3. 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
3
4. • 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
4
5. 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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7. 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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8. 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) 8
9. • 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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10. 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 10
11. • 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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12. 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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14. 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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15. 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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16. 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
17. 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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18. 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 18
19. 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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21. 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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22. 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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23. 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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24. 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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26. 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 26
27. 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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28. Beta-adrenergic Antagonists
• Principal differences:
• Receptor specificity
• Pharmacokinetics
• Indications
• Side effects
• Intrinsic sympathomimetic (partial agonist) activity
• Ability to cause vasodilation
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29. 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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30. 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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31. 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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32. 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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33. 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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34. • 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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