10-auto beta receptor antagonists

the sympathetic system _______ the radial muscle via the _____ receptor

and _____ the ciliary muscle via the _________ receptor

contracts radial via alpha1

relaxes ciliary via beta

the sympathetic nervous system _________ bronchiolar smooth muscle via the _______ receptor

relaxes via beta2

*this is an ADE we need to watch out for bc blocking beta2 may cause bronchospasm

what effect does the sympathetic nervous system have on the following

GI walls

GI sphincters

enzyme secretions

relaxes GI walls

contracts sphincters (alpha1)

inhibits secretions (alpha2)

the sympathetic NS ________ the bladder wall via _______

and ________ the sphincter via _____

relaxes bladder wall via beta2

contracts sphincter via alpha1

the sympathetic nervous system _______ gluconeogenesis and glycogenolysis via ___________

increases via beta2

the sympathetic system ________ renin release via _________

increases; beta1

enzyme and insulin secretion is mediated via which receptor

alpha-2

what are the alpha receptor subtypes

1a: know its in prostate

1b: most abundant in heart

1d: also in prostate, causes vasoconstriction in aorta and arteries

almost all adrenergic antagonists are competitive EXCEPT FOR

phenoxybenzamine= irreversible antagonist at alpha receptor

what functions will an alpha1 antagonist block

-blocks contraction of arterial and venous smooth muscle

- blocks contraction of visceral smooth muscle

what functions will an alpha2 antagonist block

-blocks increase in vagal tone

- blocks inhibition of NE (autoreceptors) and ACh release (heteroreceptors)

- blocks regulation of metabolism

- blocks platelet aggregation (alpha 2a)

what functions will a beta antagonist block

- blocks cardiac stimulation

- blocks relaxation of skeletal and visceral smooth muscle

- blocks glycogenolysis and gluconeogenesis

- blocks renin release

alpha antagonists result in vasodilation of arteries and veins leading to

___ MAP

___ cardia

___ CO

decreased MAP

reflex tachycardia and increased CO

t/f: orthostatic hypotension may be a side effect of alpha antagonists as a result of vasodilation of arteries/veins and major drop in MAP

true

t/f: a decrease in MAP is more severe if a selective alpha blocker is used

false. non-selective

MAP=

MAP= CO x TPR

CO=

CO= HR x SV

which receptor is targeted to treat benign prostatic hyperplasia (BPH) and why

alpha-1 blockade relaxes the smooth muscle at the neck of the bladder and helps w urine flow

- prostate and lower urinary tract have a lot of alpha 1A receptors

the prostate and lower urinary tract have a lot of alpha ____ receptors, and are used as a drug target for BPH

alpha 1A

(blockade causes relaxation and increases urinary outflow)

phenoxybenzamine

class and notability

non-selective ALPHA-receptor ANTagonist

= IRREVERSIBLE: forms time dependant covalent bond

- new receptor must be synthesized

- tx for pheochromocytoma

phenoxybenzamine leads to

_______ capacitance

_______ preload

_______ TPR

____HR

_____ renin

its a nonselective alpha ANTagonist that wont let vessels constrict

increased capacitance

decreased preload

decreased TPR

reflex causes increased symp activity:

increased HR

increased renin

what effect would prejunctional alpha 2 blockade have on phenoxybenzamine

phenoxybenzamine is a non-selective alpha antagonist

prejunctional alpha 2 blockade would augment its effects even more (increase) bc blocking auto receptor= increasing symp activity= causes an even greater increase in HR

is there greater orthostatic hypotension in non-selective alpha antagonists or centrally active alpha-2 agonists

non-selective alpha antagonists bc have a more central effect and block baroreceptor reflex to bring pressure back up

(alpha 2 agonists block symp outflow leading to vasodilation= blood pooling= hypotension;; they more so just turn the dial down)

phentolamine

class

use

-Nonselective α-blocker

- affects HR similar to phenoxybenzamine

used for pheochromocytoma

pheochromocytoma txs

tumor that increases catecholamine release

- phenoxybenzamine and phentolamine are possible treatments

what would be the response in only administering an alpha-1 antagonist and not an alpha-2 antagonist in pheochromocytoma

blocking only alpha1 increases BP in response to circulating EPI sincre alpha-2 mediated vasoconstriction still available

what would happen if you were to use a non-selective beta blocker in pheochromocytoma

blocking beta1 would lower HR, blocking beta2 would prevent skeletal muscle vasc from relaxing

- circulating EPI may aggravate hypertension via blocking beta 2

Prazosin

brand?

MOA/effect?

