Topic 2 - Adrenergic Drugs

Specific Objectives
1. To classify and enumerate drugs acting on
the sympathetic divisions of the autonomic
nervous system
2. To describe the sites and mechanisms of
drugs acting on the sympathetic divisions
of the autonomic nervous system
3. Understand the effects of sympathetic
agonists and antagonists
SYMPATHOMIMETICS

ADRENERGIC AGONISTS
 CLASSIFICATION OF SYMPATHOMIMETICS
(ADRENERGIC AGONISTS)

• BASED ON CHEMISTRY
– Catecholamines
– Noncatecholamines

• BASED ON THEIR MECHANISMS OF ACTION

– Endogeneous Catecholamines
– Direct-acting adrenergic agonists
– Indirect-acting adrenergic agonists
– Mixed acting adrenergic agonists
BASED ON CHEMISTRY
 DIFFERENCES BETWEEN CATECHOLAMINES
FROM NONCATECHOLAMINES
CATECHOLAMINES NONCATECHOLAMINES
 Contain the 3,4-  Not metabolized by MAO
dihydroxybenzene groups and COMT (no catechol
 High potency in activating α hydroxyl groups)
and β receptors
 Metabolized by MAO and
 Longer half-lives
COMT  Administered orally
 Short duration of action
 Do not penetrate the CNS
 CLASSIFICATION OF SYMPATHOMIMETICS
BASED ON CHEMISTRY
CATECHOLAMINES
 Dopamine
 Epinephrine
 Isoproterenol
 Norepinephrine
 Dobutamine
 CLASSIFICATION OF SYMPATHOMIMETICS
BASED ON CHEMISTRY
NON-CATECHOLAMINES
 Phenylephrine
 Methoxamine
 Ephedrine
 Amphetamine
 BASED ON
MECHANISMS OF
ACTION
 Classification of Sympathomimetics based on
Mechanism of action
Endogeneous Direct-Acting Indirect-Acting Mixed-Acting
Catecholamines
Epinephrine α agonists Releasers Direct- and
Norepinephrine β agonists Reuptake Inhibitors Indirect-acting
Dopamine
 ENDOGENEOUS
CATECHOLAMINES
 Major α and β direct-acting agonists
Epinephrine (Adrenaline) – no effect at α2
Norepinephrine (Noradrenaline,
Levarterenol)– little effect on β2
Dopamine – D1 = D2 > β1 > α1
DIRECT-ACTING
ADRENERGIC
AGONISTS
 MOA OF ADRENERGIC AGONISTS (DIRECT-ACTING)

α2 agonists

α1 agonists

β agonists (β1 β2 β3)

 Direct-acting Sympathomimetics

• Binding to 1, 2,

1, or 2 adrenergic
receptors activates
SECONDARY
MESSENGERS.
 Properties of α-Adrenergic Receptors
Type of Locations Effects
Receptor
α1 : Gq Radial muscle of the iris Pupillary dilation
Arteriolar smooth muscle Incr PR and BP
Phospho- GI and GU, trigone and Retention
lipase C sphincters
DAG, IP3 Pilomotor smooth muscle Piloerection
Seminal vesicle smooth Ejaculation
muscle
Liver Glycogenolysis and gluconeogenesis
α2 : Gi Presynaptic nerve terminals Inhibits release of NE (presynaptic
inhibition)
adenylyl Platelets Aggregation
cyclase Pancreatic β cells Inhibits insulin release
cAMP (hyperglycemia)
 Properties of β-Adrenergic Receptors

TYPE OF LOCATIONS EFFECTS

RECEPTOR

β1 : Gs Heart Increase in heart rate, contractility

and conduction
Juxtaglomerular cells Incr in secretion of renin (incr BP)
β2 : Gs Vascular smooth muscle Vasodilation (relaxation)
Bronchiolar smooth muscle Bronchodilation (relaxation)
adenylyl GI and urinary bladder Decr GI and GU motility
Cyclase (detrusor-β) smooth (relaxation)
cAMP muscle
Uterine smooth muscle Decr uterine contraction
(relaxation)
Skeletal muscle Uptake of K+ in skeletal muscles
Liver Glycogenolysis & gluconeogenesis
β3 : Gs Adipose tissue Lipolysis
 -RECEPTOR AGONISTS
 α1-selective direct-acting agonists
 Phenylephrine
 Methoxamine
 Midodrine
 α2-selective direct-acting agonists (NOT
SYMPATHOMIMETICS when orally administered)
 Clonidine
 Methyldopa
 Guanfacine
 Guanabenz
 Apraclonidine
 Brimonidine
 -RECEPTOR AGONISTS
• β-nonselective direct-acting
– Isoproterenol - aka Isoprenaline
• β1-selective direct-acting
– Dobutamine
• β2-selective direct-acting
– Albuterol – aka Salbutamol
– Metaproterenol
– Terbutaline
– Pirbuterol
– Salmeterol
– Formoterol
– Indacaterol
 Dopamine Receptors

