adrenergic 26 nov agonist

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Phenylephrine, Methoxamine Primarily directly acting vasoconstrictors by activating  1 receptors. The resulting hypertension results in a reflex bradycardia. Phenylephrine is also used as a nasal decongestant and mydriatic. Naphazoline, Oxymetazoline, Xylometazoline Propylhexedrine are used as nasal decongestant and to check epistaxis. Alpha 1 receptors Agonist

Alpha 2 receptor agonist :

Alpha 2 receptor agonist CLONIDINE Activation of alpha 2 receptors in the brain causes inhibition of sympathetic system Suppression of release of NE by presynaptic alpha 2 receptors. It also binds with imidazoline receptors . Excellent oral bioavailability. Transdermal patches are also available.

a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain:

a 2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) Kidney Heart Y Sympathetic ganglion b 1 Receptors a 2 Receptors Y b 1 Receptors Y a 1 Receptors

a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain:

a 2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) Kidney Heart Y Sympathetic ganglion b 1 Receptors a 2 Receptors Y b 1 Receptors Y a 1 Receptors Decreased sympathetic tone Decr. HR Decr. Contractility Decr. Renin release Decr. Vasoconstriction

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CLONIDINE : Adverse effects : Sedation, bradycardia, sexual dysfunction, rebound hypertension, dry mouth, contact Dermatitis, constipation .

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Uses: Management of withdrawal symptoms seen in addicts after withdrawal from opiates, alcohol, and tobacco. Hypertension. In prophylaxis of migraine Preanaesthetic medication For relief of pain- post operative, neuropathic labour pain To control diarrhea in diabetic patients with autonomic neuropathy For diagnosis of pheochromocytoma

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Methyl dopa – Hypertension in pregnancy Tizanidine It is a muscle relaxant. For treatment of spasticity. Apraclonidine and brimonidine – For the treatment of glaucoma

Beta agonists :

Beta agonists Beta 1 and Beta 2 Isoproterenol β 2 - peripheral resistance- diastolic BP and a reflex increase in heart rate. β 1 - Systolic blood pressure does not fall significantly as diastolic so the pulse pressure increases .

Beta 2 selective agonist :

Beta 2 selective agonist Utilized for Tt of asthma – as bronchodilator. Their advantage over non-selective beta agonists, - they do not cause undesired CV effects by stimulating β 1 receptors of the heart. Metaproterenol, Terbutaline, Albuterol, Pirbuterol , formoterol, salmeterol Ritodrine is a selective Beta 2 agonist which was developed as a uterine relaxant. It is used to delay the onset of premature labor.

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Adverse effect Skeletal muscle tremor is the most common. Restlessness, anxiety, tachycardia

Indirectly acting Adrenergic drugs:

Indirectly acting Adrenergic drugs AMPHETAMINE : It is a potent CNS stimulant which is orally effective. Alertness, increased concentration, increased work capacity. RAS is activated – wakefulness. Suppression of appetite – anorectic agent Adverse effects are extension of its therapeutic actions. Dry mouth, metallic taste, psychological dependence and tolerance to anorectic action

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Uses Narcolepsy Attention deficit Hyperactivity disorder (ADHD) Obesity Nocturnal enuresis

Mixed Adrenergic drugs:

Mixed Adrenergic drugs EPHEDRINE : Acts directly on alpha and beta receptors and indirectly also. Effective orally - resistant to MAO Crosses the BBB – CNS stimulation. Used in bronchial asthma and hypotension but not commonly

ALPHA ADRENERGIC ANTAGONIST :

ALPHA ADRENERGIC ANTAGONIST

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Alpha receptors mediate many important actions of endogenous catecholamines. These include: a.  1 mediated vasoconstriction, b.  2 receptor mediated inhibition of the release of NE and ACh, c.  2 mediated inhibition of insulin secretion and inhibition of lipolysis, d.  2 mediated central inhibition of sympathetic tone.

ALPHA BLOCKERS:

ALPHA BLOCKERS SELECTIVE AND NON SELECTIVE Nonselective Irreversible Phenoxybenzamine Nonselective Reversible : Phentolamine, Tolazoline

ALPHA BLOCKERS:

SELECTIVE alpha 1 blockers Prazosin, Terazosin, Doxazosin, Alfuzosin Tamsulosin, Bunazosin, Urapidil, Indoramin Alpha 2 selective : Yohimbine, Idazoxan MISC Ergot alkaloids – Ergotamine ALPHA BLOCKERS

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Pharmacological properties of ALPHA BLOCKADE : CVS Blockade of  1 - vasoconstriction – decrease peripheral resistance – hypotension The magnitude of this effect is dependent upon the degree of sympathetic tone at the time the antagonist is administered. Thus there is less hypotension in the supine than in the standing patient.

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Fall in BP followed by reflex tachycardia, also cardiac output. The reflex effects are exaggerated if the drug also has alpha 2 antagonist effects, because antagonism of alpha 2 receptors facilitates release of NE presynaptically to cause a further tachycardic effect.

