sympathomimetic drugs. alpha adrenergic agonists 1 -selective agonists major effects due to...
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SYMPATHOMIMETIC DRUGS
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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