ملخص

Adrenergic neurons release norepinephrine (NE) as the primary neurotransmitter. Found in CNS ans in sympathetic nervous system .
Norepinephrine also relased from adrenal medulla
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.
Substance activate adrenoreceptor called sympthatomimtic and the one block it called sympatholytic
Neurotransmission at adrenergic neurons:
synthesis, storage, release, receptor binding of norepinephrine, removal of the neurotransmitter from the synaptic gap
-hydroxylation of tyrosine is the rate limiting step , in the synthesis of norepinephrine.
-norepinephrine is hydrolysed by monoamine oxidase (MAO) and Catechol-O-methyl transferase

Tow type of adrenoreceptor are α (alpha) and β (beta),

α (alpha) weak response to synthetic agonist but well response to natural agonist
subdivided into alpha 1 and alpha 2
β (beta) : subdivided to
3β
2 β
1 β
lipolysis
Affinity for epi > norepi
Equal affinity to epi = norepi


Mechanisms of adrenergic receptor activation:
1. Direct receptor binding Direct interaction with receptors.
2. Promotion of norepinephrine release acting on terminals of sympathetic nerves to cause release of NE
3. Blockade of norepinephrine reuptake blocking NE reuptake cause NE to accumulate within the synaptic gap, and thereby increase receptor activation.
4. Inhibition of norepinephrine inactivation Some of the NE inside the 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

Classification of adrenergic drugs:

3.mixed-acting sympathomimetic
2.Indirect-acting drugs:

1.Direct acting:

indirectly release and also directly activate receptors
(1) by releasing or displacing NE from sympathetic nerve varicosities (vesicles )
(2) by blocking the transport of NE into sympathetic neurons (prevent reuptake)
(3) by blocking the metabolizing enzymes, MAO or catechol-O-methyltransferase
1-non-selctive act on more than one receptors subtype
2-selctive act on one certain receptor subtype


Catecholamines versus Noncatecholamines:

Noncatecholamines as ephedrine, phenylphrine, terbutaline

Catecholamine as NE, epinephrine, dopamine, dobutamine, isoproterenol.
1- can be given orally .
2- longer duration of action
3- ,ore able to penetrate BBB
1. They cannot be taken orally.
2. They have a brief duration of action.
3.They cannot cross the blood brain barrier

Characteristic responses mediated by each adrenoceptors:

مهم
All this effect is the same that mediated by Epinephrine since it activate all this receptors

On GIT decrease muscle activity and relaxation

The B2 receptors of the bladder wall mediate relaxation of the wall
Insulin secretion is stimulated by B receptors and inhibited by a2 receptors.
Renin secretion is stimulated by B1 and inhibited by a2 receptors

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
Catecholamine act on B recptorc activate enzyme adenylcyclase inside the cell increase the level of CAMP this second massnger make other reaction responsible for the response .
Note alpha2 decrase cAMP and alpha 1 increase cAMP

The drug cannot be given orally and Epinephrine has a short half life because of 2 processes: enzymatic inactivation (MAO and COMT), and uptake into adrenergic nerves.

alpha1, alpha2, beta1, beta2.

And Considered the prototype of the sympathomimetic drugs.

Epinephrine (adrenaline)

NE does not promote hyperglycemia, a response that is mediated by beta2 receptors.
NE has limited clinical applications. The only recognized indications are hypotensive states and cardiac arrest.

alpha1, alpha2, beta1.

Norepinephrine (Noradrenaline)
Therapeutic uses :
1.Cardiovascular: By activating beta1 receptors on the heart, isopreterenol can be used in
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

beta1, beta2
The drug has positive chronotropic and inotropic actions
Mediated by B1
-Beta2 selective agonists are preferred more than Isoproterenol
In treatment of asthma
Isoproterenol
1.Shock: by activating beta1 receptors in the heart, dopamine can increase cardiac output
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
in low doses, acts on dopamine receptors only.
At moderate doses activates beta1 receptors in addition to dopamine receptors
At very high doses, dopamine activates alpha1 receptors along with beta1 and dopamine receptors
Dopamine
The only indication for the drug is heart failure.


beta1
Dobutamine

Therapeutic uses:

1- Locally as nasal drops to reduce nasal congestion.
2- Parenterally to elevate blood pressure.
3- As eye drops to dilate the pupil (Mydriatic).

alpha 1

it is not a catechol derivative, it is not inactivated by COMT and has a much longer duration of action than the catecholamines.

