Unit VII

Sympathomimetics and
Sympatholytics
Rogie Royce Z. Carandang, RPh, MPH
Hazel Anne L. Catublas, RPh, MS Pharm
Objectives:
At the end of this chapter, the student is expected to:
1. Describe the synthesis of adrenergic NT
2. Understand the classification of adrenergic receptors and of
drugs acting on sympathetic NS
3. Know the specific sympathomimetic drugs
4. Know the following with regards to adrenoreceptor blockers:
 Classification
 MOA
 Pharmacokinetics
 Clinical Effects and indications
5. Study the drug list based on receptors and receptor
Activity
6. Study Adrenergic neuron-blocking agents
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 Synthesis of the Adrenergic NT
Tyrosine HO
NH2 hydroxylase
HO HO

COOH COOH
Tyrosine DOPA

Aromatic L-amino
decarboxylase
Dopamine B-
HO OH hydroxylase HO
NH2
HO HO

Norepinephrine Dopamine
OH
Phenylethanolamine N- OH Rate limiting step:
methyltransferase hydroxylation of tyrosine
NH
H3C OH
Epinephrine 3
Adrenergic Transmission
Reserpine
Metyrosine Tetrabenazine

AP Guanethidine
Guanadrel
Ca+2
NE Ca+2
DA Bretylium α1
DOPA (+)
Tyr NE β1
(-)
NE
NE NE β2
MAO
(-)

α2
Inactive COMT
metabolite
Cocaine
Re-Uptake 2
TCAs
Re-Uptake 1
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 ADRENOCEPTORS
Location Response
Alpha-1 • Blood vessels Vasoconstriction
• Radial muscles (eyes) Mydriasis
• Sphincter muscles Constriction
• Pilomotor muscles Goose bumps
Alpha-2 • Post-synaptic Same as alpha-1
• Pre-synaptic (-) feedback
• Ciliary muscles (eyes) Dec Aqueous humor
Beta-1 • Heart (+) chronotropic
(+) inotropic
(+) dromotropic
• Kidney (JGA) Renin release
 ADRENOCEPTORS cont’d.
Location Response
Beta-2 • Smooth muscles
• Bronchial Bronchodilation
• Uterine Tocolytic effect
• Intestinal Relaxation
• Bladder Relaxation
• Vascular (skeletal Peripheral vasodilation
muscle beds)
• Heart Tachycardia
• Muscle end plate Tremors
• Endothelial cells K+ influx
Beta-3 • Adipose tissues Lipolysis
 Classification of Drugs acting on the
Sympathetic Nervous System
Drugs acting on the sympathetic nervous system may
be:

1. Adrenoreceptor agonists (sympathomimetics)

2. Adrenoreceptor blockers (sympatholytics)

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 General Functions

1. Peripheral excitatory action

2. Peripheral inhibitory action
3. Cardiac excitatory action
4. Metabolic actions
5. Endocrine action
6. CNS actions
7. Presynaptic actions

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 Therapeutic Uses

Shock
Asthma
Allergic reactions
Narcolepsy
Weight reduction
Attention-deficit Hyperactivity Disorder (ADHD)

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 Classification according to MOA

 DIRECT ACTING SYMPATHOMIMETICS

 INDIRECT - ACTING SYMPATHOMIMETICS
 Which may act by displacement of stored catecholamines
 Promotes NE release (e.g. metamphetamine)
 Inhibition of reuptake of stored catecholamines
(e.g. cocaine)

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 Adrenergic Drugs
Sympathomimetic Sympatholytic

α-Blockers β-Blockers
Direct Mixed
acting acting Non- Non-
selective selective
Indirect
α1- β1-
acting selective selective

α2-
selective
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 Sympathomimetic Agents

Norepinephrine
Non-selective Epinephrine
Dopamine
Direct Acting Agents
β-non selective
β1- selective

