrenergic receptors are G protein coupled, which upon stimulation acts by either altering the production of cAMP or activating phospholipase C and IP3 and DAG.
ADRENERGIC RECEPTORS
ALPHA-1
ALPHA-2
BETA-1
BETA-2

8. EPINEPHRINE/ NOREPINEPHRINE
The mechanism of adrenergic receptors. Adrenaline or noradrenaline arereceptor ligands to either α1, α2 or β-adrenergic receptors. α1 couples to Gq, which results in increased intracellular Ca2+ which results in smooth musclecontraction. α2, on the other hand, couples to Gi, which causes a decrease ofcAMP activity, resulting in smooth muscle contraction. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart musclecontraction, smooth muscle relaxation and glycogenolysis.

9. ALPHA-1 receptors ALPHA-2 receptors
Upon stimulation, alpha-1 receptors act through Gq and activates phospholipase C and increase inositol triphosphate (IP3) and DAG
Upon stimulation, alpha-2 receptors act through Gi and inhibits adenylyl cyclase and reduce cAMP
EYE – radial fibers – contraction – mydriasis.
PRESYNAPTIC receptors -- decrease release of transmitter (NE).
BLOOD VESSELS – contraction – increase peripheral resistance.
PANCREAS -- decrease insulin release (predominant).
BLADDER trigone and sphincter – contraction – urinary retention.
PLATELETS -- increase aggregation.
VAS DEFERENS – ejaculation.
Some blood vessels (uninnervated)

10. Upon stimulation through Gs, increase AC activity and increase cAMP
BETA-1
BETA-2
Upon stimulation through Gs, increase AC activity and increase cAMP
HEART
BLOOD VESSELS to skeletal muscle - vasodilation
JG cells in kidney (increase renin release)
UTERUS - relaxation
BRONCHUS - dilation
SKELETAL MUSCLE - promote uptake K+, tremors
LIVER - glycogenolysis
Beta-2 receptors : Upon stimulation, beta-2 receptors stimulate adenylyl cyclase through Gs -- cAMP
Blood vessels to skeletal muscle -- Vasodilation
Uterus -- Relaxation
Respiratory tract -- Bronchodilation
Skeletal muscles -- Tremors
Liver – Glycogenolysis
ALPHA 2 receptors : Upon stimulation, alpha-2 receptors act through Gi and inhibits adenylyl cyclase cAMP
Platelets – increase aggregation
Prejunctional receptors -- decrease release of transmitter (NE)
Pancreas -- decrease insulin release (predominant)

11. SYMPATHETIC NERVOUS SYTEM
Circulating epinephrine then acts on both alpha and beta receptors that it comes into contact with, including β2 receptors on tissues that are not directly innervated by the SNS, including β2 receptors in the:
lung (producing bronchodilation & increased delivery of oxygen)
skeletal muscle arteries (producing increased blood flow to reduce muscle fatigue)
liver (producing increased breakdown of glycogen to glucose & gluconeogenesis)
CARDIAC CELL
SMOOTH MUSCLES

12. Signaling properties of adrenergic receptors
Norepinephrine
Epinephrine
Phenylephrine
Methyldopa
Clonidine
Guanfacine
Isoproterenol (b1,2)
Albuterol (b2)
Dobutamine (b1)
Agonist
Agonist
Agonist a1 a2
b1,2,3 Gq Gi Gs
 Inositol phosphates
(IP3)
 cAMP
 cAMP
 Calcium channels
 Diacyl glycerol (DAG)
 K+ conductance
 Calcium channels

13. SYMPATHETIC NERVOUS SYTEM
DRUGS AFFTECTING SYMPATHETIC NERVOUS SYTEM:
INTERFERE WITH THE SYNTHESIS: Metyrosine
BLOCKADE OF NET (REUPTAKE-1)AT NERVE: TERMINAL: Cocaine, Imipramine
BLOCKADE OF STORAGE IN GRANULE: Reserpine
PROMOTION OF NE/DA RELEASE: Amphetamine, Tyramine
PREVENTION OF NE RELEASE: Bretylium, Guanethidine

14. Metabolism does not play a significant role in the termination of the action of the NE .

15. SYMPATHETIC NERVOUS SYTEM
MAO
MAO –A present in the nerves / intestine / liver or Anywhere
Metabolizes NE, 5-HT, dopamine and tyramine
Inhibitors are Phenelzine, Tranylcypromine
“Cheese reaction” resulting in severe hypertension by interaction between MAO- A inhibitors and cheese containing food substances and adrenergic drugs.

