Epinephrine Receptors

(5)

• a1
• a2
• B1
• B2
• Stimulates both a and B

Epinephrine

Physiological Effects

(3)

• To some extent depends on dose and rate of administration
• At lower doses, B effects predominate
• At higher doses, a more apparent

Epi

Cardiac

(2)

• Increase heart rate and strength of ventricular contraction
• Due to activation of B-1 receptors

Epi

Vascular

Low and high doses

(2)

• At lower doses, may see decreased peripheral resistance and diastolic pressure due to B-2 receptor activation & consequent vasodilation/decreased peripheral resistance at lower doses
• At higher doses, as activation of a-1 adrenergic receptors becomes more prominent, see increased resistance and Blood pressure

Epi

Respiratory

(5)

• All B-2 receptor mediated
• Relaxes smooth muscle of airways, so dilates bronchioles
• Inhibits release of inflammatory cells
• Decrease vascular permeability in lung => decrease plasma proteing extravasation
• Increases cilial beat frequency (B receptors in bronchial epithelium)

Epi

Genitourinary

(3)

• B2 receptor
• Relaxes detrusor muscle of bladder
• Relaxes uterus

Epi

Eye

(3)

• Dilates pupil (a1)
• Relaxes ciliary muscle (B2)
• Increases outflow of aqueous humor and may decrease production of aqueous humor

Epi

Therapeutic uses

(8)

• Bronchospasm (B2)
• Hypersensitivilty rxns/anaphylaxis-treatment of choice (a1, B1, B2)
• Restoration of cardiac function
•  Important drug in advanced cardiac life support algorithms (e.g) patients with; 
• asystole
•  bradycardia
•  ventricular tachycardia/ventricular fibrilation)(B1)
• Local homostasis; prolong the actions of local anesthetics (a1)

Epi

Adverse Effects

(4)

• Cardiac: 
• Palpitations, Arrhythmias, Anginal Pain (too much B)
• Vascular:
•  Increase BP, Cerebral hemmorhage (too much a)

Epi

Contraindication/Precaution

(4)

• NOTE: There are NO absolute contraindications to the use of epinephrine in a life threatening situation
• On B receptor antagonists (a-1 receptor mediated vasoconstriction will be unapposed by B-2 receptor mediated vasodilation. May precipitate pronouned hypertension and reflex bradycardia)
• W/ CV disease: increase peripheral resistance/BP (a1) & increased cardiac workload (B1) may be harmful to such patients.
• W/ Diabetes (may disrupt glucose balance; B2)

Epi

Contraindications/Precautions

Contd

(3)

• W/ Thyrotoxicosis: Such patients already have tachycardia & high BP. Epi will exacerbate
• Pts on MAO inhibitors or tricyclic antidepressants: Inhibition of MAO will decrease the metabolism of epi. Tricyclic antideps will block the NE transporter, so the clearance of Epi via NET will be blocked. Therefore, effects of Epi can be significantly potentiated under either of these conditions
• Who are pregnant: a1 receptor activation may compromise blood flow to the fetus

Norepinephrine

Receptors

(3)

• Both a and B
• B1>>B2
• Relative to Epi, NE has much less (~100 folds) efficacy at B2 receptors. This is a significant pharmacological difference btwn the two drugs and underlies the different therapeutic indications for these two drugs.

Norepi

Vascular Effects

• Increase vasoconstriction => increases TPR

Norepi

Cardiac effects

(3)

• Complex! Depends on initial status of patient and whether baroreceptor reflexes are activated
• Get greater increase in peripheral resistance because there is little/no B2 receptor-mediated vasodilation to oppose a1 receptor mediated vasoconstriction
• Direct B1 receptor-mediated stimulation of heart rate and contractility will be offset baroreceptor REFLEX parasympathetic/cholinergic slowing of the heart.