Types Location Effect

D1 Smooth muscle Dilates renal blood
AC vessels
D2 Nerve endings Modulates
AC transmitter release

FENOLDOPAM – D1 AGONIST
 INDIRECT-ACTING
ADRENERGIC AGONISTS
A. Release neurotransmitters from presynaptic nerve
terminals to produce a sympathomimetic effect
(RELEASERS)
• Amphetamine
• Methamphetamine
• Tyramine
• Phenmetrazine
• Methylphenidate
• Modafinil
 INDIRECT-ACTING
ADRENERGIC AGONISTS
B. Catecholamine Reuptake inhibitors
• Cocaine
• Atomoxetine
• Reboxetine
• Sibutramine
 MIXED-ACTING ADRENERGIC
AGONISTS
Drugs act both directly and indirectly.
DIRECT: Receptor Activation
INDIRECT: Releaser/Reuptake Inhibition
EXAMPLES: Ephedrine
Pseudoephedrine
Mephentermine
Phenylpropanolamine
CLINICAL USES OF ADRENERGIC
DRUGS
Endogeneous Catecholamines
I. EPINEPHRINE- first line cardiac stimulant,
first line agent for anaphylactic shock;
local vasoconstrictor, glaucoma
II. NOREPINEPHRINE – first line agent for septic
shock
III. DOPAMINE – management of cardiogenic
shock, CHF
Direct-acting Sympathomimetics
• PHENYLEPHRINE & METHOXAMINE
– Marketed as nasal and ophthalmic decongestants
• CLONIDINE, METHYLDOPA, GUANFACINE,
GUANABENZ, APRACLONIDINE, BRIMONIDINE
– Hypertension
• ISOPROTERENOL
– Bronchodilator, AV Block
• DOBUTAMINE
– First line agent for cardiogenic shock, acute HF
Direct-acting Sympathomimetics
• METAPROTERENOL, ALBUTEROL, TERBUTALINE,
PIRBUTEROL, SALMETEROL, FORMOTEROL,
INDACATEROL
– Bronchodilators
• RITODRINE, TERBUTALINE, ISOXSUPRINE
– Uterine relaxant
 Indirect-acting
Sympathomimetics

–RELEASERS
• Amphetamine
• Methamphetamine
–Useful in narcolepsy,
hyperkinetic
syndrome of children,
attention deficit
hyperactivity disorder
(ADHD)
 Indirect-acting
Sympathomimetics
–RELEASERS
• Phenmetrazine - anorexiant and a popular
drug of abuse
• Methylphenidate – ADHD
• Modafinil – narcolepsy
 Indirect-acting
Sympathomimetics
• REUPTAKE INHIBITORS
– COCAINE
• Local anesthetic
– ATOMOXETINE
• Treatment of ADHD
– SIBUTRAMINE
• Treatment of obesity
Mixed Sympathomimetics

– Ephedrine – clinically used to treat narcolepsy

– Mephentermine & Metaraminol – Treatment
of hypotension
– Phenylpropanolamine – Decongestant in oral
OTC drugs
 Common Adverse Effects of
Adrenergic Agonists
• Catecholamines –extensions
of alpha- or beta- actions
• CNS disturbances –
nervousness, anorexia,
insomnia, anxiety,
aggressiveness, paranoid
behavior, convulsions

nausea
 Common Adverse Effects of
Adrenergic Agonists
• Alpha-1 agonist –
hypertension
• Beta-1 agonist – sinus
tachycardia, arrhythmias
• Beta-2 agonist – skeletal
muscle tremor
• Cocaine – drug abuse,
cardiac arrhythmias or
infarction, convulsions
ADRENERGIC ANTAGONISTS
SYMPATHOLYTICS
 Classification of Sympatholytics
(Adrenergic Antagonists)

