Adrenergic Agonists Flashcards
What is the general term for NT/hormones in the sympathetic NS?
- catecholemines
What are the major catecholamines?
- dopamine (DA)
- norepinephrine (NE)
- epinephrine (E)
What are the categories of adrenergic receptors?
- alpha 1 (a1)
- alpha 2 (a2)
- beta (1, 2, 3)
- dopamine
What type of receptors are adrenergic receptors?
- GPCRs
What are the factors that can alter the degree to which any adrenergic receptor responds?
- selectivity
- regulation
- polymorphisms
- catacholamine metabolism
What does receptor selectivity allow for?
- specific binding
- i.e. drug x only binds to a1 receptors but not a2 or b receptors
What effects degree of drug binding?
- [drug]
What does [low drug] allow for?
- selective binding
What does [high drug] cause?
- non-selective binding
- i.e. larger [ ] flood receptors that usually do not bind the drug
What is receptor regulation?
- increasing or decreasing the number of receptors based on the long term exposure
- i.e. up/down regulation
What does receptor regulation result in?
- changes in the observed response to sympathomimetic drugs
What is an example of receptor regulation?
- desensitization (aka: tolerance, refractoriness, tachyphylaxis)
Describe desensitization
- decrease responsiveness of that cell/tissue to additional stimulation
What are the mechanisms of desensitization?
- altered transcription/translation of DNA and/or RNA
- modifications of receptors via interactions with enzymes or other proteins
- long term exposure to an agonist
- interactions or messages from other receptors
What is the desired therapeutic benefit of using desensitization?
- results in an increased response followed by the desired decreased physiological action
Describe receptor polymorphism
- slight changes in a.a. sequences can occur in different people
- explains why some drugs work better in some people vs. others
What are the mechanisms of NT termination?
- NE transporter (NET)
- diffusion
- metabolism by COMT or MAO
What is the most important mechanism of NT termination?
- NET
Describe the action of NET
- pre-synaptic pump to move NE out of synapse and back into neuron (reuptake)
How does NET act as a therapeutic target?
- NET inhibition prolongs the presence of NE in the synaptic cleft leading to increased stimulation of adrenergic receptors
What are drugs that are able to bind and inhibit NET action?
- atomoxetine (used in ADHD)
- cocaine
What is the action of catechol-O-methyl transferase (COMT)?
- metabolizes all catecholemines
What is a drug that inhibits COMT and what is its clinical use?
- entacapone
- Parkinson’s
What is the action of monoamine oxidase (MAO)?
- metabolizes endogenous monoamines (i.e. linezolind)
Define sympathomimetic
- drug that mimics actions of NE, E, and DA
Define direct agonist sympathomimetics
- structure allows for binding to adrenergic receptors resulting in activation
Define indirect agonist sympathomimetics
- cause release of stored catecholamines
- inhibits reuptake of catecholamines
What are the locations that changes can be made on sympathomimetic drugs?
- benzene ring
- beta C
- alpha C
- amino group
What is the major target of sympathomimetics?
- CV system
Where are a1 and b2 receptors in CV system?
- vascular
Where are b1 receptors in CV system?
- heart
What is the outcome of giving a drug dependent on?
- selectivity for a v. b receptors
- pharmacologic action at the receptors (agonist/antagonist)
- action of body’s compensatory mechanisms to maintain homeostasis
Which receptors in the CV system cause vasoconstriction?
- a1
Which receptors in the CV system cause vasodilation?
- b2
What are the effects in the CV of a1 receptor activation?
- vasoconstriction leads to increased BP which causes reflex decrease on HR
What is an example of a CV system a1 agonist and when is it used?
- phenylephrine
- nasal decongestion and maintaining BP
What is the effect of peripheral a2 agonists in the CV system?
- vasoconstriction, but only when given locally, IV push, or very high oral doses
- rare
What is the effect of central a2 agonists in the CV system?
- inhibits sympathetic vascular tone
- lowers BP
What is an example of a CV system a2 agonist and when is it used?
- clonidine
- HTN
What are the effects of a b1 receptor agonist in heart?
- increase contractility
- increase HR
- increase CO
What are the effects of a b2 receptor agonist in the vasculature?
- decrease resistance aka vasodilation
- decreased BP
What is the effect of DA on d1 receptors in CV system?
- vasodilation
Where does DA bind in low doses?
- b2 receptors, specifically renal
Where does DA bind in medium doses?
- b1 receptors to increase HR and contractility
Where does DA bind in high doses?
- a1 receptors to increase BP
What receptors are activated by sympathomimetics in the lungs and what is the effect?
- b2
- bronchodilation
What receptors are activated by sympathomimetics in the eye and what is the effect?
- a
- mydriasis, increase outflow of aqueous humor, decreases IOP
What receptors are activated by sympathomimetics in the GU tract and what is the effect?
- a receptors
- urine retention and mediate ejaculation
What receptors are activated by sympathomimetics in the salivary glands and what is the effect?
- b receptors
- increase salivation
What is the effect of sympathomimetics on the apocrine sweat glands in the hands?
- increased sweat production in response to stress
What receptors are activated by sympathomimetics in metabolism and what is the effect?
- b receptors
- increased glycogenolysis increases serum glucose which results in increased insulin
What are the effects of sympathomimetics on the CNS dependent on?
- ability to cross BBB
What are the endogenous catecholamines?
- NE
- E
- DA
At which receptors does E act as an agonist?
- a1 & 2
- b1 & 2
What are the primary effects of E?