Norepi

Therapeutic Uses

(2)

• Blood pressure control in acute hypotensive states
• Cardiac arrest and profound hypotension

Norepi

Adverse Effects

Cardiac and vascular

(4)

• Cardiac:
•  Brady cardia(Slow, forceful beat)
•  Arrhythmias
• Vascular: 
• Decreased blood flow to vital organs
• Extravasation necrosis at IV site

Norepi

Contraindications/Precautions

(3)

• Patients with Mesenteric or peripheral vascular thrombosis (contraindicated unless for a life-threatening condition) a1 receptor mediated vasoconstriction will exacerbate ischemic injury
• Extravasation at IV site(precaution) due to a1 receptor-mediated vasoconstriction in the tissue surrounding IV site
• Patients on MAO inhibitors or tricyclic antidepressants (precaution; same as Epi)

Dopamine

Receptors

(4)

• Depends on dose
• DA>B>a
• So, at low concentrations, D1 dopamine(DA) receptors will be selectively activated
• As the dose is increased (including clinically relevant doses), B (increased HR and contractility) and then a (vasoconstriction) receptor mediated effects will come into play

Dopamine

Physiological effects

Cardiac, vascular, and renal

(10)

• Cardiac: Increase heart rate, Increase cardiac output (B)
• Vascular: 
• At low doses see unchanged or decreased systemic vascular resistance due to D1 DA receptor-mediated vasodilation in;
•  renal
•  mesenteric
•  coronary
•  and cerebral vasculature. 
• At higher doses, see increased cardiac output and BP due to additional a and B adrenergic receptor stimulation. Maintain/increase vital organ perfusion.
• Renal: 
• Increased glomerular filteration, Increased renal blood flow. 
• Natriuresis/diuresis

Dopamine

Therapeutic Uses

(3)

• Hypotension due to inadequate cardiac output (e.g. cardiogenic shock)
• Heart failure/low cardiac output states
• Shock (e.g. septic shock)

Dopamine

Adverse Effects

Cardiac and vascular

• Cardiac: Tachycardia, Other arrhythmias, Anginal pain(too much B1)
• Vascular: Hypertension, Local ischemic necrosis (too much a1)

Dopamine

Contraindications/Precautions

(4)

• Pheochromocytomas: Tumors that produce NE and Epi, contradiction, as precursor loading with DA will lead to more NE and Epi production and consequent adverse effects on cardiovascular system.
• Uncorrected tachyarrhythmias or ventricular fibrilation (contraindication, as additional B1 stimulation will be detrimental)
• Pts w/ a history of occlusive vascular disease, such as atherosclerosis and reynaud disease(precaution, as a1 stimulation will exacerbate vasoconstrictive condition)
• MAO inhibitors/tricyclic antidepressants(same as EPI)

a-1 agonists

Drugs

(6)

• Phenylephrine
• Midodrine
• Oxymetazoline
• nephazoline
• tetrahydrozoline
• xylometazoline
• Hint; all end with "ine"

a1 agonists

Physiological Effects

(5)

• Vascular: Increased MAP (due to a1 stimulation)
• Cardiac: Decreased HR (reflex slowing of the heart secondary to increased BP)
• Ocular: Mydriasis (a1 stimulation on radial muscle of iris)
• Genitourinary: Urinary retention (a1 stimulation of sphincter muscle of urinary bladder)

a1 agonist

Therapeutic Uses

Phenylephrine and midodrine

(6)

• Phenylephrine: 
• Treatment of hypotension/shock
•  Nasal decongestion
•  Mydriasis
•  Local Vaso constriction
• Midodrine: Orthostatic hypotension associated with autonomic failure

a1 agonists

Adverse Effects

(8)

• Cardiovascular: 
• Hypertension
•  Stroke
•  MI
•  Bradycardia
•  Too much a1
•  NOTE: Midodrine commonly is associated with supine and sitting hypertension
• Urinary retention (too much a1)

a1 agonists

Contraindications/Precautions

(4)

• Severe hypertension or ventricular tachycardia: 
• Contraindication, as additional a1 receptor-mediated vasoconstriction will be detrimental
• Patients on MAO inhibitor or tricyclic anti-depressants:
• Contraindication or precaution depending on route of administration; (e.g. topical vs. IV)

a2 Agonists

The Drugs

(3)

• Brimonidine
• Aproclonidine

• Topically to eye for glaucoma

a2 Agonists

Physiological effect
(2) 

• Decreases production of aqueous humor
• Increases uveoscleral outflow

a2 Agonists

Therapeutic Uses

(2)

• Treatment of open-angle glaucoma
• Ocular hypertension

a2 Agonists

Adverse Effects

(3)

• Eye redness or stinging
• Allergic rxns
• Bradycardia, hypotension (see discussion on anti adrenergic agents for explanation of how an a2 agonist decreases sympathetic nervous system activation and thus induces these adverse side effects)

a2 Agonists

Contraindications/Precautions

(2)