Phenylephrine

1.Asthma: stimulation of beta2 receptors in the bronchi, causing bronchodilation.
2. Delay of preterm labor:
By activating beta2 receptors in the uterus, terbutaline can relax uterine smooth muscle
beta2
noncatecholamine
Terbutaline is preferred to isoproterenol and related drugs for therapy of asthma, because it is selective for B2 only without activation of B1
Terbutaline

Factor that determine suitable drug to be used :

1.Whether activation of alpha or beta is required
2.preffered route of administration
3.duration of action desired


Adverse effects of alpha 1 activation:
Therapeutic uses of alpha 1 activation:

1- Hypertension due to side spread vasoconstriction

1.Hemostasis cause vasoconstriction and arrest bleeding

2- Necrosis lack of blood flow secondary to excessive vasoconstriction

2.Nasal decongestion cause vasoconstriction of dilated and engorged blood vessels of nasal mucosa this lead to stop congestion

3- Bradycardia vasoconstriction elevate blood pressure barorecptors reflex cause decrease in heart rate
3.Adjunct to local anesthesia :
Alpha 1 agonist combined with anesthetic agent ( lidocaine ) to
a- to prolong anesthetic action
b- reduction in anesthetic dose
c- reduce systemic effect ( toxicity ) of anesthetic agent
d-delay anesthetic absorption
epinephrine is the most commonly used .

4.Elevation of blood pressure cause vasoconstriction and elevate blood pressure and used in hypotensive state but not primary therapy


5.Mydriasis

Therapeutic uses of alpha 2 activation:

Centrally acting alpha 2 agonists: Includes clonidine and methyldopa.
They reduce sympathetic outflow centrally to heart and blood vessel
Their activation inhibits NE release.
These drugs are used as antihypertensive drugs.

Adverse effects of beta 1 activation:

Therapeutic uses of Beta 1 activation:
Over stimulation of B1 tachycardia and dysrhythmia
1.Cardiac arrest activate cardiac B1 receptor initiate beat in heart that stopped baeting

2. Angina pectoris increased work of heart increase oxygen demand in patient with compromised coronary blood flow in risk of angina

2.Heart failure activate cardiac B1 has positive intropic effect increase force of cardiac contraction

3.Shock increase heart rate and contraction increase cardiac output and improve tissue perfusion

4.Atrioventricular heart block B1 activation enhance impulse conduction through AV node

Adverse effects of beta 2 activation:
Therapeutic uses of beta 2 activation:
1.Hyperglycemia activation of B2 lead to increase liver and muscle glycogenolysis

1.Asthma activation of B2 receptor in lung lead to bronchiodilation

2. Tremor activation of B2 in skeletal muscle enhance contraction .
2.Delay of preterm labor activation of B2 receptor in uterus relax uterine smooth muscles

Adverse effects of alpha adrenergic blocking agents:

Therapeutic uses of alpha blockade
1. Orthostatic hypotension

1. Essential hypertension

2. Reflex tachycardia

2. Reversal of toxicity from alpha 1 agonists

3. Nasal congestion


3. Benign prostatic hyperplasia

4. Inhibition of ejaculation

4. Pheochromocytoma.

5. Raynaud's disease

Contraindications
Adverse effects of beta blockade:
Therapeutic uses of Beta blockade:
1. Asthma.

1.Bronchoconstriction.

1.Angina pectoris

2. Chronic obstructive pulmonary disease.

2.Heart block.


2.Hypertension

3. Peripheral vascular diseases (vasospasm).

3.Decrease peripheral blood flow causing cold extremities.

3.Cardiac dysrhythmias

4. Combination with Ca channel blockers, particularly verapamil.

4.Decrease blood flow to the liver and kidneys

4.Myocardial infarction

5. IDDM patients.

5.Increase lipids Concentration.

5.Hyperthyroidism

6. Heart failure and bradycardia.


6.Mask hypoglycemic symptoms.

6. Migraine

7. Psychiatric disorders.

7.CNS.

7.Pheochromocytoma

8.Allergy: skin rash, fever.

8. Glaucoma

9.Impotence (sexual dysfunction).