PPT 9- Adrenergic Agonists Flashcards
exam 2
Differentiate between direct acting and indirect-acting adrenergic agonists
Direct agonist - bind to receptors and illicit response
Indirect agonist - Increase amount of catecholamines in synapse; either facilitating removal or preventing reuptake
What is the structure of catecholamines?
Catechol group + amine group
Benzene ring with adjacent hydroxyl groups at positions 3 & 4 (catechol) and an amine group on side chain
How are catecholamines inactivated?
In the gut by catechol-O-methyltransferase (COMT) - can’t take epinephrine or NE orally
Why can non-catecholamines be taken orally?
Non-catecholamines (ephedrine) not inactivated in gut because they lack catechol hydroxyl group
Changes in the alpha carbon of catecholamines affect the activity of which enzyme?
monoamine oxidase (MAO) - prolonged action by blocking oxidation
Changes in the benzene ring of catecholamines affect the activity of which enzyme?
catechol-O-methyltransferase (COMT) - greatly reduces potency
List the affinity for binding of epinephrine, NE, and isoproterenol at alpha receptors
Epinephrine = Norepinephrine
>Isoproterenol
List the affinity for binding of epinephrine, NE, and isoproterenol at beta receptors
Isoproterenol > Epinephrine ≥ Norepinephrine
B1 (heart): Equal affinity for Epi and Norepi
B2 (lungs): Epi > Norepi
Alpha 1 vs alpha 2 effects
- α1: Gq → phospholipase C → increases IP3 and DAG
- contracts vascular smooth muscle, prostate contraction, heart - increases force of contraction
- α2: Gi → decreases cAMP
- inhibited transmitter release at adrenergic and cholinergic nerve terminals
Compare the effects of beta 1, 2, 3
Gs - all increase cAMP
- β1: increases force and rate of contraction (heart) and increases renin release (juxtaglomerular cells)
- β2: promotes smooth muscle relaxation at respiratory, uterine, and vascular smooth muscle
- β3: activates lipolysis in fat cells
Describe the mechanism of action for alpha 1 receptors
Describe the mechanism of action for G inhibitory vs G stimulatory receptors
What are the 3 monoamine transporters?
- NET: transports back to presynaptic terminal (NE, dopamine)
- DAT: dopamine transporter
- ST: serotonin transporter
Differentiate the mechanism of actions of amphetamines vs cocaine
Amphetamines - increasing NE released
Cocaine - blocking reuptake NE
What effect does D1 receptor have?
Dilates renal blood vessels in smooth muscles
Describe what happens in the cardiovascular system after the administration of an alpha-agonist
- Increases vascular resistance/tone
- HR decreases (indirect effect)
- BP increases
Describe what happens in the cardiovascular system after the administration of a beta-agonist
- Decreases vasculature resistance/tone
- Increased contractility and HR
- BP decreases overall
Describe what happens in the cardiovascular system after the administration of a mixed agonist
- Mixed vascular resistance
- Increased contractility and HR
- Increased BP
Describe the effects of epinephrine
- Potent vasoconstrictor
- α receptors
- Cardiac stimulant (β1)
- Positive inotropic (force)
- Positive chronotropic (rate)
- β2 activation in some vessels
- Dilation of skeletal muscle vessels
- Dilation in bronchioles
Describe the effects of norepinephrine
- Effects on α and β1
- Little effect on β2
- Results
- Increase in systolic and diastolic
- Vagal reflexes overcome chronotropic effects
Describe the effects of isoproterenol
- Potent β agonist - vasodilator - heart
- Little effect on α receptors
- Results
- Increase cardiac output
- Fall in Mean arterial pressure
- Slight decrease or increase in systolic BP
Describe the effects of dopamine
Triphasic response:
- Low dose: Activates D1 receptors - vasodilation,
decrease in peripheral resistance
- Higher dose: mimics action of epinephrine; β1 receptors in the heart
- Highest dose: activates alpha, increases BP
Describe the effects of dobutamine
- β1 selective agonist
- Cardiac shock, acute heart failure
Define non-catecholamine
Not targets for COMT
What are the effects of phenylephrine
- Pure α agonist, non-catecholamine
- Decongestant, raise blood pressure - push blood back into systemic
- Tetralogy of Fallot
What are the 4 issues of the heart in TOF?
- overarching aorta
- pulmonic stenosis
- VSD
- right ventricular hypertrophy
What is Midodrine used for? What receptors is it selective for?
- α1 receptor selective
- Primarily – postural hypotension (orthostatic)
- Can cause hypertension in primarily supine patient
What is ephedrine used for? How does it work?
- Orally active, OTC
- Releases stored catecholamines (indirect)
- Mimics epinephrine (direct)
- Does cross BBB
- Nasal decongestant (pseudoephedrine)
How do amphetamines work?
- Readily enter CNS
- Mood elevator, appetite suppressant
How does cocaine work?
Readily enters CNS - Amphetamine-like effects
Inhibits dopamine reuptake into neurons in the pleasure centers (and addictiveness) of the brain
What is tyramine and how does it work?
- Tyrosine by-product, increases PANS
- High concentrations in fermented foods
- Indirect action - Releases stored catecholamines
- Metabolized by MAO
- MAOIs may increase blood pressure significantly after eating fermented foods (increased NE)
What questions should you ask before picking a sympathomimetic?
- Which receptor activation is required?
- Route of administration?
- Dosing – monitoring therapeutic response
What are the 6 major clinical applications of adrenergic agonists?
Hypotension, shock, reduce blood flow, cardiac, respiratory, anaphylaxis
What is a pressor agent?
Increases blood pressure
How are adrenergic agonists used to treat hypotension?
Enhance blood flow or pressure (direct acting α agonists - NE, phenylephrine)
- most important thing is to maintain cerebral, renal, and cardiac perfusion
What is the treatment for shock?
volume replacement (underlying cause) and vasoconstrictors or dilators (depends on if cardiogenic shock of non-MI cause)
How are adrenergic agonists used to reduce blood flow? What is the drug target?
Hemostasis in surgery
Reduce diffusion of local anesthetics away from the desired site
Reduce mucous membrane congestion
Drug target - α receptor agonist (epinephrine and lidocaine)
How are adrenergic agonists used to treat cardiac issues?
complete heart block and cardiac arrest (isoproterenol and epinephrine); target vasodilation of coronary arteries
How are adrenergic agonists used to treat respiratory issues?
Bronchial asthma - β2 selective agonists
List the most common toxicities associated with sympathomimetic and the adverse effects
Pressor agents
- Elevated blood pressure
- Cerebral hemorrhage
- Pulmonary edema
- Angina
- Cardiac tamponade
- MI
CNS Toxicity
- Catecholamines - rare, but can cross BBB at high levels
- Cocaine - cross BBB
- Convulsions
- Cerebral hemorrhage
- Arrhythmias
- MI
What are the two commonly used α2 agonists and how do they work?
Clonidine and dexmedetomidine; decrease BP by shutting down NE
Increase firing of vagal nerve - decrease in SV and HR
Decrease firing of sympathetic nerves - vasodilation