Selective β2- selective

α1- selective
α2- selective

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 Sympathomimetic Agents
• Prototype: Catecholamines
• Low dose: beta-rec
• High dose: alpha-rec
• Never given PO
NON-SELECTIVE ADRENERGIC AGONIST (beta and alpha)
1. EPINEPHRINE (Adrenaline)
• DOC – Anaphylaxis/ anaphylactoid rxn
• Cardiac stimulant
• Local vasoconstrictor – combined w/ lidocaine
• Given in the form of Dipivefrin (pivalic ester derivative) –
prodrug for Mx of glaucoma
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 Sympathomimetic Agents
2. Norepinephrine (Levophed)
• Primarily stimulates the alpha-1 and beta-1
• Mx of shock (esp septic shock due to overwhelming
infection
3. Dopamine (Docard)
• 1-3ug/kg/min - D1 - renovasodilation (diuresis) for
oliguria (urine volume is <500cc/24h), acute renal failure
(given w/ furosemide)
• 2-5ug/kg/min - B1 - inotropic effect (Mx of cardiogenic
shock)
• >5ug/kg/min - A1 - vasoconstriction
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 Sympathomimetic Agents
BETA – NONSELECTIVE ADRENERGIC AGONIST
1. Isoproterenol/Isoprenaline
> synthetic catecholamine
– Before for BA
– Problem: cardiotoxicity (arrhythmia)
– Now used as inotropic agent (cardiac stimulant)

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 Sympathomimetic Agents
B1-SELECTIVE ADRENERGIC AGONIST
1. Dobutamine (Dobutrex)
at low dose:
- cardiac stimulant
- Mx of cardiogenic shock
- Mx of acute HF
- Diagnostic agent
- P’cologic stress testing (dobutamine stress test)

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 Sympathomimetic Agents
B2- SELECTIVE ADRENERGIC AGONISTS
• E.g. Terbutaline (Bricanyl) , Salbutamol (Ventolin), Fenoterol,
Formoterol, Salmeterol, Bambuterol, Ritodrine, Isoxuprine
(Duvadilan)
• Clinical Use:
– Mx of BA (relievers of acute attack, controllers)
– Control premature labor
– Mx of symptomatic bradycardia (terbutaline)
– Mx of hyperkalemia
• S/E:
– Tremors, fasciculations
– Hypocalcemia
– Tolerance (fenoterol) 17
 Sympathomimetic Agents
A1 - SELECTIVE ADRENERGIC AGONIST
a. Phenylephrine (Neo-Synephrine, Dimetapp)
b. Phenylpropanolamine (Neozep, Decolgen, Tuseran, Disudrin,
Sinutab)
c. Methoxamine
d. Propylhexidrine
e. Tetrahydrozoline
f. Oxymetazoline
g. Xylometazoline

- Use: decongestant
 Sympathomimetic Agents
A1 - SELECTIVE ADRENERGIC AGONIST

- SE:
- Oral admin:
- Can cause or exacerbate HTN
- Ppt urinary retention in Px w/ BPH
- Can interact w/ MAO-I leading to HTNsive crisis
- Tolerance – if taken more than 5 days
- Local admin:
- Rhinitis medicamentosa (rebound hyperemia/congestion)
- If nasal spray is used >3days
 Sympathomimetic Agents
A2- SELECTIVE ADRENERGIC AGONISTS
1. Clonidine (Catapress)
- Dual effect
- Use:
- Mx of HTNsive crisis
- Alternative for mx of HTN
- Maybe useful in Mx of ADHD
- SE:
- Sedation/depression
- Rebound HTN (clonidine-induced HTNsive crisis)
- Remedy: reinstitute, give labetalol, give Na
nitroprusside
 Sympathomimetic Agents
A2- SELECTIVE ADRENERGIC AGONISTS
2. Apraclonidine, Brimonidine
3. Methyldopa (Aldomet)
- prodrug
- Eclampsia
- SE:
- Sedation.depression
- (+) coomb’s test – Penicillin also give this rxn
- Hepatotoxicity – dose >2g/day