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They block the vasoconstriction and hypertensive effects of exogenous sympathomimetics. For example, pressor responses to phenylephrine (a pure  1 agonist) are completely blocked. Pressor responses to EPI can be transformed to depressor responses (EPI reversal) because of stimulation of beta 2 receptors by EPI.

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Alpha 2 antagonists increase sympathetic outflow by an action on the CNS. This potentiates the release of NE from sympathetic nerve endings leading to activation of  1 receptors in vascular smooth muscle, and beta 1 receptors in the heart among others. The net result is an increase in mean blood pressure, and a reflex bradycardia.

Other Actions of Alpha Adrenergic Antagonists :

Other Actions of Alpha Adrenergic Antagonists Alpha antagonists can block  1 receptors that mediate contraction of nonvascular smooth muscle such as the trigone and sphincter muscles of the bladder, leading to decreased resistance to urinary outflow. 2. Activation of  2 receptors causes inhibition of insulin secretion. Blockade of these receptors facilitates insulin release.

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Nasal stuffiness – V.D – congestion of nasal mucosa Miosis Failure of ejaculation – inhibition of contractions of vas deferens and ejaculatory duct

Nonselective alpha adrenergic blockers :

Nonselective alpha adrenergic blockers Phentolamine and tolazoline Competitive antagonist for both  1 &  2 receptors Imidazoline derivative They stimulate GI smooth muscle and gastric secretion Phentolamine is poorly absorbed from GIT, given by I.V while tolazoline is less potent

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Therapeutic uses – For the diagnosis and management of pheochromocytoma For peripheral vascular disease To prevent dermal necrosis To treat hypertensive crisis Adverse effects – Postural hypotension Reflex cardiac stimulation Nausea , vomiting , abdominal pain and ppt peptic ulcer

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Phenoxybenzamine Form covalent bond with alpha receptors – irreversible binding Effects lasts 3-4 days. It also inhibits the uptake of CAs into nerve terminals and extraneuronal uptake sites It irreversibly inhibits responses to ACh, 5-HT, and histamine in higher doses than those required for alpha receptor blockade. Penetrates BBB. Oral absorption is erratic.

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Therapeutic uses – Pheochromocytoma – preferred drug for the preparation of surgery. Inoperable or malignant Pheochromocytoma Given along with metyrosine. Sometime for the treatment of BPH and autonomic hyperreflexia. To treat hemorrhagic and endotoxic shock – to reverse peripheral V.C

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Adverse effects Postural hypotension Reflex cardiac stimulation Reversible inhibition of ejaculation Salt and water retention Cardiac arrythmias Fatigue Sedation Nausea

Selective alpha adrenergic blockers :

Prazosin potent and very selective  1 receptor antagonists. It has 1000X greater affinity for  1 vs  2 receptors. It inhibits phosphodiesterase – thus increase c- AMP By not blocking  2 receptors – does not promote NE release – no tachycardia. Selective alpha adrenergic blockers

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It decreases cardiac preload and afterload It suppress sympathetic outflow from CNS – it appears to depress baroreceptor reflex. Favorable effects on lipid profile – decrease LDL and TGs and increase HDL. It relaxes smooth muscle in the bladder neck, prostatic capsule, prostatic urethra and hence improves urine flow in cases of BPH.

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Therapeutic uses- Hypertension- given at bed time reduces the risk of postural hypotension. To treat BPH For Raynaud’s disease In patients with MR & AR – as it decreases cardiac afterload.

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Adverse effect – First dose effect -That is marked postural hypotension and fainting 30-90 minutes after the first dose. Impotence, nasal congestion, GIT upset and Na+ and water retention

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Terazosin and Doxazosin Same as prazosin but with longer duration of action T1/2 – prazosin is 2-3 hours T1/2 – terazosin is 12 hours T1/2 – doxazosin is 20 hours Once daily dosing Well absorbed after oral absorption Used for hypertension and BPH. Induction of apoptosis in prostate smooth muscle cells

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Tamsulosin Alpha 1 blocker, with little effect on alpha 1B receptors and considerable efficacy at the alpha 1A receptor which is believed to be predominant in human bladder and prostate. It is used in the treatment of BPH because it decreases the resistance to urinary flow, with Less effects on blood pressure

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Alfuzosin is another related compound used in the treatment of benign prostatic hypertrophy. Shorter half life Extensively metabolized by liver , should be avoided in hepatic insufficiency

Receptor regulation :

Receptor regulation Desensitization Continued receptor stimulation by an agonist causes desensitization of the receptor – less responsive to agonist. Develops rapidly Due to phosphorylation of β receptor by β ARK – increase association with β arrestin – disrupts coupling with G protein

Receptor regulation :

Down regulation of receptor Prolonged exposure to high conc. Of agonist causes a reduction in the number of receptors due to internalization or endocytosis of receptor. Receptor regulation

Receptor regulation :

Up regulation of receptor Prolonged exposure to antagonist causes a increase in the number of receptors due to externalization of receptor out again from inside of the cell surface. Supersensitivity – results from denervation, prolong blockade by antagonist, depletion of NT. Receptor regulation

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