auto sympathomimetics: beta and alpha agonists (part 2 and 3)

2 examples of non-selective beta 2 agonists

isoproterenol (prototype), dobutamine

effects of isoproterenol on TPR, SBP, and DBP

- lowered TPR (via beta vasodilation and no effect on alpha)

this causes decrease in DBP

unchanged or raised (via beta 1) SBP

effects of isoproterenol on MAP and CO

MAP decreased

CO increased (via HR, contraction, and lowered TPR)

t/f: isoproterenol relaxes almost all smooth muscle

true

how is isoproterenol metabolized

in liver by COMT

(not by MAO or reuptake)

isoproterenol adverse effects

tachycardia, palpitations, arrhythmias, headache, flushing, afib, vtach

therapeutic use of isoproterenol

bradycardia and heart block

dobutamine

+ vs - isomer

+ isomer: beta AGonist and alpha ANTagonist

- isomer: beta AGonist (more potent) and alpha AGonist

(alpha activity cancels out, making it a non-selective beta agonist)

dobutamine therapeutic uses

cardiac decompensation after surgery, congestive heart failure, cardiogenic shock, acute MI

* note short half life (about 2 mins)

tx aim of selective beta 2 agonists

asthma or COPD (via bronchial smooth muscle relaxation)

metaproterenol

beta-2 selective agonist

- less selective than others; greater potential for cardiac stimulation

- resistant to COMT

albuterol

beta-2 selective agonist

- inhaled for COPD and asthma

terbutaline

beta-2 selective agonist

- given orally (1-2hrs)

- NOT metabolized by COMT

for COPD and bronchospasms

(higher chance for cardiac adverse effects)

levalbuterol

r-enantiomer of albuterol

selective beta- 2 agonist

pirbuterol

beta 2 selective agonist

inhaled q4-6hrs

salmeterol

LABA

long duration: >12hrs

slow onset

- for COPD, NOT acute asthma attacks

formoterol

LABA

quick onset and long acting (up to 12hrs)

arformoterol

r- enantiomer of formoterol; 2x more potent

indaceterol

quick onset, long acting; doesnt antagonize SABAs

ritodrine

beta 2 agonist; developed for uterine relaxation

- removed from US market

adverse effects of beta 2 agonists

-potential risk for cardiovasc disease

- risk to pts on MAO inhibitors

- may lead to hyperglycemia

- tremor

mirabegron

selective beta-3 agonist

- relaxes detrusor muscle, helps bladder filling

- approved for overactive bladder

therapeutic uses of dopamine, NE, and EPI

raise bp under hypotensive conditions (ex: shock)

alpha-1 selective agonists

cardiovasc effects?

uses?

vasoconstriction via alpha 1 on vascular smooth muscle

causes increased TPR and increased MAP

used for hypotensive states, nasal decongestants, and mydriasis

phenylephrine

alpha-1 selective

- venous and arterial vasoconstriction

uses: nasal decongestant; mydriasis

does phenylephrine cross bbb

no. polar (like EPI)

oxymetazoline

alpha-1 agonist

(alpha 2 partial agonist; less selective for 1)

vasoconstrictor, decongestant, eye drops to reduce redness

mephentermine

- both direct AND indirect

- alpha-1 selective= vasoconstriction

- NE release= increased cardiac contractility (for acute hypotensive states)

crosses BBB!= CNS excitation, hypertension, arrhythmias (unlike metaraminol)

can mephentermine cross bbb

yes-> can cause CNS excitation

mephentermine contraindications

MAO inhibitors (bc mephentermine stimulates NE release)

caution: TCAs

t/f: mephentermine is an alpha agonist that can also cause NE release and stimulate beta receptors

true

metaraminol

- both direct AND indirect

- alpha-1 selective= vasoconstriction

- NE release= increased cardiac contractility (for acute hypotensive states and atrial tachycardia)

does NOT cross BBB! unlike mephentermine

midodrine

- given orally, onset about an hour, duration 4-6hrs

PRODRUG converted to desglymidodrine= selective alpha 1 agonist

does NOT cross BBB

use: for orthostatic hypotension, autonomic insufficiency

midodrine uses

for orthostatic hypotension, autonomic insufficiency

t/f: midodrine crosses the BBB

false

midodrine counseling point

pts on midodrine can have supine hypertension (bp rises when they lay down)

- do not give 4hrs before bed, and give to pt while upright during the day

- elevate the head of the bed

alpha 2 selective agents are often _______philic meaning they ______ cross the BBB

lipophilic; do cross

what are alpha 2 selective agents most often used to treat

hypertension; ocular therapy

alpha 2 selective agonist prototype

clonidine

which receptors does clonidine target

alpha-2 selective but concentration dependant (will target alpha 1 at high doses)

IV vs oral clonidine

IV: biphasic

- acute increase in bp (via vasoconstriction)

followed by prolonged decrease in bp and hr (via CNS)

oral: lowers bp and hr (no increase in bp at all)

where are alpha 2 receptors found

brain stem vasomotor centers (CNS)

post ganglionic presynaptic receptors (PNS)

describe clonidine's moa and effect

alpha-2 selective agonist (low dose alpha 2 predominates, high dose targets alpha 1)

