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Pharmacology-1 PHL 211

Fourteenth Lecture
By

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

The main sites of action of drugs that affect adrenergic neurotransmission

Drugs Affecting Adrenergic Neurotransmission
I.
A.

Sympathomimetics:
Directly acting sympathomimetics, which directly stimulate adrenergic receptors. They are either:
1. 2. 3. 4. Non-selective a-agonists such as NE and epinephrine. These drugs stimulate both a1- and a2-adrenergic receptors Non-selective b-agonists such as isoprenaline and epinephrine. These drugs stimulate both b1- and b2-adrenergic receptors Selective a1-agonists such as phenylephrine. Selective a2-agonists such as clonidine (remember that stimulation of a2adrenergic receptors results in inhibition of NE release). Thus, clonidine is useful in the treatment of hypertension Selective b1-agonists such as dobutamine (remember that the cardiac adrenergic receptors are b1) Selective b2-agonists such as salbutamol (remember that the bronchial adrenergic receptors are b2). Thus, salbutamol and other b2-agonists are useful in the treatment of bronchial asthma

5. 6.

Note that:
epinephrine  all α & all β norepinephrine  all α, β1 & β3 isoproterenol (isoprenaline)  all β

Drugs Affecting Adrenergic Neurotransmission
I. Sympathomimetics:
B. Indirectly acting sympathomimetics are agents that elevate the concentration of NE at neuroeffector junctions, because they either:
1. inhibit re-uptake of NE into noradrenergic neurons, e.g., cocaine. Therefore, NE is not inactivated and has a prolonged action on both a and b receptors
2. facilitate NE release. These drugs (e.g., amphetamine, tyramine) enters noradrenergic neurons and cause NE release 3. slow NE breakdown by monoamine oxidase (MAO), such as tranylcypromine 4. or exert all three of these effects (e.g., amphetamine, methamphetamine)  The effectiveness of such indirect sympathomimetics diminishes or disappears (tachyphylaxis) when vesicular stores of NE are depleted

C. Dual (mixed) acting sympathomimetics such as ephedrine. It enters noradrenergic neurons and cause NE release and also activates b receptors (this probably accounts for its earlier use in asthma)

Drugs Affecting Adrenergic Neurotransmission
II. Sympathomlytics:
A.Noradrenergic receptor blockers which include
1.Drugs which antagonize the effects produced by both a and b-receptor stimulation such as labetalol (a1 and b-receptor antagonist; it is effective in hypertension) 2.Drugs which antagonize the effects produced by a-receptor stimulation:
 Non-selective a-blockers such as phentolamine (used in the treatment of pheochromocytoma “tumor in the adrenal medulla that releases a mixture of EP and NE”  Selective a1-blockers such as prazosin (effective in the treatment of hypertension)  Selective a2-blockers such as yohimbine

3.Drugs which antagonize the effects produced by b-receptor stimulation:
 Non-selective b-blockers such as propranolol (it is used in the treatment of hypertension, angina pectoris, cardiac arrhythmia)  Selective b1-blockers such as atenolol (used as propranolol)  Selective b2-blockers. Not in clinical use

B.Drugs that prevent noradrenergic transmission which include:
1.Noradrenergic neuron blockers such as guanethidine (used in the treatment of hypertension) which inhibits the release of NE from sympathetic nerve terminals 2.Drugs that deplete NE from noradrenergic neurons such as reserpine (used in the treatment of hypertension). They prevent the storage of NE in vesicles at noradrenergic nerve endings, thus NE is immediately inactivated by MAO 3.Drugs that interfere with the synthesis of NE such as methyldopa (used in the treatment of hypertension, its use during pregnancy appears to be relatively safe)

Mechanism of Activation of a1 Responses by Catecholamines
Stimulation of a1 receptors by catecholamines leads to the activation of a Gqcoupling protein

The activated a subunit (aq*) of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5bisphosphate (PtdIns 4,5P2)
IP3 stimulates the release of sequestered stores of Ca2+ , leading to an increased concentration of cytoplasmic Ca2+ Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC)

Mechanism of Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors
Binding to b adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its a subunit charged with GTP This activated as subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP a2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an activated ai subunit charged with GTP and a bg unit cAMP binds to the regulatory subunit (R) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression
Alpha 2 receptor

Individual Sympathomimetics Chatecholamines
Catecholamines are compounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side-chain

Epinephrine (adrenaline; EP)
 EP is a hormone secreted by the adrenal medulla. It is a very potent vasoconstrictor and cardiac stimulant. It increases blood pressure by its +ve inotropic and chronotropic actions on the heart (b1 receptors) and the vasoconstriction induced in many vascular beds (a receptors)  EP also activates b2 receptors in some vessels (e.g., skeletal muscle blood vessels), leading to their dilation. Consequently, total peripheral resistance may fall, explaining the fall in diastolic pressure that is seen with epinephrine injection. Activation of b2 receptors in skeletal muscle contributes to increased blood flow during exercise.  EP is used to treat ventricular fibrillation arrest as well as other forms of cardiac arrest  EP is indicated for treatment of acute hypersensitivity (anaphylactoid reactions to drugs, animal serums and other allergens)  It is used with local anaesthetics to prolong their action

Norepinephrine (noradrenaline; NE)
 NE is a transmitter released by sympathetic nerve terminals. NE and EP have similar effects on b1 receptors in the heart and similar potency at a receptors. NE has relatively little effect on b2 receptors  Consequently, NE increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory vagal reflexes tend to overcome the direct +ve chronotropic effects of NE; however, the +ve inotropic effects on the heart are maintained

Individual Sympathomimetics, Chatecholamines
Isoproterenol (isoprenaline)
 It is a synthetic derivative of NE, not present in the body. It is a very potent b-receptor agonist and has little effect on a receptors. It has +ve chronotropic and inotropic actions. Because isoproterenol activates b receptors almost exclusively, it is a potent vasodilator  These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure  It is indicated for episodes of heart block that do not require electric shock

Dopamine
 It is the immediate metabolic precursor of NE. It activates D1 receptors in several vascular beds, which leads to vasodilation. It activates pre-synaptic D2 receptors, which suppress NE release  Dopamine activates b1 receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine  It is indicated for the correction of hemodynamic imbalances present in the shock syndrome due to myocardial infarctions, trauma, endotoxic septicemia,…etc

Dobutamine
 It is a relatively b1 -selective synthetic catecholamine. Dobutamine also activates a1 receptors. It is indicated for patients with acute hypotensive heart failure or shock

Individual Sympathomimetics, Non-Chatecholamines
Ephedrine
 It enters noradrenergic neurons and cause NE release and also activates b receptors.  Because ephedrine is not a catechol derivative, it has high bioavailability and a relatively long duration of action. Since it is a weak base, its excretion can be accelerated by acidification of the urine  Its ability to activate b receptors probably accounted for its earlier use in asthma.  Because it gains access to the central nervous system, it is a mild stimulant  Pseudoephedrine, one of four ephedrine enantiomers, is available over the counter as a component of many decongestant mixtures

Phenylephrine

 Phenylephrine is a selective a agonist. It acts directly on the receptors. Because it is not a catechol derivative, it is not inactivated by COMT and has a much longer duration of action than the catecholamines.  It is an effective mydriatic and decongestant and can be used to raise the blood pressure