4. Guanfacine
5. Guanabenz
- Hypotensive agents
 Sympathomimetic Agents

Cocaine
Re-Uptake 1
Inhibitors
TCAs

Indirect Acting
Agents
Amphetamine
Ephedrine
Releasers
Angiotensin II
Tyramine

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 Sympathomimetic Agents
Indirect Acting Agents
1. Tyramine
- Red wine, beer, cheese, chocolates, smoked fish, fava
beans
- Can cause HTN in patients taking MAO inhibitors

2. Amphetamines
- Use for Attention Deficit Hyperactivity Disorder (ADHD)
- Also as appetite suppressant
- S/E: HTN, tachycardia, dependence, insomnia, seizures,
psychosis 23
 Sympathomimetic Agents
Phenylpropanolamine

Ephedrine
Mixed Amphetamine
Acting
Agents Hydroxyamphetamine

Propylhexedrine

Pseudoephedrine

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 Sympathomimetic Agents
Mixed Acting Agent
1. Ephedrine
- Alkaloid from ma huang (Ephedra sinica)
- I: Urinary incontinence, bronchospasm, hypotension,
nasal congestion, narcolepsy
- S/E: HTN, tachycardia, arrhythmia, insomnia

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 OH OH
N-CH3 N

CH3 CH3
Ephedrine PPA

Hyrdoxyamphetamine

N-CH3 N N
HO
CH3 CH3 CH3
Methamphetamine Amphetamine

CH3
N-CH3 N N
HO

CH3 CH3 Tyramine

Propylhexedrine Phentermine
 Adrenoceptor Blockers
Counter sympathetic effects
 Classified as:
A. Alpha-blocking agents
B. Beta-blocking agents

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 Sympatholytic Agents
Phenoxybenzamine
Non-
selective Phentolamine
Tolazoline

Alpha
Blockers Prazosin
Doxazosin
α1- selective
Terazosin

Selective Tamsulosin

α2- selective Yohimbine

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 Classification of Alpha-blocking agents
Classification based on:
1. Selectivity for α1 versus α2 receptors
e.g. prasozin is α1 selective
yohimbine and rauwolscine are α2 selective
2. Reversibility and duration of action
e.g. Phenoxybenzamine is irreversible and long acting
Phentolamine and tolazoline are reversible and short
acting

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 Clinical Effects and Indications
Drug Effects Clinical Uses
Classification
Non-selective  Block a mediated  treatment of
α-blockers responses pheochromocytoma
 reduce vascular tone  treatment of
 cause baroreceptor hypertension due to
reflex tachycardia overdose with cocaine,
 reversal of amphetamine
epinephrine mediated  male sexual dysfunction
pressor effects (direct penile injection of
phentolamine or
yohimbine)

Pheochromocytoma  tumor of adrenal glands producing excessive Epi, NE

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 Clinical Effects and Indications

Drug Effects Clinical Uses

Classification
Selective α –  less marked  hypertension
blockers tachycardia than non-  urinary hesitancy
selective agents Prevention of urinary
retention

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 Beta-blocking Drugs
• These drugs clinically resemble isoproterenol
• Propranolol (prototype drug)
similar in function with to isoproterenol
hypertension and thyrotoxicosis
• Metoprolol and Atenolol
Hypertension
 preferred in patients with diabetes and peripheral
vascular disease

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 Classification of β - blockers
1. Receptor selectivity
 β1 receptor selectivity: Metoprolol, atenolol,
acebutolol
 β2 receptor selectivity: butoxamine (research
drug only)
 Non-selective: labetalol (also block α1 receptors)

2. Partial agonist activity

 Intrinsic sympathomimetic activity (ISA)
 Partial bronchodilation: pindolol, acebutolol 33
 Classification of β - blockers
3. Local Anesthetic Activity
 Membrane stabilizing activity (through blockade of Na+
channels): absent from timolol