• Patients on MAO inhibitors: (Contraindication because drug is metabolized by MAO therefore, such patients are at more risk for system effects)
• Pts on tricyclic antidepressants: (Precaution: Pharmacological basis for this precaution is not clear)

B agonists

The Drugs

(6)

• Non Selective (activates both B1 and B2 receptors): Isoproteronol

•  B2 Selective:
• Albuterol
• Levalbuterol
• Terbutaline
• Formoterol

      others:

• Meta proterenol, Salmeterol, Pirbuteron

B Agonists

Iso proterenol

(6)

• Non-selective
• Use limited to a few selective cardiac indications such as heart block
• May also be used for:
•  Low cardiac output
•  Hypotensive Shock States

B Agonists

Albuterol

(2)

• B2 selective
• Often given nebulized in ER for acute exacerbations of asthma

B Agonist

Levalbuterol

(3)

• B2 Selective
• Active R-Isomer of albuterol
• Approved for use in relief and prevention of bronchospasm

B Agonist

Terbutaline

(3)

• B2 Selective
• Oral, injection
• Only B2 bronchodilator available in solution for parenteral use for emergency treatment of status asthmaticus

B Agonist

Formoterol

• B2 Selective
• More lipophilic B2 agonist-Duration of action is longer
• Black Box Warning: Long-acting B2 adrenergic agonists may increase the risk of asthma realated death. Concern that there may be a greater incidence of respiratory/asthma-related adverse events/death in pts receiving long-acting B2 agonists in general (SMART trial, more deaths, esp African American)(Salmeterol)
• Budesonide/formoterol & fluticasone/salmeterol are corticosteroids/long acting B2 agonist combo medications

B2 Agonists

Physiological Effects

(4)

• Bronchodilation (B2)
• Enhancement of mucociliary clearance (B2 receptor activation increases ciliary beat frequency)
• Inhibits release of inflammatory mediators from mast cells and basophils(B2)
• Decreased peripheral resistance: Due to stimulation of B2 receptors in vasculature of skeletal muscle and liver leading to vasodilation in those vascular beds

B Agonists

Physiological Effects

Cardiac

(4)

• Increased cardiac output
• For Isoproterenol, this will be due to a direct effect on B1 receptors on the heart
• For the B2 receptor agonists, it will be due to the B2 receptor mediated decrease in peripheral resistance
• If the decrease in peripheral resistance is sufficiant to decrease BP, there will be a baroreceptor reflex-mediated increase in sympathetic nervous system activity & consequent NE release & stimulation of B1 receptors in the heart

B Agonist

Therapeutic Uses

(5)

• Brochospasm: B2 specific agonists are the drugs of choice when using a sympathomimetic in the treatment of asthma
• Cardiovascular(Isoproterenol only): 
• Heart block
•  Cardiac arrest
•  Hypovolemic states/shock

B Agonists

Adverse Effects

cardiac and muscle

(3)

• All side effects are generally transient & less likely w/ administration by inhalation
• Cardiac: Palpitation, Tachycardia  (too much B1)
• Skeletal muscle tremor: This is a peripheral effect of B2 receptor activation possibly due to B2 receptor-mediated facilitation of ACh release(ie. B2 excitatory heteroreceptor on terminal of lower motor neuron), It is a potentiation of postural tremor

B Agonists

Contraindications/Precautions

(7)

• Pts w/ 
• tachyarrhythmias
• ventricular arrhythmias
•  angina
• heart block caused by digitalis
•  contraindication for isoproterenol which will directly stimulate B1 receptors in the heart, thereby further increasing heart rate and increasing cardiac workload
• Pts w/ cardiovascular disorder: Precaution for B2 selective as decreased BP induced by B2 receptor-mediated vasodilation will lead to reflex cardiac stimulation which may be detrimental for such pts
• Pts w/ diabetes: Precaution due to disrupted glucose regulation b/c B2 receptors stimulate gluconeogenesis and glycogenolysis

Mixed Agonists

(3)

• Dobutamine
• Ephedrine
• Pseudophedrine

Dobutamine

Pharmacology, Physiological Effects,

And Therapeutic Uses

• Pharmacology:
• Cardioselective mixed agonist
• Interacts w/ both a and B receptors but B1 effects predominate in the heart
• Physiological effects:
• relatively more potent inotropic than chronotropic effects
• peripheral resistance is largely unchanged
• Therapeutic Uses:
• Cardiac decompensation due to organic heart disease or cardiac surgery

Dobutamine

Adverse Effects/Contraindications/Precautions

(5)

• Adverse effects:
• Cardiac: May increase HR significantly due to too much B1 stimulation
• Vascular: May increase BP significantly (too much a1 stimulation)
• Contraindications/Precautions
• Idiopathic hypertrophic subaortic/hypertrophic obstructive cardiomyopathy (contra indication): Such pts, due to outflow obstruction, are unlikely to experience cardiac output with dobutamine & increased cardiac contractility may be detrimental in such pts.

