Adrenergic Drugs

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 Outlines
1. Adrenergic agonists
 Direct acting
• Alpha agonists
• Beta agonists
 Indirect acting
2. Adrenergic antagonists
 Indirect acting
 Direct acting
• Non-selective
• Selective
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1. Adrenergic Drugs

A. Adrenergic Agonists
 Sympathomimetics
• Drugs that bind to and activate adrenoceptors directly or
indirectly.
• Resemble sympathetic nervous stimulation in their effect
 Classification Adrenergic agonists
 Based on chemistry:
1. Catecholamines
• Contain a catechol nucleus & an amine group
 Includes
• Natural: NE, EP & DA
• Synthetic: Isoproterenol & dobutamine

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• Common properties:
1. Relatively potent
2. Orally inactive
3. A brief duration of action
4. Cannot cross the BBB
2. Noncatecholamines
• No catechol nucleus
• Ephedrine, phenylephrine, amphetamine, terbutaline,…
• Direct or indirect action
• Common features:
1. Less potent
2. Orally active
3. Longer duration of action
4. CNS active
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Based on mechanism of action:

1. Direct acting
• Mimic noradrenergic transmission by activating adrenoceptors
2. Indirect acting
a) Promotion of norepinephrine (NE) release
a) Amphetamines
b) Blockade of NE reuptake
• Cocaine and the tricyclic antidepressants (e.g.,
imipramine)
c) Inhibition of NE inactivation
• MAOIs & COMTIs
3. Mixed-acting- direct & indirect
• Ephedrine
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 Both types of sympathomimetics, direct or indirect,
ultimately cause activation of adrenoceptors leading to
some or all characteristic effects of the catecholamines.
Cardiovascular Actions
• The SNS plays an important role in regulating the CV
system.
• By interacting with receptors, adrenergic drugs directly
alter:
• The rate & force of contraction of the heart
• Tone of blood vessels
• This can result in compensatory reflexes to regulate BP,
i.e., drugs that cause vasoconstriction cause reflex
slowing of the heart.
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Direct-Acting Adrenergic Agonists

• Most common
• Mimicking the actions of natural transmitters (NE, EP, DA).
 Alpha1 activation
• Epinephrine, NE, phenylephrine, ephedrine & dopamine
 Therapeutic applications
• Because of its ability to cause alpha1-mediated
vasoconstriction [skin, viscera & mucous membranes]
used:
1. Mydriasis- eye examination & ocular surgery
2. Hemostasis- control superficial bleeding - EP
3. Reduce nasal congestion- phenylephrine (topically) &
ephedrine (PO)
4. Adjunct to local anesthesia- EP
5. Elevation of BP-hypotensive pts
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• Adverse effects
1. HTN
2. Necrosis- extravasation (Rx-phentolamine)
3. Reflex bradycardia

 Alpha2 activation
• Eg. Guanabenz, guanfacine, clonidine, tizanidine
• Alpha 2 receptors are found both in the brain and the
periphery
• Alpha2 receptors in the periphery are located presynaptically
• Their activation inhibits NE release
• Epinephrine, NE, ephedrine
• No therapeutic applications related to activation of
peripheral alpha2 receptors
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Centrally Acting Alpha2 Agonists

• Act within the CNS to reduce the firing of

sympathetic neurons
• Inhibit the firing of sympathetic neurons
• Decrease the release of NE from sympathetic nerves
• Decrease activation of peripheral adrenergic receptors
1. Clonidine
• An antihypertensive drug that acts within the CNS
• An alpha2-adrenergic agonist
• Causes selective activation of alpha2 receptors in the CNS, in
brainstem
• Reduces sympathetic outflow to blood vessels and the heart

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• Pharmacologic effects
• ↓ BP by VD
• But not ↓HR or CO

• Therapeutic uses
• HTN

• Adverse effects
• Hemolytic anemia- Hg/hematocrit/RBC count
• Hepatotoxicity- LFT
• Others- xerostomia, sexual dysfunction, orthostatic
hypotension, and a variety of CNS effects

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2. Guanabenz and Guanfacine
• Similar action as clonidine
• Activate brainstem alpha2-adrenergic receptors
• Share the major adverse effects of clonidine

3. Methyldopa and Methyldopate

• Methyldopa is an oral antihypertensive agent
 Action is identical to clonidine
 But it is a prodrug of methyl NE
 Lowers BP by acting at sites within the CNS
• Methyldopate is an IV agent
 It is nearly identical to methyldopa in structure &
action

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 Beta1 activation
• Activated by epinephrine, NE, isoproterenol, dopamine,
dobutamine, and ephedrine
• Therapeutic applications
1. Cardiac arrest-[Rx-EP]
2. Heart failure—dobutamine
3. Shock—dopamine
4. Atrioventricular (AV) heart block--EP
• Adverse effects
• Altered heart rate or rhythm [tachycardia &
dysrhythmias]
• Angina pectoris