• Based on Mechanism of Action

– Direct acting Sympatholytics (direct acting alpha and
beta blockers)
– Centrally-acting Sympatholytics (alpha2-adrenergic
agonists)
– Peripherally-acting Sympatholytics (adrenergic
neuronal blockers)
 Classification of Sympatholytics: Direct-acting:
α-blockers

• α1 – adrenergic selective, • α1,α2 – nonselective,

reversible irreversible
– Prazosin – Phenoxybenzamine
– Doxazosin • α1,α2 – nonselective,
– Terazosin reversible
– Tamsulosin – Phentolamine
– Alfuzosin • α2 – selective, reversible
– Yohimbine
Classification of Sympatholytics: Direct-acting:
β-blockers
• β1-selective blockers
– Bisoprolol, Betaxolol
– Esmolol
– Atenolol, Acebutolol
– Metoprolol
• Non-selective β-adrenergic antagonists
– Nadolol
– Sotalol
– Timolol
– Propranolol
 Classification of Sympatholytics: Direct-acting:
β-blockers
• β-blockers with Intrinsic Sympathomimetic Activity (ISA)
– Acebutolol
– Pindolol
• β-blockers with α-blocking capacity
– Labetalol
– Carvedilol
• β2-selective blocker
– Butoxamine
Centrally & Peripherally Acting Sympatholytics

• Centrally Acting • Peripherally Acting

Sympatholytics Sympatholytics
(α2-agonists) (Adrenergic Neuronal
– Clonidine Blockers)
– Methyldopa – Reserpine
– Guanfacine – Guanethidine
– Guanabenz – Guanadrel
– Bretylium
 Peripherally-acting
Sympatholytics

Centrally-acting
sympatholytics

α2 antagonists

β antagonists α1 antagonists
CLINICAL USES OF ADRENERGIC
BLOCKERS
 SELECTIVE ALPHA1-ANTAGONISTS
• Prazosin and Prazosin analogs (terazosin,
doxazosin, trimazosin, tamsulosin)
HYPERTENSION
 Selective alpha1 blocker
• Management of urinary
BENIGN PROSTATIC hesitancy
HYPERPLASIA
• Prevention of urinary
retention in men with BPH
 Clinical Uses of Nonselective Alpha blockers
– Presurgical management of
pheochromocytoma
– Phenoxybenzamine
▫ Carcinoid tumor
▫ Mastocytosis
• Phentolamine
▫ Tissue damage – accidental local infiltration of
potent alpha agonists
▫ Rebound hypertension /Hypertension –
overdose of drugs
▫ Erectile dysfunction
 β1-selective antagonists
▫ HYPERTENSION
▫ ANGINA
▫ MI
▫ THYROID
STORM
 Non-selective β-blockers

▫ ARRHYTHMIA
▫ ACUTE PANIC SYNDROME
▫ MIGRAINE HEADACHE
 β-blockers with α blocking
capacity

CHRONIC CHF
ADVERSE EFFECTS OF ADRENERGICS
ANTAGONISTS
 α-Blockers
• Orthostatic hypotension
• Reflex tachycardia
(Nonselective alpha
blockers)
• Syncope (Selective alpha1
blocker)
• exaggerated orthostatic
hypotensive response to
the first dose
• Nausea and vomiting
• Sexual Dysfunction
 β-Blockers
• Bradycardia
• AV blockade
• Heart failure
• Asthma -
bronchoconstriction
• Augmentation of
hypoglycemia
• Lipidemia
• Sedation, fatigue & sleep
alterations
• Dizziness
• Orthostatic hypotension
 Common Adverse Effects of
Adrenergic Neuronal Blockers

• Reserpine
– CNS depression
– Bradycardia
– GI disturbances
– Extrapyramidal effects
 Adverse Effects of Drugs that Interfere with
Central Sympathetic Outflow (α2-agonist)

• Methyldopa (α2-agonist)
– Edema
– Sedation (drowsiness)
– Dry mouth & nasal mucosa
– Headache
– Reduced libido (impotence)
– (+) Coomb’s test (hemolytic
anemia)
– Hepatotoxicity
– Lactation (incr prolactin
secretion)
 Adverse Effects of Drugs that Interfere with
Central Sympathetic Outflow (α2-agonist)

• Clonidine
– Sedation (dizziness)
– Rebound hypertension
– Dry mouth
– Itching & redness of skin
(patch)
– Mild orthostatic
hypotension
– Endocrine problems