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Pharmacology-1 PHL 211

Thirteenth Lecture
By

Abdelkader Ashour, Ph.D.
Phone: 4677212 Email: aeashour@ksu.edu.sa

Drugs Acting on the Sympathetic Nervous System

Autonomic Nervous System

Sympathetic Nervous System (SNS),

Overview

 SNS regulates the expenditure of energy and is operative when the organism is confronted with stressful situations, such as danger, intense emotion, or severe illness  SNS is referred to as “Fight-or-flight” system  SNS promotes adjustments during exercise
 Blood flow to organs is reduced, flow to muscles is increased

 SNS prepares the body for emergency situations
 Heart rate increases and breathing is rapid and deep

 The neurohormones (neurotransmitters) of the SNS are epinephrine (EP) and norepinephrine (NE), in addition to ACh
ACh serves as the chemical transmitter at ganglionic synapses between pre- and postganglionic neurons, NE is the mediator at synapses of the postganglionic neuron with the effector organ

 EP is secreted by the adrenal medulla. NE is secreted mainly at nerve endings of sympathetic (also called adrenergic) nerve fibers

Drugs Acting on the Sympathetic Nervous System, Responses to sympathetic activation
1. Pupils dilate (contraction of radial muscles) 2. Bronchioles dilate, enabling alveolar oxygen uptake to be increased.
 This is not due to a direct innervation by sympathetic nerves. Instead, adrenaline released from the adrenal glands cause the dilation

3. Increased heart rate and force of contraction 4. Blood vessels (especially in the skin and viscera) constrict 5. Skeletal muscle blood vessels dilate so muscles can get more blood 6. GIT and urinary bladder: relaxation of the walls and constriction of sphincters 7. Salivary secretion: vicid (remember; in response to PSNS, it is watery and copious) 8. Increased sweating

9. Blood sugar rises (increased glycogenolysis and gluconeogenesis)
10. Hair becomes erected on skin 11. Increased lypolysis in adipose tissues 12. Ejaculation (remember; in response to PSNS, erection occurs)

Noradrenergic Neurotransmission
Tyrosine is transported into the noradrenergic ending by a sodium-dependent carrier (A) Tyrosine is converted to dopamine, which is transported into the vesicle by a carrier (B) that can be blocked by reserpine.  The same carrier (B) transports NE and several other amines into these granules Dopamine is converted to NE in the vesicle by dopamine-b-hydroxylase Release of transmitter occurs when an action potential opens voltage-sensitive Ca2+ channels and increases intracellular Ca2+ Fusion of vesicles with the surface membrane results in expulsion of NE, cotransmitters, and dopamine-b-hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium  After release, NE diffuses out of the cleft or is transported into the cytoplasm of the terminal (uptake 1, blocked by cocaine, tricyclic antidepressants) or into the postjunctional cell (uptake 2)

Biosynthesis of Catecholamines

Termination of catecholamine action
 Catecholamines are metabolised (inactivated) mainly by two enzymes: monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)  MAO occurs within cells, bound to the surface membrane of mitochondria
 It is abundant in noradrenergic nerve terminals but is also present in many other places, such as liver and intestinal epithelium  MAO can also oxidise other monoamines, such as dopamine and 5-HT  It is inhibited by various drugs, which are used mainly for their effects on the CNS  Within sympathetic neurons, MAO controls the content of dopamine and NE

 COMT is absent from noradrenergic neurons but present in the adrenal medulla and many other cells and tissues
 The final product formed by the sequential action of MAO and COMT is partly conjugated to sulfate or glucuronide derivatives, which are excreted in the urine, but most of it is converted to vanillylmandelic acid and excreted in the urine in this form  In the periphery, neither MAO nor COMT is primarily responsible for the termination of transmitter action, most of the released NE being quickly recaptured by uptake 1. Circulating catecholamines are usually inactivated by a combination of uptake 1, uptake 2 and COMT

Adrenergic Receptors (Adrenoceptors)
 Adrenergic nerve fibers have either alpha (a) or beta (b) receptors.  Adrenergic drugs may act on a receptors only, b receptors only, or on both a and b receptors  Agonists at adrenoceptors (direct sympathomimetics) mimic the actions of the naturally occurring catecholamines (norepinephrine and epinephrine), and are used for various therapeutic effects.

 For example, phenylephrine acts chiefly on a receptors; isoproterenol acts chiefly on b receptors; and epinephrine acts on both a and b receptors
 The a and b receptors can be further divided into a1- and a2-adrenergic receptors and b1-, b2- and b3-adrenergic receptors

Distribution of Adrenergic Receptors
a1

Ejaculation

a2