Adrenergic

* * Adrenergic Drugs

Objectives of the lectures: Understanding of how adrenergic drugs act is crucial in order to use them to the best advantage and with safety. 1. Adrenergic mechanisms 2. Classification of sympathomimetics: by mode of action and selectivity for adrenoceptor 3. Individual sympathomimetics

* * Overview:

Adrenergic neurons release norepinephrine (NE) as the primary neurotransmitter. These neurons i.e. most postganglionic sympathetic fibers and adrenal medullary cells release NE.

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All preganglionic neurons are cholinergic in both the sympathetic and the Para- sympathetic nervous system. Either all or almost all of the postganglionic neurons of the parasympathetic system are cholinergic. Most of the postganglionic sympathetic neurons are adrenergic. However; the postganglionic sympathetic nerve fibers to the sweat glands, piloerector muscles of the hair and to a very few blood vessels are cholinergic.

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* * The adrenergic neurons and receptors, are the sites of action of the adrenergic drugs.

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* * Neurotransmission at adrenergic neurons:
The process involves five steps: synthesis, storage, release, receptor binding of norepinephrine, removal of the neurotransmitter from the synaptic gap.

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* * Adrenergic receptors (adrenoceptors):
Two families of receptors, designated α (alpha) and β (beta), were initially identified on the basis of their responses to the adrenergic agonists epinephrine, NE, and isoproterenol.

* * Adrenoceptors

* * Mechanisms of adrenergic receptor activation:
Drugs can activate adrenergic receptors by four basic mechanisms: 1. Direct receptor binding. 2. Promotion of norepinephrine release. 3. Blockade of norepinephrine reuptake. 4. Inhibition of norepinephrine inactivation.


* * Direct receptor binding: Direct interaction with receptors is the most common mechanism by which drugs activate peripheral adrenergic receptors.

* * Promotion of NE release: By acting on terminals of sympathetic nerves to cause release of NE, drugs can bring about activation of adrenergic receptors. Examples: Ephedrine, amphetamines.


* * Inhibition of NE reuptake: By blocking NE reuptake, drugs can cause NE to accumulate within the synaptic gap, and thereby increase receptor activation. Examples: Cocaine, and the tricyclic antidepressants.



* * Inhibition of NE inactivation: Some of the NE in terminals of adrenergic neurons is subject to inactivation by monoamine oxidase (MAO). Hence, drugs that inhibit MAO will increase the amount of NE available for release, and will thereby enhance receptor activation. Examples: MAO inhibitors.

* * Classification of adrenergic drugs:

1.Direct acting: Direct-acting sympathomimetic drugs act directly on one or more of the adrenergic. receptors These agents may exhibit considerable selectivity for a specific receptor subtype

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* * Catecholamines versus Noncatecholamines:
Catecholamine: Catecholamine: means drugs that contains catechol group and ethylamine group. They includes NE, epinephrine, dopamine, dobutamine, isoproterenol.

* * Properties

1. They cannot be taken orally. 2. They have a brief duration of action. 3.They cannot cross the blood brain barrier.

* * Noncatecholamines

The noncatecholamines have ethylamine in their structure but do not contain the catechol portion, that characterizes the catecholamine, such as ephedrine, phenylephrine, terbutaline.

* * Characteristic responses mediated by adrenoceptors:

* * Desensitization of receptors:
Prolonged exposure to the catecholamine and other sympathomimetic drugs reduces the responsiveness of these receptors Mechanisms: 1. sequestration of the receptors 2. down-regulation of the receptors 3. inability to couple to G protein

* * Consequences of activating the adrenoceptors:

* * Adrenergic agonist drugs

* * Effects of adrenergic agonists on body organs

Blood Vessels Alpha receptors increase arterial resistance, B2 receptors promote smooth muscle relaxation.

* * Heart

1.Heart rate is increased (positive chronotropic effect). 2.Conduction velocity in the AV node is increased, and the refractory period is decreased. 3.Intrinsic contractility is increased (positive inotropic effect).

* * Eye

The radial muscle and iris sphincter muscle contains a1 receptors; Activation by drugs such as phenylephrine causes mydriasis.


* * Respiratory Tract
Bronchial smooth muscle contains B2 receptors that cause relaxation. Activation of these receptors results in bronchodilation.