Ephedrine and Pseudophedrine

Pharmacology, Physiological effects,

& Therapeutic uses

(10)

• Pharmacology:
  
• Acts directly on both a and B receptors
• Acts indirectly by releasing NE
• Physiological effects
• cardiac- increased HR and contractility (B1)
• Vascular- increased peripheral resistance (a1)
• Respiratory- bronchodilation (B2)
• CNS- penetrates blood brain barrier-produces CNS stimulation
• Therapeutic uses
• Hypotension (ephedrine injection)
• nasal congestion
• asthma

Ephedrine, Pseudophedrine

Adverse Effects

(7)

• Cardiac
• palpitation
• arrhythmias
• tachy/bradycardia (will depend on balance btwn direct B1 receptor stimulation by the drug & baroreceptor-mediated reflex activation of parasymp/cholinergic input to the heart
• Vascular- hypertension (too much a1 receptor activated)
• Genitourinary- urinary obstruction, particularly in pts w/ benign prostatic hypertrophy (too much a1 receptor activation in sphincter muscle of urinary bladder)
• CNS
• nervousness
• insomnia

Ephedrine, Pseudophedrine

Contraindications/Precautions

(6)

• Pts on MAO inhibitors(contraindicate): Because these drugs are indirect agonists (ie exert effects of adrenergic receptors indirectly by causing release of NE) the effects of the drugs can be markedly potentiated in pts w/ increasaed levels of NE due to MAO inhibition.
• Pts w/(precaution); 
• cardiovascular disease
• hyperthyroidism
• diabetes
• prostatic hypertrophy
• Such pts may be more susceptible to adverse effects of increased a and B adrenergic receptor activation (increased peripheral resistance, BP, HR, and contractility, disruption of glucose balance, urinary retention)

Fenoldapam

Pharmacology, Physiological Effects, Therapeutic Use,

Adverse Effects, Contraindications/Precautions

(8)

• Pharmacology: Activates Dopamine D1 receptors
• Physiological effects: 
• Vascular: Hypotension;
• renal vasodilation (Due to activation of D1 dopamine receptors on renal, mesenteric, coronary, and cerebral vasculature, which relates the VSM)
• Therapeutic use: Hypertension: Given IV, it is safe and effective treatment for severe hypertension in the hospital setting
• Adverse effects: 
• Headache
• hypotension
• tachycardia
• Contraindications/Precautions: Pts with glaucoma, Pts with increased intraocular pressure (precaution)

Indirect Agonists/Sympathomimetics

(5)

• Cocaine
• Methylphenidate
• Tyramine
• Dextroamphetamine/amphetamine
• Methamphetamine

Cocaine

Pharmacology, Therapeutic uses

(4)

• Pharmacology:
• Blocks re-uptake of catecholamines by NET
• Will therefore lead to increased sympathetic/NE signaling through a & B receptors
• Therapeutic Uses:
• Topical use to mucous membrane of oral, laryngeal, & nasal cavities for hemostasis (a1 receptor activation)
• local anesthesia (this effect is not due to effects on adrenergic system)

Methylphenidate

Pharmacology

(3)

• Blocks re-uptake of catecholamines by NET and DAT
• Clinical relevance to ANS pharmacology is tachycardia
• B1 stimulation or increased BP may be observed as adverse effects in individuals treated with methylphenidate

Tyramine

Pharmacology

(5)

• Releases NE from storage vesicles
• A by-product of tyrosine metabolism by aromatic-amino-acid-decarboxylase
• Also found in fermented foods like wine and cheese
• Readily metabolized by MAO. So it is not normally a problem. However, it will accumulate in pts taking MAOIs if they eat foods that contain high amounts of Tyramine
• Can produce hypertensive crisis due to extensive NE release