Minipress

prototype alpha 1 antagonist for all subtypes

- will NOT increase HR

why does prazosin have similar effects as phentolamine but does not increase HR

-does not block prejunctional alpha2 so does not enhance NE release

- reflex increase in beta 1 stimulation is therefore less than phentolamine

will prazosin pass the BBB

yes, its lipophilic. it decreases symp tone via a central effect

t/f: both blocking alpha 1 (ex: prazosin) and stimulating alpha 2 (ex: clonidine) in the brain can lower SNA activity via central mechanisms

true

what is the first dose effect seen in prazosin

BIGG decrease in MAP at first dose. give the initial dose at bedtime

compare terazosin and doxazosin to prazosin

both are also alpha 1 antagonists but with LONGER duration of action

- used to treat HTN

- have additional apoptotic effect in BPH

alfuzosin

alpha 1 antagonist (nonselective)

- only approved for BPH

Tamsulosin

alpha 1 antagonist

- higher affinity for 1A and 1D (not rlly 1B)

- used for BPH tx and less effect on BP

Silodosin

alpha 1 antagonist

- higher affinity for 1A than 1B

- used for BPH tx and less effect on BP

which alpha subtypes are associated with prostate

1A and 1D

alpha 1___ has more effect on BP and no effect on prostate than the other alpha subtypes

1B

explain how tamsulosin works in BPH treatment

alpha 1A and 1D antagonist in trigone, sphincter, urethra, and prostate (1A especially)

-tamsulosin relaxes the smooth muscle and allows for urinary outflow

t/f: antagonists tend to be larger than agonists

true

how can alpha 1 antagonists improve lipid profiles

alpha 1 agonists INCREASE lipolysis so by blocking this you have less lipids in the blood

how can alpha antagonists be used to treat congestive heart failure (CHF)

they lower preload and afterload by dilation veins/arterioles

= this helps increase CO and decrease pulmonary congestion

ADEs of alpha 1 antagonists

syncope (fainting)

orthostatic hypotension

first dose effect

what antagonists would we add to EPI to look like NE? isoproterenol?

for EP to look like NE we need to eliminate beta 2 vasodilation. add beta-2 blocker

for EPI to look like isoproterenol we need to eliminate both alpha-1 and alpha2 receptors. add non-selective alpha receptor antagonist

what effect would there be in blocking alpha-2 receptors centrally and peripherally

central= increase symp outflow

peripheral= increase NE release via loss of autoreceptor fxn

central alpha 2 blockade in the brain ________ sympathetic activity

increases

(note alpha 2 blockade in periphery increases it even more via autoreceptor blockage)

yohimbine

moa and notability

alpha 2 antagonist

- crosses BBB

- actions opposite to clonidine (increases both BP and HR)

- someee data shows efficacy for ED like viagra

identify each by generation/moa

propranolol:

metoprolol:

labetalol:

nebivolol:

propranolol: non selective 1st gen

metoprolol: beta 1 second gen (heart)

labetalol: non selective 3rd gen (all beta and also alpha blockade)

nebivolol: beta 1 3rd gen

(beta 1 and also increased NO)

why do beta blockers have little effect on the normal heart of an individual at rest

bc predominate tone is parasymp. beta blockers have larger effect when symp system is active

eNOS

endothelial nitric oxide synthase, causes relaxation of skeletal smooth muscle

t/f: exercise induced increase in stroke volume still occurs with beta blockade

true. but tends to decrease work capacity

beta 2 blockade

____ skeletal muscle dilation

____ glucose metabolism and lipolysis

____ positive inotropic effect

_____ bronchospasms

everything is diminished EXCEPT for bronchospasm which are increased

propranolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

1st= non selective

membrane: ++

intrinsic: 0

lipid: HIGH

pindolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

1st= non selective

membrane: +

intrinsic activity: +++

(can stimulate receptor at low symp activity)

lipid: LOW

timolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

1st= non-selective

membrane: 0

ia= 0

lipid= low

metoprolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

2nd= beta 1 selective

membrane= +

ia= 0

lipid= mod

less bronchospasm due to selectivity!

atenolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

2nd= beta 1 selective

membrane= 0

ia= 0

lipid= low

less bronchospasm due to selectivity!

labetalol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

3rd= non selective + additional

membrane= +

ia= +

lipid= low

carvedilol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

3rd= non selective + additional

membrane= ++

ia= 0

lipid= mod

carteolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

3rd= non selective + additional

membrane= 0

ia= ++

lipid= low

nebivolol

selectivity?

membrane stabilizing?

intrinsic activity?

lipid solubility?