* * Gastrointestinal Tract

Beta receptors appear to be located directly on the smooth muscle cells and mediate relaxation

Alpha stimulants, especially a2-selective agonists, decrease muscle activity

* * Genitourinary Tract
The human uterus contains B2 receptors, which on stimulation causes uterus relaxation. The bladder base, urethral sphincter, and prostate contain a1 receptors that mediate contraction. The B2 receptors of the bladder wall mediate relaxation.

* * Metabolic Effects

Lipolysis Glycogenolysis Fall in extra cellular potassium

* * Effects on endocrine function

Insulin secretion is stimulated by B receptors and inhibited by a2 receptors. Renin secretion is stimulated by B1 and inhibited by a2 receptors

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* * Epinephrine (adrenaline)
Receptor specificity: alpha1, alpha2, beta1, beta2. Chemical classification: Catecholamine. Considered the prototype of the sympathomimetic drugs.


* * Epinephrine may be administered topically, by injection, and by inhalation. The drug cannot be given orally because, epinephrine and other catecholamines undergo destruction by MAO and COMT before reaching the systemic circulation. Following subcutaneous injection, absorption is slow because of epinephrine induced local vasoconstriction. Absorption is more rapid following intramuscular injection. When epinephrine is inhaled (to treat asthma), systemic absorption is usually minimal.


* * Inactivation: Epinephrine has a short half life because of 2 processes: enzymatic inactivation (MAO and COMT), and uptake into adrenergic nerves. Epinephrine is dispensed in solution for administration by several routes: IV,SC,IM, intracardiac, intraspinal, inhalation, and topical.

* * Norepinephrine (Noradrenaline)

Receptor specificity: alpha1, alpha2, beta1. Chemical classification: Catecholamine. Norepinephrine differs from epinephrine only in that NE does not activate beta2 receptors. Accordingly, NE can elicit all of the responses that epinephrine can, except those that are beta2 mediated.


* * In contrast to epinephrine, NE does not promote hyperglycemia, a response that is mediated by beta2 receptors. Despite its similarity to epinephrine, NE has limited clinical applications. The only recognized indications are hypotensive states and cardiac arrest. NE is dispensed in solution for administration by IV infusion only.

* * Isoproterenol

Receptor specificity: beta1, beta2. Chemical classification: Catecholamine. The drug has positive chronotropic and inotropic actions



* * Therapeutic Uses: 1.Cardiovascular: By activating beta1 receptors on the heart, isopreterenol can benefit patients with several cardiovascular disorders: 1.Can help overcome AV heart block. 2. In cardiac arrest. 3.Can increase cardiac output during shock.


* * 2.Asthma: By activitating beta2 receptors in the lung, isoproterenol can cause bronchodilation, thereby used for the treatment of asthma (Beta2 selective agonists are now preferred). The drug is available in solution for parenteral administration and in tablets for sublingual administration, and as metered dose aerosol device for treatment of asthma.

* * Dopamine

Chemical classification: Catecholamine. Receptor specificity: When administered in low therapeutic doses, dopamine acts on dopamine receptors only. At moderate therapeutic doses, dopamine activates beta1 receptors in addition to dopamine receptors. At very high doses, dopamine activates alpha1 receptors along with beta1 and dopamine receptors. Administration as solution by IV infusion

* * Therapeutic uses:

1.Shock: by activating beta1 receptors in the heart, dopamine can increase cardiac output, thereby improving tissue perfusion. By activating dopamine receptors in the kidney, dopamine can dilate renal blood vessels, thereby improving renal perfusion, which in turn reduces the risk of renal failure. 2. Heart failure. Dopamine can help alleviate symptoms by activating beta1 receptors on the heart, which increases cardiac output by increasing myocardial contractility.


* * Dobutamine Receptor specificity: beta1. Chemical classification: Catecholamine. The only indication for the drug is heart failure. Administration as solution by IV infusion


* * Phenylephrine Receptor specificity: alpha 1. Chemical classification: noncatecholamine. Because it is not a catechol derivative, it is not inactivated by COMT and has a much longer duration of action than the catecholamines. Therapeutic uses: Locally as nasal drops to reduce nasal congestion. Parenterally to elevate blood pressure. As eye drops to dilate the pupil (Mydriatic).