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Beta2 activation
• Ephedrine, epinephrine, isoproterenol, and terbutaline
• Therapeutic applications
1. Asthma-terbutaline [inhalation]
2. Delay of preterm labor [retodrine]
• Adverse effects
• Hyperglycemia- liver & muscle glycogenolysis
• Tremor- enhanced skeletal muscle contraction
 Dopamine receptor activation
• Causes dilation of the vasculature of kidneys
• Treatment of shock
• Dopamine

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Non-selective Direct Acting Adrenergic Agonists

1. Epinephrine [Adrenaline]
• A catecholamine
• Acts on alpha1, alpha2, beta1, beta2
Therapeutic uses
1. To delay absorption of LAs
2. To control superficial bleeding
3. To elevate BP
4. Nasal decongestion
5. Mydriasis
6. To overcome AV block
7. To overcome cardiac arrest
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8. Promotes BrD- asthma
9. For anaphylactic shock
 Pharmacokinetics
• May be administered:
 Topically
 By injection (IM)
 By inhalation
 Inactivation
• Enzymatic (MAO, COMT)
• Uptake
Adverse effects
1. Hypertensive crisis- cerebral hemorrhage
2. Dysrhthmias- hyperthyriod pts
3. Angina pectoris- pts with coronary atherosclerosis
4. Necrosis- following extravasation (IV phentolamine)
5. Hyperglycemia-beta2-mediated liver & muscle
glycogenolysis- diabetic pts 16
6. Severe vasoconstriction- gangrene of extremities
2. Norepinephrine

• A catecholamine
• Acts on alpha1, alpha2, beta1
• Similar to EP
• Only differ from EP, does not act on beta2 receptor
• Nearly identical adverse effects to EP
• But not promote hyperglycemia
• Similar drug interaction as EP
• But limited clinical applications
 Only for hypotensive states and cardiac arrest
• Given as IV infusion

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3. Isoproterenol, metaproterenol (noncatecholamine)

• A catecholamine
• Acts on beta1 and beta2
Therapeutic uses
1. Cardiac disorders- AV block, cardiac arrest & shock
2. Asthma
3. Bronchospasm- during anesthesia
Adverse effects
1. Tachydysrhythmias
2. Angina pectoris
3. Hyperglycemia
Drug interactions
Similar to EP
Available as isoproterenol HCl [Isuprel] solution
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4. Dopamine, fenoldopam (HTN)

• A catecholamine
• It is a unique adrenomimetic drug in that it exerts its
cardiovascular actions by
1. Interacting with beta1 & alpha1
2. Releasing NE from adrenergic neurons
3. Interacting with specific dopamine receptors
 Dose-dependent effects
 At low therapeutic doses=D1- dilates renal vasculature
o ↑GFR, & urinary output
o Used to treat renal failure
 At moderate therapeutic doses=beta1
 At very high doses= alpha1

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 Therapeutic uses
1. Shock [cardiogenic or septic]-↑CO(beta1) &
↑RBF(D1)
2. Heart failure-↑myocardial contractility & CO
3. Acute renal failure-↑RBF
 Adverse effects
1. Tachycardia
2. Dysrhythmias
3. Anginal pain
4. Necrosis

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5. Dobutamine
• A catecholamine
• Acts on beta1
 Therapeutic use
 Heart failure
 Adverse effect
 Tachycardia
• Similar drug interaction as dopamine
 Available as dobutamine HCl solution

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6. Phenylephrine

• A noncatecholamine
• Acts on alpha1
 Uses
1. For nasal congesion-locally
2. Hypotension-injection
3. Mydriasis- as eye drop
4. With local anesthetics
7. Terbutaline, Albuterol; formeterol& salmeterol (nocturnal
asthma)
• A noncatecholamine
• Acts on beta2
Therapeutic uses
1. Asthma
2. Delay of preterm labor

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 Adverse effects
• Tremor
• Tachycardia
7. Ephedrine
• A noncatecholamine
• Acts on alpha1, alpha2, beta1, beta2
• Mixed acting drugs
• Limited uses
1. Asthma
2. Shock
3. Nasal decongestion
• Similar adverse effects as EP
Insomnia- CNS active

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2 Direct-acting Adrenergic Antagonists

• Either irreversible or reversible (competition)

binding

• Most are more selective vs. agonists

1. Alpha-adrenergic blocking agents

2. Beta-adrenergic blocking agents

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Alpha-adrenergic Antagonists

