SYMPATHOMIMETIC DRUGS. ALPHA ADRENERGIC AGONISTS 1 -Selective Agonists Major effects due to...

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SYMPATHOMIMETIC DRUGS

Transcript of SYMPATHOMIMETIC DRUGS. ALPHA ADRENERGIC AGONISTS 1 -Selective Agonists Major effects due to...

Page 1: SYMPATHOMIMETIC DRUGS. ALPHA ADRENERGIC AGONISTS  1 -Selective Agonists  Major effects due to stimulation of  1 receptors in vascular smooth muscle.

SYMPATHOMIMETIC DRUGS

Page 2: SYMPATHOMIMETIC DRUGS. ALPHA ADRENERGIC AGONISTS  1 -Selective Agonists  Major effects due to stimulation of  1 receptors in vascular smooth muscle.

ALPHA ADRENERGIC AGONISTS

1-Selective Agonists

Major effects due to stimulation of 1 receptors

in vascular smooth muscle

Increase in peripheral vascular resistance & BP

Clinical utility limited – some use in hypotension and shock states

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PhenylephrineDirect simulation of 1 receptors

Methoxamine

Methoxamine: Relatively selective 1-agonist; No action at receptors.CV effects : BP, Reflex bradycardiaMay be used IV in hypotensive states

Phenylephrine: 1 selective, actions at much higher dosesEffects similar to methoxamineUses: nasal decongestant,

mydriatic – local instillation

1 – Selective Agonists

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Xylometazoline Oxymetazoline Naphazoline:

Direct 1 – agonists,

Used as nasal decongestants

Rebound hyperaemia occurs

1 – Selective Agonists

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Used primarily for treatment of systemic hypertension.

Selective actions on 2-adrenoceptors

Decrease release of NE from presynaptic terminals

Act at brainstem level to central sympathetic tone

2 – Selective Agonists

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Clonidine:– Selective action on 2 (partial agonist with high affinity) Developed as a nasal decongestant Produces hypotension, sedation, bradycardia and mild analgesiaMajor effects on BP IV : in BP (peripheral receptors on blood vessels) – short lasting Followed by prolonged hypotensive effect Mainly central (lower brainstem) + NE release from terminals. Oral: The early hypertensive phase is not seenAdditional effects: Bradycardia ( Vagal tone)

Sedation Mild analgesia

2 – Selective Agonists

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Well absorbed orally – 100 % bioavailability

Peak effect 1-3 hours

50 % excreted unchanged

ADVERSE EFFECTS : Dry mouth, sedation, sexual dysfunctionMarked bradycardia in someRebound hypertension following sudden stoppage

USES: HypertensionTt. of symptoms of narcotic withdrawal Menopausal hot flashes (lower doses)

Guanfacine and Guanabenz : similar to clonidine

Clonidine….

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α-Methyldopa : Converted to α-MNA which acts like clonidine

Prodrug

Tizanidine: Has same effects like clonidine Used mainly for relieving muscle spasticity of cerebral or spinal origin

Apraclonidine: Used locally to IO pressure ? aqueous formation

2 – Selective Agonists

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Isoproterenol ( Isoprenaline)

Synthetic catecholamine

Extremely potent receptor agonist – NON SELECTIVE

Little effect on receptors

+ve inotropic and chronotropic actions – palpitations, HR, arrhythmias

Potent vasodilator – marked in CO, in diastolic and mean BP

Relaxes all smooth muscles (esp. bronchial and GIT)

USES: Bradycardia and heart block – has been replaced by other drugs

BETA ADRENERGIC AGONISTS

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DOBUTAMINE : 1- selective agonist (also has receptor actions) Resembles Dopamine But no action on DA receptors Major actions are receptor mediated

EFFECTS: +ve inotropic and chronotropic effects > isoprenaline in SA node automaticity < than Isoprenaline Total peripheral resistance not affected much

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ADVERSE EFFECTS:

Excessive in HR and BP (specially in hypertensives)

Ventricular ectopics may occur

in infarct size in MI – ( in oxygen demand)

Tolerance to effects may develop in some cases

USES:

Short term Tt. of cardiac decompensation

eg. Cardiac surgery, MI

Plasma t ½ of 2 minutes hence given by infusion

DOBUTAMINE :

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2- selective agonists

Selectivity is relative – lost at higher doses

Developed mainly for use as Bronchodilators with low CV effects

Also used for Uterine Relaxant effect

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Terbutaline, Albuterol (salbutamol), Metaproterenol , Salmeterol