3rd= non selective + additional

membrane= 0

ia= 0

lipid= low

only beta blocker with high lipid solubility

propranolol

which beta blockers have membrane solubility

propranolol (H)

carvedilol (M)

metoprolol (M)

betaxolol (M)

which beta blockers are membrane stabilizing

propranolol, pindolol, metoprolol, labetalol, carvedilol, betaxelol

not: timolol, atenolol, carteolol, nebivolol

which beta blockers have some intrinsic activity? what does this mean?

pindolol +++

carteolol ++

labetalol +

may act as agonist when symp activity is low, leads to vasodilation

[pin lab cart[

classify the following beta blockers based on receptor activity

propranolol

pindolol

timolol

metoprolol

atenolol

labetalol

carvedilol

carteolol

nebivolol

(summary)

1st NON-selective:

propranolol $

pindolol !!!

timolol

2nd beta 1:

metoprolol $

atenolol

3rd NON and ADDITIONAL:

labetalol !

carvedilol $

carteolol !!

3rd beta 1 and ADDITIONAL:

nebivolol

!!!= intrinsic activity

$= lipid soluble

which beta blockers also assist in nitric oxide production

nebivolol

carteolol

which beta blockers act as vasodilators and how

pindolol= stimulates beta 2

labetalol= alpha-1 blocker and stims beta 2

carvedilol= alpha 1 blocker

carteolol= NO production

nebivolol= NO production

which beta blockers also have alpha 1 receptor antagonism

carvedilol

labetalol

which beta blockers also block calcium

carvedilol

betaxolol

which beta blocker also has antioxidant activity

carvedilol

which additional vasodilating properties does carvedilol have

-alpha 1 receptor antagonism

-calcium blocker

- antioxidant activity

betaxolol

selective for beta 2, also blocks calcium

used for HTN anddd glaucoma

less bronchospasm due to selectivity

4 stereoisomers of labetalol and what are their actions

1. alpha 1 ANTagonist (like prazosin)

2. non selective beta blocker-> partial activity at beta 2 (ISA)

and 2 inactive

this lowers TPR from alpha 1 antagonism and beta 2 agonism

then beta 1 antagonism blocks reflex

t/f: carvedilol does not have reflex tachycardia due to beta 1 blockade

true

which beta blockers are used in glaucoma

timolol (and cardio)

carteolol

betaxolol (and cardio)-

which beta blocker is specifically only for glaucoma and NOT cardio

carteolol

mechs of vasodilation for the third generation

1. ISA= intrinsic activity works on beta-2 receptors and vasodilates

ex: pin, lab, cart

2. NO production= increases cGMP leading to vasodilation

ex: neb, bet

3. calcium channel blocker= stops contraction leading to vasodilation

ex: carvedilol

therapeutic use of beta blockers

-HTN (dont reduce in normal pts)

- ischemic heart disease

-MI

- CHF

- arrythmias

- glaucoma

while there are many mechs of beta blockers treating HTN, what is the most prominent mech

blocking beta 1 symp drive to heart and blocking renin release

1st gen= beta blockers WITHOUT ISA initially ___ CO and _____ TPR

decrease CO (blocking B1)

increase TPR (reflex as pressure drops) orr no change with long term therapy

1st gen= beta blockers WITH ISA initially see ___(more/less?)____ decrease in CO/HR and ______ TPR than compared to no ISA

less decrease in CO/HR (bc partial agonist activity)

lower TPR (no reflex increase TPR like those without ISA) bc of beta 2 stimulation

t/f: beta blockers have withdrawal syndrome like clonidine

true. do not d/c abruptly

contraindications to beta blockers

asthmatics (beta2), CHF (if depend on symp drive), SA/AV nodal dysfunction

t/f: beta blockers with ISA predominantly lower TPR and have little to no effect on CO and HR, while those without ISA lower HR and CO

true.

-those w ISA partially stimulate B1 while blocking them= milder effect. lower TPR bc beta-2 agonist activity

- those without ISA are pure antagonists, which significantly reduce HR and CO by blocking beta-1 receptors. cause reflex increase in TPR before it lowers again

blocking ______ receptor in the ciliary body can lower aqueous humor production and help tx glaucoma

beta 2

Inhibition of receptor mediated vasoconstriction of veins

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

so alpha 1 blockers

f. labetalol

g. carvedilol

Inhibition of receptor mediated vasoconstriction of arterioles

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

so alpha 1 blockers

f. labetalol

g. carvedilol

Blockade of renin release (beta-1 receptor)

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

all of them. they all block beta 1

Active vasodilation by non-receptor mediated mechanism

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

h. carteolol (NO and ISA)

i. nebivolol (NO)

Active vasodilation by receptor mediated mechanism

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

have ISA activity at beta 2

b. pindolol

f. labetalol

h. carteolol (but mainly glaucoma)

Inhibition of reflex tachycardia

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

all of them. they all block beta 1

Blockade of Beta-receptor mediated vasodilation in skeletal muscle

a. propranolol

b. pindolol

c. timolol

d. metoprolol

e. atenolol

f. labetalol

g. carvedilol

h. carteolol

i. nebivolol

j. betaxolol

non selective beta blockers

a. propranolol

b. pindolol

c. timolol

f. labetalol

g. carvedilol

h. carteolol (but for glaucoma)