1. targets alpha 2 receptors on post gang presynaptic neurons= lowers NE release

2. targets alpha 2 receptors in brainstem vasomotor center= increases parasymp tone

=this causes lower bp and hr

(note IV will cause temporary increase in BP)

clonidine administered _______ has a biphasic effect meaning ________

IV;

1. acute increase in BP due to vasoconstriction

2. followed by prolonged decrease in BP and HR due to CNS

t/f: clonidine acts on both the PNS and CNS

true

PNS: activation of pre-synaptic receptors on post gang neurons which decreases NE release (auto)

CNS: stimulates alpha 2 receptors in CNS= decreases symp tone and increases para tone

why is there no increase in BP in oral clonidine but there is in IV clonidine

IV clonidine goes straight to blood and targets alpha 2 receptors on vascular smooth muscle causing vasoconstriction before it reaches CNS to lower symp tone

oral clonidine must first be absorbed and metabolized and has time to reach CNS and avoid instant vasoconstriction

cardiovasc response to IV clonidine (slides 8/9)

what happens to mean BP, symp nerve activity (SNA), HR

BP: initial rise (only for IV) that then lowers as baroreceptor reflex kicks in

SNA: large drop due to rise in BP (baroreceptor reflex), once bp restored, SNA goes back up BUT still lower than baseline (bc clonidine is being distributed to brain)

HR: drop bc SNA drops (baroreceptor), but still says lower than initially due to lower SNA

given an IV clonidine vs BP/SNA/HR graph, how do you know when the baroreceptor reflex is activated vs when the response is a result of clonidine's central action

if BP is elevated, then the drop in symp NA would most likely be due to the baroreceptor reflex. but if the bp is normal/ below normal and SNA is still low, thats probably clonidine and not the reflex

clonidine ADE

- xerostomia (dry mouth)

- sedation

- sexual dysfunction

- excessive bradycardia, hypotension

- withdrawal rxn (rebound increase in symp activity and bp)

withdrawal reaction present in clonidine

rebound increase in symp activity and bp when clonidine is removed.

clonidine lowers setpoint when you take the drug away, you may get hypertensive crisis->> titrate down!

therapeutic uses of clonidine

HTN, diarrhea in diabetes, addiction tx (narcotics, alcohol, tobacco), preoperative med to lower anesthetic need, ADHD, Tourette's

apraclonidine

moa?

use?

BBB?

selective alpha 2 agonist

topically into eye to lower IOP via aqueous humor reduction (open angle glaucoma)

does NOT cross BBB (unlike clonidine/brimonidine)

brimonidine

moa?

use?

BBB?

selective alpha- 2 agonist

topically into eye to lower IOP via aqueous humor reduction (open angle glaucoma)

CAN cross BBB and produce hypotension/sedation

t/f: unlike apraclonidine, brimonidine does not cross the BBB and is the primary choice in glaucoma pts to prevent hypotension/sedation

false.

apraclonidine= does NOT cross BBB

brimonidine= DOES cross BBB and might cause hypotension

is guanfacine or clonidine more selective for alpha-2

guanfacine

guanfacine

moa?

use?

BBB?

selective alpha 2 agonist (MORE selective than clonidine)

lipophilic so DOES cross BBB

use/ADEs same as clonidine BUTT withdrawal symptoms are better bc longer half life

main difference between guanfacine and clonidine

both are selective alpha 2 agonists with similar uses

- guanfacine is more selective

- guanfacine has longer half life so more mild withdrawal rxn

guanabenz

moa

use

BBB

selective alpha 2 agonist

lipophilic-> crosses BBB

- use/ADEs same as clonidine/ guanfacine

BUTT extensively metabolized in liver (watchout for liver disease pts)

alpha methyldopa

moa?

what is it converted to and what happens?

BBB?

selective alpha 2 agonist

analog of DOPA

crosses BBB

-converted to alpha-methylnorepinephrine which is stored in adrenergic vesicles.->> released as a false transmitter instead of NE

- this stimulates central alpha-2 receptors and lowers BP/HR (like clonidine)

which selective alpha-2 agonist must be converted into another form before it can exert its effect and into what?

alpha-methyldopa

converted into alpha- methylnorepinephrine

released as false transmitter to stimulate central alpha-2 receptors

(uses catecholamine synthesis pathway)

tizanidine

moa

use

selective alpha-2 agonist

similar to clonidine. also used as muscle relaxer (so both central and motor neuron activity)

alpha 1 receptor subtypes

1A:

- only one in prostate!

- vasoconstriction

- responds to IV non-selective alpha-1 agonists

1B:

- MOST abundant subtype in heart; cardiac growth

- LESSER role in pressor response in IV

1D:

- vasoconstriction in aorta/ coronary arteries

-all present in brain

-A and B in lungs and vasculature, D is not

which alpha 1 subtype is present in the prostate

alpha 1A

which alpha 1 subtype is the most abundant in the heart

alpha 1B

alpha 2 receptor subtypes

where?

what do they do?

2a:

- brain, spinal cord, post gang symp neurons

- knockout: decreased prejunctional adrenergic neuron modulation

- can decrease SNA through CNS and decrease NE release through nerve terminal

2b:

- kidney, liver, vasc

- knockout: peripheral pressor response

- vasoconstriction

2c:

- brain, adrenal medulla

- inhibits epi release from adrenal medulla