16. SYMPATHETIC NERVOUS SYTEM
MAO – B
Present mainly in the Brain
Metabolizes dopamine, norepinephrine and serotonin.
Inhibitors are Selegiline, Rasagiline
COMT INHIBITORS : Tolcapone, Entacapone

17. SYMPATHETIC NERVOUS SYTEM
Drugs acting on adrenergic receptors:
Alpha-1 receptors: Phenylephrine,
Alpha-2 receptors : Clonidine, α-methyldopa
Beta-1 and beta-2 receptors : Isoproterenol
Beta-1 receptors : Dobutamine
Beta-2 receptors : Albuterol, Salmeterol, Terbutaline, Ritodrine
Dopamine-1 receptor agonist : Fenoldopam

18. Guanethidine is transported by uptake 1 into the presynaptic terminal transported by Norepinephrine transporter (NET). (In this it competes with norepinephrine so can potentiate exogenously applied norepinephrine). It becomes concentrated in norepinephrine transmitter vesicles, replacing norepinephrine in these vesicles. This leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the release of norepinephrine in response to arrival of an action potential.
Classification of adrenergic receptor agonists (sympathomimetic amines) or drugs that produce sympathomimetic-like effects. For each category, a prototypical drug is shown. (*Not actually sympathetic drugs but produce sympathomimetic-like effects.)

19. EPINEPHRINE EPINEPHRINE: CVS ACTIONS HEART: β-1
Increases the contraction of heart and heart rate.
BLOOD VESSELS:
Constriction of vessels -- rise in BP (alpha-1) -- high dose.
Dilatation of blood vessels to skeletal muscle (beta-2) -- low dose.

20. EPINEPHRINE
Epinephrine at low dose result in decrease diastolic pressure and increase in heart rate.
Low dose

21. EPINEPHRINE
Epinephrine at medium dose result in increase pulse pressure and increase in heart rate.
Epinephrine at medium dose increase the mean blood pressure, heart rate and pulse pressure
Medium dose
Medium dose

22. Dale's vasomotor reversal: Epinephrine Reversal when alpha-1 receptors are blocked, epinephrine produce hypotension because of uninhibited beta 2 receptors.

23. EPINEPHRINE EPINEPHRINE : SMOOTH MUSCLES
GIT: Peristalsis is reduced and sphincters are constricted by both alpha and beta receptors.
BLADDER (α-1): Trigone and sphincter is contracted.
UTERUS (β-2): Relaxation at term.
BRONCHUS (β-2): Bronchodilation.

24. EPINEPHRINE EPINEPHRINE
EYE: Mydriasis due to contraction of radial muscle fibers (α-1).
Epinephrine do not affect accommodation significantly.
METABOLIC ACTIONS:
Promotes uptake of K+ into the skeletal muscle (β-2) leading to hypokalemia.
Renin secretion is increased (beta-1).
Glycogenolysis and lipolysis (alpha-1 and beta).

25. SYMPATHETIC NERVOUS SYSTEM EFFECTS
ORGAN
EFFECT
Eye
Dilates pupil
Heart
Increases rate and force of contraction heart
Lungs
Dilates bronchioles
Blood Vessels
Constricts blood vessles
Sweat Glands
Activates sweat secretion
Digestive tract
Inhibits peristalsis
Kidney
Increases renin secretion
Male genitals
Promotes ejaculation

26. EPINEPHRINE : ADVERSE EFFECTS : Palpitation, restlessness, tremors, increase in BP, arrhythmia
Contraindicated in angina pectoris