* * Terbutaline

Receptor specificity: beta2 Chemical classification: noncatecholamine 1.Asthma: stimulation of beta2 receptors in the bronchi, causing bronchodilation. Terbutaline is preferred to isoproterenol and related drugs for therapy of asthma, because it produces much less activation of cardiac beta1 receptors at therapeutic doses than does isoproterenol.



* * 2. Delay of preterm labor: By activating beta2 receptors in the uterus, terbutaline can relax uterine smooth muscle, thereby delaying labor.

* * Therapeutic uses of adrenergic drugs

Therapeutic uses of alpha 1 activation: 1.Hemostasis 2.Nasal decongestion 3.Adjunct to local anesthesia 4.Elevation of blood pressure 5.Mydriasis

* * Adverse effects of alpha 1 activation:

Hypertension Bradycardia Necrosis

* * Therapeutic uses of alpha 2 activation:

Their activation inhibits NE release. Centrally acting alpha 2 agonists: Includes clonidine and methyldopa. These drugs are used as antihypertensive drugs.

* * Therapeutic uses of Beta 1 activation:

1.Cardiac arrest 2.Heart failure 3.Shock 4.Atrioventricular heart block

* * Adverse effects of beta 1 activation:

1.Altered heart rate or rhythm 2. Angina pectoris

* * Therapeutic uses of beta 2 activation:

1.Asthma 2.Delay of preterm labor


* * Adverse effects of beta 2 activation:
1.Hyperglycemia 2. Tremor

* * Adrenergic Antagonists

Adrenergic antagonists can be divided into two types depending on the type of the receptors that are blocked: 1. Alpha adrenergic antagonists. 2. Beta adrenergic antagonists.

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* * Alpha Adrenergic antagonists
Classification:Reversible: Phentolamine, tolazoline, prazosin.Irreversible: Phenoxybenzamine. Selective α1 receptor blockade: prazosin, terazosin, doxazosin.Non-selective(α1andα2): Phentolamine, tolazoline, phenoxybenzamine.

* * Therapeutic uses of alpha blockade

1. Essential hypertension 2. Reversal of toxicity from alpha 1 agonists 3. Benign prostatic hyperplasia 4. Pheochromocytoma. 5. Raynaud's disease

* * Adverse effects of alpha adrenergic blocking agents:

1. Orthostatic hypotension 2. Reflex tachycardia 3. Nasal congestion 4. Inhibition of ejaculation

* * Beta Adrenergic Antagonists

Classification:Pure antagonists: Atenolol, metoprolol, propranolol, nadolol.Partial agonists: penbutolol, pindolol, acebutolol.Membrane stabilising effect: acebutolol, metoprolol, propranolol (local anaesthetic effect). β1 Selectivity: acebutolol, atenolol, metoprolol.Non selectives: nadolol, propranolol, penbutolol, pindolol, timolol (β1 and β2).


* * Therapeutic uses of Beta blockade:
1.Angina pectoris 2.Hypertension 3.Cardiac dysrhythmias 4.Myocardial infarction 5.Hyperthyroidism 6. Migraine 7.Pheochromocytoma 8. Glaucoma

* * Adverse effects of beta blockade:

1.Bronchoconstriction. 2.Heart block. 3.Decrease peripheral blood flow causing cold extremities. 4.Decrease blood flow to the liver and kidneys 5.Increase lipids Concentration.


* * 6.Mask hypoglycemic symptoms. 7.CNS. 8.Allergy: skin rash, fever. 9.Impotence (sexual dysfunction).

* * Contraindications:

1. Asthma. 2. Chronic obstructive pulmonary disease. 3. Peripheral vascular diseases (vasospasm). 4. Combination with Ca channel blockers, particularly verapamil. 5. IDDM patients. 6. Heart failure and bradycardia. 7. Psychiatric disorders.

Study Questions

Remedies for nasal stuffiness often contain which one of the following drugs? A. Albuterol. B. Atropine. C. Epinephrine. D. Norepinephrine. E. Phenylephrine.
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Which one of the following drugs, when administered intravenously, can decrease blood flow to the skin, increase blood flow to skeletal muscle, and increase the force and rate of cardiac contraction? A. Epinephrine. B. Isoproterenol. C. Norepinephrine. D. Phenylephrine. E. Terbutaline.
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