4. Pharmacokinetics
 Short-acting ester beta-blocker: esmolol (used only
parenterally)
 Longest acting beta-blocker: Nadolol
 Lipid solubility: acebutolol and atenolol are less lipid
soluble

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 Sympatholytic Agents
Propranolol
Non-selective Nadolol
Timolol

Beta Metoprolol
Blockers Acebutolol
Atenolol
β1- selective
Bisoprolol
Betaxolol
Esmolol
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 Sympatholytic Agents
USES of Beta-blockers:
• 1st line in HTN
• Mx of stable CHF
• Prophy for angina – ‘DOC in Mx of chronic stable
angina
• Antiarrhythmic – Propranolol, Esmolol, Acebutolol
• Prophylaxis for Migraine
• Mx Sx of hyperthyroidism
• Mx of Glaucoma
• Mx of Familial tremors
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 Sympatholytic Agents
Cautions/ Precautions/Side effect of beta blockers
• Mask Sx of hypoglycemia
• Avoided in Px w/ peripheral arterial occlusive disease
– blocking B2 will ppt vasospasm and pain
• Avoided in Pxs w/ bronchospastic diseases
• Avoid concomitant use w/ non-DHP CCBs
• Dec exercise tolerance
• Bradycardia, heart block
• Rebound tachycardia & HTN when abruptly
withdrawn (upregulation of receptors)
• Dyslipidemia (inc cholesterol level) 37
 Summary
CATECHOLAMINES

DRUG RECEPTORS
Epinephrine α1,α2, β1, β2
Norepinephrine (Levophed) α1,α2, β1
Isoproterenol (Isuprel) β1, β2
Dobutamine (Dobutrex) β1 (α1)
Dopamine (Intropin) D-1 (α1 and β1 at high doses)

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 Summary
DIRECT ADRENOCEPTOR AGONISTS
DRUG RECEPTORS
Phenylephrine (Neo-synephrine) α1
Methoxamine (Vasoxyl) α1
Oxymetazoline (Afrin) α1,α2
Clonidine (Catapress) α2
Ritodrine (Yutopar) β2
Terbutaline (Brethine) β2
Albuterol (Ventolin, Proventil) β2
Salmeterol (Serevent) β2
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 Summary
INDIRECT SYMPATHOMIMETICS
DRUG RECEPTORS
Ephedrine, pseudoephedrine Release and direct
receptor activation
Cocaine Uptake 1 inhibitor
Tyramine release
Amphetamine See ephedrine but
greater CNS actions

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 Summary
ALPHA ADRENOCEPTOR ANTAGONISTS
DRUG RECEPTORS
Prazosin (Minipress) α1
Terazosin (Hytrin) α1
Doxazosin (Cardura) α1
Phentolamine (Regitine) Non-selective
Phenoxybenzamine Only slightly selective for α1
(Dibenzyline) (non-competitive)
Tolazoline (Priscoline) Non-selective
Labetalol (Trandate, α1 (also non-selective beta
Normodyne) antagonist)
Yohimbine (Yocon) α2 41
 Summary
BETA ADRENOCEPTOR ANTAGONISTS
DRUG RECEPTORS
Propranolol (Inderal) Non-selective
Metoprolol (Lopressor) β1
Esmolol (Brevibloc) β1
Atenolol (Tenormin) β1
Nadolol (Corgard) Non-selective
Timolol (Blocadren) Non-selective
Pindolol (Visken) Non-selective (partial agonist)
Labetalol (Trandate, Non-selective (selective α1 –
Normodyne) antagonist)
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 Summary
ADRENERGIC NEURON BLOCKING DRUGS
DRUG RECEPTORS
Reserpine  non-selective blockade of
vesicular uptake and storage of
biogenic amines
Guanethidine (Ismelin)  similar to reserpine: uptake 1
dependent

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End of Lecture! ^o^

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