Adrenergic agonists Flashcards
What are the three subtypes of “sympathetomimetic drugs” or agonists?
- Direct acting - can be selective or nonselective
- Indirect-acting - via facilitating release or blocking reuptake
- Mixed acting - i.e. Ephedrine acts on receptors as agonist, and also a releasing agent
How do they three subclasses of agonists differ with respect to their effect given prior treatment of reserpine?
Direct acting - unaffected or increased by prior treatment (upregulation of receptors for agonist to bind)
Indirect acting - completely blocked due to loss of NT packaging in vesicles which leads to their breakdown via MAO
Mixed acting - Reduction in activity (due to two components)
When is a sympathomimetic amine considered a “catecholamine” and what are its properties with regards to potency, inactivation, and penetration into the CNS?
If they contain a 3,4-dihydroxybenzene group (makes them very hydrophilic)
They are really potent agonists to alpha and beta receptors, but are rapidly inactivated by COMT and MAO.
Since they are hydrophilic, they poorly penetrate the CNS, although they still can cause anxiety, tremor and headaches
Where are MAO and COMT present? Why is this relevant?
COMT - posysynaptic cleft
MAO - intraneuronally, and high concentration in liver
Both MAO and COMT are present on the gut wall -> relevant because catecholamines are rapidly inactivated when taken orally = poor oral bioavailably. Must be given parenterally or topically
What is a noncatecholamine agonist, and what are its properties regarding potency, inactivation, and penetration into the CNS?
Compounds which lack both the hydroxyl groups on the benzene ring, so they are not as easily inactivated by COMT, and are also poor substrates of MAO -> longer halflife.
Can be given orally or via inhalation due to higher bioavailability.
Have increased lipid solubility from lack of polar groups -> better access to CNS
What are the four catecholamines commonly used in therapy?
- Epinephrine
- Norepinephrine
- Dopamine
- Dobutamine
How does the action of epinephrine differ between low and high dose, generally?
Generally, epinephrine has a higher affinity for better receptors than alpha receptors.
Low levels: Beta receptors dominate -> vasodilation, acts like isoproterenol
High levels: Alpha receptors have strongest effect -> vasoconstriction, acts like norepinephrine
What happens to the cardiovascular system when low doses of epinephrine are administered? What does this do to oxygen demand in heart?
B1 receptors -> increase in force and rate of contraction of heart, increased renin release from kidneys (to raise systolic blood pressure)
B2 receptors -> Vasodilation in peripheral vasculature, vasodilation to liver, vasodilation to skeletal muscle -> drop in diastolic blood pressure
Increases oxygen demand in heart
What happens to the cardiovascular system with higher levels of epinephrine?
Peripheral vasoconstriction via alpha receptors becomes more important, there is a drop in renin release from the kidneys, and both systolic / diastolic blood pressures rise
How does epinephrine influence the pulmonary system?
Increases bronchodilation via beta-2 activity
How does epinephrine influence blood glucose levels?
Beta2 receptors: Increase glycogenolysis + gluconeogenesis (via glucagon)
Alpha2 receptors: Decrease insulin release (decreasing glucose storage)
Net effect is hyperglycemia
How does epinephrine influence lipolysis?
Initiates it, via agonist activity on beta3 receptors of adipose tissue
What are four indications for the usage of epinephrine?
- Bronchospasm - beta2 agonist, acute asthma
- Anaphylactic shock - hypotension, bronchospasm, angioedema
- Cardiac arrest - restores cardiac rhythm
- Anesthestics - used with anesthetics to produce vasoconstriction at injection site -> prolonged action
What receptors does norepinephrine effect? How is this relevant to where it’s not useful?
Mostly alpha receptors, with alpha 1 > alpha 2 > beta 1.
Will have NO EFFECT on beta 2 -> not good for bronchospasm or anaphylaxis (bronchospasm)
What is the effect on BP of norepinephrine and why?
Mostly stimulates alpha receptors -> vasoconstriction
Will not stimulate beta2 like epinephrine -> no vasodilation, much greater effect on BP
What will the effect of norepinephrine be on the heart?
Due to increased BP, there will be a reflex bradycardia mediated by baroreceptors and vagal activity -> can cause tachycardia if atropine is pre-administered
What is the only therapeutic indication of norepinephrine?
Treatment of shock -> rapidly increases the blood pressure
What is primary adverse effect of norepinephrine and how is this prevented?
Since it is given IV, if some norepinephrine seeps out of the injection site, it can cause local vasoconstriction and tissue necrosis.
This can be treated with topical alpha-receptor agonist phentolamine
What are the contraindications and side effects of epinephrine injection?
Nonselective Beta-antagonist -> hypertensive crisis possible
Possible side effects: cerebral hemorrhage, cardiac arrhythmia
What drug equally stimulates beta1 and beta2 receptors, and what its only therapeutic use?
Isoproterenol - nonselective beta agonist
Only used in emergencies to stimulate heart in AV block
What receptors can dopamine activate, and at what doses? General effects?
Low: D1 (increases renal and splanchnic bloodflow)
Medium: D1, beta1 (stimulates heart, increased systolic BP)
High: D1, beta1, alpha1 (increased diastolic blood pressure)
Why is dopamine considered better than norepinephrine in the treatment of cardiogenic and septic shock?
