Sympathetic Agonist and Antagonist

Sympathetic Nervous System

• Adrenergic System
• Fight or Flight response
• Release NE from nerve terminals which activates adrenoreceptor from target sites
• IN response to stress the adrenal medulla releases epinephrine to act on target tissues
• Norepinephrine – neurotransmitter, Epinephrine – Hormone

Found on Thoracolumbar area

Collateral Ganglia

• Celiac ganglion
• Superior mesenteric ganglion
• Inferior mesenteric ganglion

Activated in the four E’s

• Excitement
• Emergency
• Embarrassment
• Exercise

COMPARISON OF ACTION OF PNS AND SNS

Adrenoceptors

• Alpha 1- formation of IP3 and Dag, increases intracellular Calcium

• Alpha 2 – inhibits adenylyl cyclase, decreased cAMP
• Beta 1- stimulation of adenylyl cyclase, increased cAMP
• Beta 2 - stimulation of adenylyl cyclase, increased cAMP, activates cardiac G1 under some
conditions
• D1 & D5 – stimulation of adenylyl cyclase, increased cAMP
• D2 – inhibits adenylyl cyclase and increase Potassium Conductance
• D3 – inhibits adenylyl cyclase
• D4 – inhibits adenylyl cyclase

TYPES, TISSUE AND ACTIONS

Alpha 1- activates G q coupling protein, activates PLC then IP3 and DAG

IP3- increase cytoplasmic CA

DAG- activates PKC, GDP and GTP

Alpha 2 – inihibit thru Gi decreasing or inactivating adenylyl cyclase

Beta receptor- GDP to GTP by Gs to stimulates Adenylyl cyclase leading to increase in cAMP

Sympathetic Agonist or Sympathomimetic Agonists

Divided into 2:

• Direct acting
o Alpha- agonists
▪ Non selective
▪ A1 selective
▪ A2 selective
o Beta- agonists
▪ Non selective
▪ B1 selective
▪ B2 selective
• Indirect acting
o Releasers
o Reuptake Inhibitors

Examples:

• Direct acting
o Epinephrine
o Phenylephrine
o Isoproterenol
 o Norepinephrine
o Dobutamine
o Clonidine
• Indirect acting
o Tyramine
o Amphetamine
o Cocaine
• Mixed Acting
o Dopamine
o Amphetamine
o Metaraminol
o Ephedrine
o Phenylpropanolamine

Endogenous Catecholamines

o Epinephrine
▪ Alpha and beta agonist
▪ Very potent vasoconstrictor and cardiac stimulant
▪ Released from the adrenal medulla
o Norepinephrine
▪ Alpha 1 and alpha 2 agonists,
▪ Beta 1 agonists
▪ No effect on beta 2 receptors
▪ Increases peripheral resistance and both diastolic and systolic blood pressure
o Dopamine
▪ Immediate precursor of NE
▪ Regulate Na excretion and renal functions
▪ CNS neurotransmitter; involved in the reward stimulus in addiction

Direct Acting Sympathomimetics

• Phenylephrine
o Pure alpha 1 agonist
o Effective mydriatic and decongestant; can be used to raise BP
• Midodrine
o Prodrug that is enzymatically hydrolyzed to desglymidodrine
o A selective A1 receptor agonist
o Treatment for orthostatic hypotension, typically due to impaired ANS function
• Clonidine
o Alpha 2 selective agonist
o Centrally acting antihypertensive
o Has analgesic effect
o Decrease intraocular pressure
 o Diagnostic for pheochromocytoma
o Reduce withdrawal symptoms for narcotic abuse
• Dexmedetomidine
o 7x more selective alpha 2 agonist than clonidine
o Clinical effects: sedation, BP and HR reduction
o Decrease catecholamine levels, little respiratory depression
Side effects: rebound hypertension, rebound hyperexcitability, arrythmias
• Oxymetazoline
o Alpha 2A agonist that is used as a decongestant
o Promotes constriction of the vessels in the nasal mucosa and conjunctiva
• Isoproterenol
o VERY POTENT BETA RECEPTOR AGONIST
o Potent vasodilator
o Increases cardiac output with a decrease in MAP and diastolic pressure
• Dobutamine (with weak a1 and b2 agonism)
o Beta 1 selective agonist
o Increases cardiac output with less reflex tachycardia as compared to non selective beta
agonists
• Ephedrine
o High bioavailability and relatively long duration of action
o Mild stimulant

INDIRECT ACTING SYMPATHOMIMETICS

• Amphetamine- like
o Amphetamine
o Metamphetamine
o Methylphenidate
o Modafinil
o Tyramine
• Catecholamine reuptake inhibitor
o Atomoxetine – attention deficit disorder
o Reboxetines – major depression disorder
o Duloxetine – anti-depressant
o Cocaine - inhibit dopamine reuptake into neurons in the pleasure center of the brain

DOPAMINE AGONISTS

• Levodopa
o Parkinson’s diseases and prolactinemia
• Fenoldopam
o D1 receptor agonist that selectively leads to peripheral vasodilation in some vascular
beds
o IV treatment of severe hypertension
Clinical uses for Sympathetic Agonists

Cardiovascular:

• Acute hypotension
• Chronic orthostatic hypotension
• Cardiac Application: Dobutamine stress test
• Local Vasoconstriction

Pulmonary:

• COPD
• Asthma

Treatment for :

• Anaphylaxis
• Ophthalmic application
• Genitourinary
• CNS

Sympathetic Antagonists

Adrenergic Neuro Blockers (ANB)

• Guanethedine, Reserpine

Adrenergic Receptor Blockers (ARBS)

