What are the Non-catecholamines (Indirect Acting)? Name them
How do they work?
How are they compare to catecholamines?
1) Tyramine 2) Amphetamine 3) Ephedrine
NE release NOT by vesicle - causes cytoplasmi NE release bc reversal of the NET (NE transporter)
Compared to catecholamines, these are les spotent, effective by mouth!, many have CNS effects, and they last longer bc more resistant to breakdown by COMT and MAO
NE-releaser found in fermented foods
Oxidized by MAO in gut and liver before reaching circulation but CAN be bad for people taking MAO Inhibitors
1 asymmetric carbon - Dextroamphetamine (more psychoactive enantiomer)
Potent Monoamine releaser in CNS (NE, 5HT, Da) and used to treat narcolepsy and ADD
Related Phenylethylamines are peripheral NE releasers
CV effects can be bad!
Ephedrine (or pseudoephedrine) has 2 asymmetric carbons and is a mild psychostimulant that also acts as a Beta-2 Agonist
Stress Urinary Incontinence - increases tone of spinctor
Pseydoephedrine = Sudafed with less CNS effects but used to make meth! Breaking Baddddddd
How does tolerance occur with non-catecholamines (indirect acting)?
Tolerance occurs from exhaustion of releasable NE
What is the Dietary Tyramine interaction in patients on MAO Inhibitors?
In presence of MAO-Inhib, dietary Tyramine from wine and cheese etc can now enter circulation and accumulate in nerve terminals
Not only enters circulation, but increased amounts of it concentrating in nerve terminals bc MAO blocked in mitochondria there too!!
therefore, LOTS of NE being released bc blocked MAO and can get hypertensive crisis
What are the contraindications for Phenylethylamines (Amphetamine derivatives) and CNS stimulants?
Black Box Warning - increased risk for CVD events
*Especially in people with pre-exisitng cardiovascular conditions
What are the acute effects of cocaine on the heart?
Alpha and/or beta adrenergic effect = increased BP, HR but also increased Oxygen demand of heart!
Alpha adrenergic effect - coronary spasm and decreased Oxygen delivery to heart
Both can lead to ISchemia, Infarction, and Arrhythmia
What are the chronic effects of cocaine on the heart?
Dilated or hypertrophic cardiomyopathy
Contraction-band necrosis from Ca overload
What are the non-CVD effects of Cocaine? (besides for one helluva good time!)
Persistent Hyperthermia - myoglobin release and renal damage
Neutropenia - Levamisole causes this which is commonly cut with cocaine and is a MAO/COMT inhibitor
What are some Amphetamine derivatives? What is their specific pathological effects on the heart?
Serotonin Agonists- MDMA and Fenfluramine
Ergot derivatives - ERgotamine
Da Agonists - Pergolide
Cause Valvular Heart Disease bc activation of 5-HT receptors leads to proliferation and thickening of valvular tissue and can cause regurgitation of leaflets
Name the Non-catecholamine Direct active Alpha-1 Receptor Agonist and it's uses
decongestant, vasopresser, mydriatic (topical)
Replaced Pseudoephedrine in Sudafed!
Name the Non-catecholamine Direct Acting Alpha-2 Receptor Agonist?
What does it do?
How is it used?
Clonidine [Analogues include Brimonidine to lower IOP]
Stops NE release - Sympatholytic!!
Low concentrations - only CNS effect to stop Sympathetic outflow; Middle Concentrations inhibits NE release and get less SM contraction; High concentrations then get powerful SM contraction!! (lose A2 selectivity and see A1 mediated contraction of SM)
Non-selective BEta 1/2 catecholamine used to be used in asthma medications but causes cardiac palpitations
Name the Selective Beta-2 Agonists and how are they used in airway disease?
1) Albuterol (short acting for symptomatic relief in asthma) and 2) Salmeterol (longer acting with slower onset) - both are Partial Agonists
Airway Disease - INCREASE bronchodilation, increase mucociliary clearance, decrease bacterial adherence, decrease cholinergic transmission and plasma exudation
Decrease Mast cell degranulation
*Caveat - may be evidence of adverse pro-inflammatory response with Beta-arrestin activation
"Stepped Care Approach" with central role of inhaled corticosteroids
What is the role of beta-2 agonists in labor?
Delay Pre-term LAbor (Tocolysis)
Give IV/Oral Riodrine to relax near-term myometrium
Caveat - only lasts ~48 hours bc tolerance and desensitization
What are the Adverse effects of systemic Beta-2 Agonists?
Which ones effect a fetus in utero?
Desensitization and Tolerance
Pulmonary Edema in mother
(Bold in fetus)
What is the Beta-3 Agonist? What is it used for?
What is unique about this mechanism of action?
Used as treatment for Overactive Bladder syndrome to relax Detrussor muscle
NO TOLERANCE - Beta3 receptors lack intracellular phosphorylation sites and so not desensitized and down-regulated like other beta receptors