Not metabolized by COMT -- Better oral bioavailability

Pharmacological effects: Bronchodilatation - 2 receptors on bronchial

smooth muscleMay also :- Suppress release of leukotrienes and

histamine

Enhance mucociliary function microvascular permeability

phospholipase A2 activity

Uterine relaxant action -- 2 receptors on uterine muscle

2- selective agonists

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2- selective agonists

Adverse effects:

Mainly due to excessive dosage loss of selectivity 1 CVS effectsAdverse effects are limited when used by inhalational route in Asthma

Terbutaline and Albuterol : Effective orally, sc, inhalation Rapid onset, duration 3 – 6 hrs

Use: Long term Tt of COPD ; Ac bronchospasm; Tocolytic

Metaproterenol : less 2 selective

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2- selective agonists

Salmeterol : 2 selective and long acting (12 hours)Onset of action slowNot suitable alone for Acute attack

Ritodrine: Developed specially as a uterine relaxant Properties similar to other agents Rapidly absorbed after oral intake Administered IV to arrest premature labour

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Receptor Affinity

Alpha agonists

Phenylephrine, methoxamine

Clonidine, MNA

α1> α2 >>>>> β

α2> α1 >>>>> β

Mixed α and β agonists

Noradrenaline

Adrenaline

α1= α2 ; β1>> β2

α2= α1 ; β1= β2

Beta agonists

Dobutamine

Isoproterenol

Terbutaline, Albuterol, Ritrodine

β1> β2 >>>> α

β1= β2 >>>> α

β2 > β1 >>>> α

Dopamine agonists

Dopamine D1 = D2 >> β >> α

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INDIRECTLY ACTING SYMPATHOMIMETICS

A. By releasing catecholamines from neurones Amphetamine: Powerful CNS stimulant actions Orally effective Abused for psychic effects wakefulness, mood elevation, alertness, self-confidence, concentration, fatigue Performance enhanced but chances of errors ↑ Tolerance occurs Long term use followed by fatigue and exhaustion

Toxicity: Acute – extension of sympathomimetic effects Chronic – Wt. Loss, psychotic reactions, dependence

Uses: NarcolepsyAttention-deficit hyperactivity disorderObesity - apetite suppression ?

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INDIRECTLY ACTING SYMPATHOMIMETICS

Tyramine : Not used clinically Importance – Present in several foods

(cheese, beer, red wine) Interaction with MAO inhibitors : severe toxic effects – severe hypertensive crisis “Cheese Reaction”

Methylphenidate : Structurally related to amphetamine Mild CNS stimulant – actions on mental > motor functions Used for Attention-deficit hyperactivity disorder

Modafinil : Newer agent, Similar to amphetamine , lower side effects

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Ephedrine : (& pseudoephedrine) Mixed actions ( release + direct effects ) Stimulates and receptors Effective orally: BP, HR, Bronchodilatation, CNS ↑ Duration : several hours – t1/2 3-6 hrs ; Tachyphylaxis occurs USES: Bronchodilator, decongestant ADVERSE EFFECTS : BP, Insomnia, Urinary retention in elderly

INDIRECTLY ACTING SYMPATHOMIMETICS

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Mephentermine Direct & +

Metaraminol Indirect (release of NE)

Effects due to 1 stimulation + Indirect ( + )HR, force of contraction, CO, systolic and

diastolic BP.

Uses : To prevent excessive hypotension during spinal anaesthesia, Other hypotensive states To relieve attacks of PAT

Adverse effects: CNS stimulation, Excessive BP,

Arrhythmias

INDIRECTLY ACTING SYMPATHOMIMETICS

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THERAPEUTIC USES OF SYMPATHOMIMETIC AGENTS

ShockHypotensive statesHypertension (2 –agonists)

Local vascular effectsNasal decongestant (α1 agonists)

Ophthalmic uses {Mydriasis (α1); Glaucoma (α2)

Asthma and COPD (β2 agonists)

Allergic reactionsNarcolepsyWeight reductionAttention-deficit hyperactivity disorder in childrenTocolytic (2 – agonists)

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INDIRECTLY ACTING SYMPATHOMIMETICS

B. By blocking reuptake of released transmitter

Cocaine :

Peripheral sympathomimetic actions,

Amphetamine like CNS actions - drug of abuse.

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Alpha methyl NA ( selective action on α2 )

Alpha methyl DA

Alpha methyl DOPA