It can still raise your blood pressure like NE, but it also keeps bloodflow to the kidneys -> prevents renal shutdown
Other than shock, what is dopamine used for?
Treatment of hypotension and severe congestive heart failure (when patient needs to raise BP)
What are the adverse effects of dopamine?
Normal sympathetic side effects: nausea, hypertension, and arrythmias which are shortlived due to rapid COMT inactivation
What is the mechanism of action of fenoldopam and what is its indication?
FenolDOPAm -> acts on peripheral D1 receptors
Indicated in severe hypertension -> relieves it by increasing blood flow to kidney, coronary arteries, and mesenteric arteries
What is dobutamine and when is it typically used?
Synthetic catecholamine - selective beta1 agonist
Typically used in acute heart failure to increase cardiac output -> does not significantly elevate oxygen demands either! (think of do a bugling shirt person cranking up the heart)
When is dobutamine contraindicated?
Patients with atrial fibrillation -> can increase AV conduction and cause significant tachycardia
What receptors does oxymetazoline bind and what is it used for?
alpha1 and alpha2 agonist, used in nose (decongestant) and eyes (relief of redness) via vasoconstriction
What is oxymetazoline’s side effect of concern?
Rebound congestion and dependence in long-term use (downregulation of receptors) + CNS adrenergic effects (insomnia, headaches)
What does phenylephrine bind and what is it used for?
Synthetic alpha1 agonist, nasal decongestant when given topically or orally (think of the guys wearing flannel)
Also put in eyes for mydriasis, or to treat hypotension in hospitalized / surgical patients with a tachycardia
Why are the side effects of phenylephrine concerning?
It is given OTC, but can still cause hypertensive headache and cardiac irregularities
What does phenylephrine do the heart when administered systemically?
Will cause vasoconstriction and thus reflex bradycardia (similar to norepinephrine)
If phenylephrine is the selective alpha1 agonist, what is the selective alpha2 agonist?
Clonidine
What does clonidine do?
Binds presynaptic alpha2 receptors in CNS -> inhibits sympathetic vasomotor centers -> decreases total peripheral resistance and blood pressure, but also reduces all sympathetic activity
What is clonidine used for clinically?
- Treatment of resistant hypertension (two or more drugs haven’t worked) and especially of hypertension in complicated renal disease (Does not decrease renal blood flow)
- Treatment of withdrawal from opiates, benzodiazepines, and tobacco (reduces stimulant effect)
It’s a rare AGONIST that can treat hypertension
What are the short-acting beta-2 agonists (SABAs)?
Albuterol and Terbutaline (also used to prevent labor by relaxing uterus)
What are SABAs used for?
Treatment of acute asthma and chronic asthma + COPD, + prevention of exercise-induced bronchospasm
3-5 hours of relief
What are the common side effects of SABAs? More severe?
tremor, restlessness, and anxiety
More severe: Tachycardia or arrhythmia if administered orally (due to beta1 activation at high doses)
What are the long-acting beta-2 agonists (LABAs)?
Salmeterol and Formoterol -> 12 hour effects
What are LABAs used for?
Chronic treatment of asthma for bronchodilation, especially for those with nocturnal asthma symptoms
When are LABAs contraindicated? Why?
Contraindicated as monotherapy (should only be used in combination with low to medium dose inhaled corticosteroids)
This is because in monotherapy they have increased risk of severe asthma exacerbations + death (due to receptor modification)
How does amphetamine work as an indirect-acting agonist?
Blocks the reuptake of NE by actually reversing the normal NET in the membrane, leading to leakage from the cleft. It also competes for VMAT2 to keep non-vesicular NE concentrations high, to facilitate further leakage through NET
What are the therapeutic uses of amphetamines?
CNS stimulant -> ADHD, narcolepsy, and appetite control
What are the adverse effects of amphetamines?
CNS overstimulation -> dizziness, tremor, hyperreflexivity
At highest levels: Aggressiveness, panic, hallucinations (paranoid), CV effects like hypertension and arrythmias
How can amphetamines cause a hypertensive crisis?
When used with MAO inhibitors -> dangerously high NE levels
How do tyramines function and when is this a problem?
Function like amphetamines -> non-vesicular release of NE
A problem when you are taking a MAO-inhibitor, so the GI tract cannot detoxify fermented foods like aged cheeses and wines -> hypertensive crisis
What is the mechanism of action of cocaine?
Blocks NET reuptake of norepinephrine
What is the mechanism of action of ephedrine?
Mixed-acting agonist. Binds all receptors (though less potently than epinephrine), and stimulate release of stored NE from nerve endings (like amphetamines)
What is the length of ephedrine action and why?
Long-acting, not well metabolized by COMT or MAO
What are the clinical uses of ephedrine?
Hypotension - via alpha and beta effects
also gets CNS and increases alterness, as a stimulant
Why is pseudoephedrin a controlled substance?
It is a nasal decongestant sold OTC, but is used to produce methamphetamine
What must never be done with clonidine? What drug can treat the complications?
Stopping cold turkey -> can cause a hypertensive crisis due to increased levels of NE from a rebound.
Complications can be treated with phentolamine -> block the alpha1 / alpha2 action of norepinephrine
Give an example of an adrenergic agonist used in glaucoma and how does this work?
Alpha-2 receptors decrease the production of aqueous humor
Example: Apraclonidine (derivative of clonidine).