• Reversible- Prazosin, Phentolamine, Tolazoline, Labetalol, Ergot Alkaloids

• Irreversible- Phenoxybenzamine, DIbenamine
 Yohimbine
• Treatment of orthostatic hypotension
• Promotes NE release through blockade of alpha 2 receptors
• Used as a drug for Erectile Dysfunction
• Reverses the antihypertensive effect of Clonidine
• Increases BP if given with NE transport blocking drug

Prazosin

• Highly selective for alpha 1 receptor than alpha 2 receptor a1>a2

• Relaxes both arterial and venous vascular smooth muscle, smooth muscle in the
prostate
• Blockade to alpha 1 receptors at the base of the bladder decreases resistance to urine
flow
• Extensively metabolized in the liver
• 50% of the drug is available after oral administration
• Half life: 3 hours
Doxazosin

• Hypertension and Benign Prostatic Hyperplasia

• Half life: 22 hours
Tamsulosin

• Competitive alpha 1 antagonist

• High Bioavailability
• Half life: 9-15 hours
• Greater potency in inhibiting contraction in prostate smooth muscle vs other alpha 1
selective antagonists
CAUTION: CATARACT surgery- intraoperative floppy iris syndrome
PHENOXYBENZAMINE (NON SELECTIVE ALPHA BLOCKER)

• Irreversible non competitive blockade (half life14-48 hrs)

• Inhibits NE reuptake
• Blocks H1, acetylcholine and serotonin receptors
• Blocks catecholamine- induced vasoconstriction
• Epinephrine Reversal
• Clinical Indication:
o Pheochromocytoma
o Male erectile dysfunction
o Peripheral vascular diseases
Adverse effect: postural hypotension and tachycardia
 PHENTOLAMINE
• Competitive antagonist
• Half life 4 hrs
• (it is reversible) Epinephrine used for reversal
• Reduce PVR
• Cardiac Stimulation that leads to baroreflex and High NE release
• Inhibit serotonin responses
Indication:
Pheochromocytoma, male erectile dysfunction
Adverse effect: severe tachycardia, arrythmia, myocardial ischemia and GI stimulation

Clinical Uses for Sympathetic Antagonists:

• Pheochromocytoma
• Hypertensive emergencies
• Chronic Hypertension
• Peripheral Vascular Disease
• Urinary Obstruction
• Erectile Dysfunction
Beta blockers:
Types:

• Classical non selective beta blockers (1st gen)

o Nadolol, Pebutolol, Pindolol
o Propranolol, Timolol
• Beta 1 selective beta blockers (2nd gen)
o Acebutolol, Atenolol, Bisoprolol
o Esmolol, Metaprolol
• Non selective beta blocker with additional action (3rd gen)
o Carteolol, Carvedilol, Labetalol (A1,B1,B2) with a1 but weak
• Beta 1 selective blocker with additional actions (3rd gen)
o Betaxolol, Celiprolol (additional action of betaxolol is calcium channel blockage
which leads to vasodilation)
PHARMAKOKINETICS:

• ORAL: PEAK IN 1-3 HRS

• EXTENSIVE FIRST PASS METABOLISM
HALF LIVES: 3-10 HOURS
o ESMOLOL: 8-10 MIN
o NADOLOL: 24 HRS
PHARMACODYNAMICS

• CVS: (-) INOTROPIC AND (-) CHRONOTROPIC

• Leads to respiratory bronchoconstriction
• Eye: Reduce intraocular pressure
• Metabolic and Endocrine:
o Inhibits lipolysis
o Partial inhibition of glycogenolysis
o Increases VLDL and Lowers HDL and HDL: LDL ratio
• MSA- has local anesthetic action (MEMBRANE STABILIZING ACTIVITY)
PROPERTIES OF BETA-BLOCKERS
Intrinsic sympathomimetic activity (ISA) - characterizes a group of β blockers that are able to
stimulate β-adrenergic receptors (agonist effect) and to oppose the stimulating effects of
catecholamines (antagonist effect) in a competitive way.
Some beta-blockers also possess what is referred to as membrane stabilizing activity (MSA). This
effect is similar to the membrane stabilizing activity of sodium-channels blockers that
represent Class I antiarrhythmics.
SELECTIVE BETA 1 BLOCKERS:

NON SELECTIVE BETA 1 BLOCKERS

CARVEDILOL

• NON-selective with alpha 1 blocking activity

• Inhibits beta receptors than alpha 1 receptors
• Attenuate oxygen free radical- initiated peroxidation
• Inhibit vascular smooth muscle mitogenesis
• Beneficial effects in chronic heart failure
LABETALOL

• Reversible adrenoreceptor antagonist

• (S,R) isomer- is an alpha blocker which is alpha 1 selective
• (R,R) isomer- beta blocker
• Causes Hypotension but with less tachycardia
NEBIVOLOL

• Most highly selective beta 1 adrenergic receptor blocker

• Vasodilator due to its action on endothelial nitric oxide production
• May increase insulin sensitivity and does not affect lipid profile

Third generation beta blockers (b1 selective) with additional cardiovascular action

CLINICAL USES OF BETA BLOCKERS:

• Hypertension
• Cardiac Arrthymias
• Angina
• CHF: Metaprolol, Bisaprololl, Carvedilol, Propanolol
• Glaucoma: Timolol, Betaxolol.Carteolol, Levobunolol
• Neurologic: Migraine, somatic management of anxiety, alcohol withdrawal
• Misc: reduce portal vein pressure in cirrhosis
TOXICITIES IN BETA BLOCKER

• Drug Allergy: rare

• CNS effects: Sedation, sleep disturbances, depression and psychotic reactions
• Worsening of preecisting asthma and airway obstruction
• Depress myocardial contractility and excitability
• Hypoglycemic episodes
DRUG INTERACTION:

• Verapamil
o SEVERE HYPOTENSION
o BRADYCARDIA
o CHF
o ARRYTHMIA