- vasoconstrictor
- cardiac stimulant
What are the secondary effects of E?
- increased systolic BP due to a1 binding
- increased HR and CO due to b1 binding
- vasodilation due to b2 binding but only in skeletal m.
At which receptors does NE act as an agonist?
- a1 & 2
- b1
What are the primary effects of NE?
- vasoconstrictor
- cardiac stimulant
What are the secondary effects of NE?
- increased systolic BP due to a1 binding
- increased HR and CO due to b1 binding
same as E
What is a brand name for NE?
- Levophed (leave them dead)
What are the effects of DA in the CV system based on?
- doses
What is the effect of low does DA on the CV and where does it bind?
- vasodilation
- b2
What is the effect of medium dose DA on the CV and where does it bind?
- increase HR and CO
- b1
What is the effect of high dose DA on the CV and where does it bind?
- vasoconstriction
- a1
What is an action of DA on the CNS?
- development of addiction based on reward stimuli
A deficiency of ______ can contribute to ______ disease.
- DA
- Parkinson’s
What type of receptors are targets for antipsychotic drugs?
- DA
What are the main effects of direct a1 agonists?
- vasoconstriction
- increase BP
What are two examples of direct a1 agonists and what are their uses?
- phenylephrine (neosynephrine): decongestant and raise BP
- midodrine (Amantine): increase BP and tx orthostatic HTN
What is the main effect of direct a2 agonists?
- decrease BP
What is the classic example of a direct a2 agonist and what is it used for?
- clonidine (Catapres): reduce BP and tx HTN (preeclampsia)
What are the effects of direct a1 AND a2?
- local vasoconstriction
What is an example of a direct a1 AND a2 drug and what is it used for?
- oxymetazoline (Afrin): decongestant
What is an example of a nonselective b agonist and what are the effects?
- isoproterenol (Isuprel): vasodilation via b2; decreased BP and MAP; increased HR and CO
What is the primary effect of b1 selective agonists?
- increase CO and HR
How does dobutamine produce its effects without changing BP?
- (+) isomer gives b1 action and a1 antagonism
- (-) isomer gives a1 agonism
- a1’s cancel each others effects out*
What is the effect of b2 selective agonist?
- bronchodilation
- relax uterine smooth m.
What are examples of b2 selective agonists for each of its effects and what are they used to treat?
- albuterol/salmeterol: asthma and COPD
- ritodrine/terbulatine: premature labor
What effects are seen with mixed-acting sympathomimetics?
- both a and b, combo effects
- i.e. vasoconstriction, decongestion, bronchodilation, appetite suppression, and CNS stimulation (fight or flight)
What are examples of mixed-acting sympathomimetic?
- ephedrine
- pseudoephedrine
What are the indications and contraindications for psuedoephedrine?
- indications: congestion (decongestant)
- contraindications: HTN
What are two mechanisms for indirect-acting sympathomimetics?
- displace stored catecholamines
- inhibit reuptake of released NT by interfering with NET
What are examples of indirect-acting sympathomimetics?
- amphetamine/meth/phenmetrazine/methylphenidate (Ritalin)
- tyramine
- catecholamine reuptake inhibitors
What are the actions of indirect-acting sympathomimetics?
- release stored NE and DA
- increase mood and alertness
- decrease appetite
What is a therapeutic use for methyphenidate and how does it work?
- Ritalin
- tx: ADHD
- reduces uptake of NE, ‘evens things out’
What is the action and therapeutic use of modafinil or armodafinil?
- indirect sympathomimetic
- inhibits NE and DA transporters in CNS
- increases wakefulness
- tx: nacolepsy, obstructive sleep apnea, and shift work disorders
What is the action of tyramine?
- releases stored catecholamines
What metabolizes tyramine?
- MAO
Who should avoid foods containing tyramine?
- patients on MAOIs
What are the therapeutic uses of catecholamine reuptake inhibitors?
- ADHD
- appetite suppressant
- antidepressant
What is the key feature of cocaine?
- inhibition of DA reuptake in pleasure center of brain leading to rapid addiction via stimulation of b1
What could be used to treat hypotension?
- a1 agonists to raise BP
- i.e. NE, phenylephrine
What could be used to treat HTN?
- a2 agonists
- i.e. clonidine
What could be used to treat orthostatic HTN?
- a1 agonist
- i.e. midrodrine
What is used in emergency cardiac resuscitation?
- a1 and b2
- E
What can be used to reduce blood loss at surgical site?
- a1 agonist
- E or cocaine
What can be used to slow diffusion of anesthetics away from admin site?
- a1 agonist
- lido + E, NE, phenyleprine
What can be used to treat sinus congestion?
- a1 agonist
- oxymetazoline (Afrin)
What is a concern when taking an a1 agonist to treat sinus congestion?
- limit use to no more than 3 days due to risk of rebound effect
What can be used to treat asthma and COPD?
- b2 selective agonists
- albuterol/salmeterol
How are anyphylactic reactions treated?
- a1, b1, b2 agonists
- E (EpiPen) often in combo with steroid of antihistamine
What can be used to facilitate eye examinations?
- a1 agonists
What can reduce eye redness associated with allergies?
- a1 agonist
What can reduce IOP in patients with glaucoma?
- a2 agonist
- apraclonidine (Lopidine) and brimonidine (Alphagan)
What can be used to prevent premature labor?
- b2 selective agonists
- ritodrine, terbutaline
What can be used to improve patient comfort in the ICU?
- a2 agonists