A. Nonselective alpha blockers

1. Phentolamine- competitive & reversible
2. Phenoxybenzamine- noncompetitive & irreversible
Clinical uses
1. Pheochromocytoma
2. Necrosis
3. Orthostatic hAdverse effects
4. ypotension- EP but not NE or IV fluids
5. Greater reflex tachycardia vs. selective ones- beta
blockers
6. Nasal congestion
7. Inhibition of ejaculation
8. Aggravate angina pectoris and myocardial infarction (MI)

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B. Selective alpha1 blockers
1. Prazocin 4. Silodosin
2. Alfuzosin 5. Terazosin
3. Doxazosin 6. Tamsulosin
• Competitively block alpha1
Therapeutic application
1. Essential HTN- prazosin, terazosin, doxazosin
2. Reversal of toxicity from alpha1 agonists [HTN,
necrosis- phentolamine]
3. Benin prostatic hyperplasia (BPH)-terazosin, doxaosin,
tamsulosin, alfuzosin, silodosin
4. Pheochromocytoma- severe HTN [Phenoxybenzamine]
5. Raynaud's disease- peripheral vascular disorders
involving vasospasm in toes and fingers. Local pain &
cold
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 Beta-adrenergic Antagonists
• Principal differences:
• Receptor specificity
• Pharmacokinetics
• Indications
• Side effects
• Intrinsic sympathomimetic (partial agonist) activity
• Ability to cause vasodilation

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Based on receptor specificity

1. First-generation(nonselective)
 Carteolol, nadolol, penbutolol, pindolol,
propranolol, sotalol & timolol
2. Second-generation (cardioselective—β1)
 Acebutolol, atenolol, betaxolol, bisoprolol,
esmolol, metoprolol & nebivolol
3. Third-generation beta blockers (Vasodilation)
 Carvedilol, labetalol, and nebivolol
 Beta1, beta2, alpha1
 Cause VD by two mzms:
1. Blocking alpha1 on blood vessels
2. Promoting synthesis and release of NO

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Based on PK
• High lipid solubility
CNS active
E.g., Propranolol, metoprolol
Elimination via liver
• Low lipid solubility
CNS inactive
E.g., nadolol, atenolol
Elimination via kidney
Intrinsic sympathomimetic activity (ISA)
• Ability of certain beta blockers to act as partial agonists at
beta-adrenergic receptors
• E.g., pindolol
• Preferred to use in bradycardia
• Not given to MI
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Indirect-Acting Antiadrenergic Agents
• Drugs that prevent activation of peripheral adrenergic
receptors, indirectly.
• Two types:
1. Adrenergic neuron-blocking agents
• Drugs that act within the terminals of sympathetic neurons
• To decrease NE release
2. Centrally acting alpha2 agonists
• Drugs that act within the CNS
• To reduce the outflow of impulses along sympathetic
neurons.
 With both groups, the net result is reduced activation
of peripheral adrenergic receptors.
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Adrenergic Neuron-blocking Agents

• Act presynaptically to reduce the release of NE from

sympathetic neurons
1. Prevents storage [Reserpine]
• Rauwolfia alkaloid (Rauwolfia serpentina)
• Causes depletion of NE from postganglionic sympathetic
neurons
• Decrease activation of all forms of adrenoceptors
• Depletes NE in two ways:
1. Displacement of NE from its storage sites[vesicles]- exposing
to MAO
2. Suppression of NE synthesis- by blocking DA uptake into
presynaptic vesicle
3. Also cause depletion of serotonin, catecholamines in CNS-
deep emotional depression

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Pharmacological effects

• Peripheral Effects.
• ↓alpha & beta receptors activation
• ↓HR & CO
• Vasodilation
 ↓ BP
2. Effects on the CNS
• Sedation
• Severe depression
• Therapeutic Uses
• Mild hypertension with diuretics
• Psychotic States- schizophrenia

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• Adverse Effects
• Depression
• Cardiovascular Effects- bradycardia, orthostatic
hypotension & nasal congestion
• GI Effects- ↑gastric acid (ulcer formation), cramps &
diarrhea

2. Inhibit NE release [Guanadrel and

Guanethidine]
• Similar action as reserpine
• CNS inactive
• Diarrhea and severe orthostatic hypotension

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• Pharmacological effects
• Bradycardia
• ↓CO
• Vasodilation
 Decrease BP (in both supine & standing)
• Therapeutic uses
1. HTN
2. Severe pain
3. Migraine
4. Minimize withdrawal symptoms [alcohol, opiates, BZD, tobacco
smoking]
• Adverse effects
1. Drowsiness (CNS depression)
2. Xerostomia
3. Rebound hypertension—abrupt withdrawal
4. Use in Pregnancy
5. Others- constipation, impotence, gynecomastia, adverse CNS effects, &
skin rash

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Group assignment
• Anti-microbial, Anti-helminthic and Anti-protozoal
drugs of the GIT.

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