Lecture 11 (The Adrenergic System 3) *CUT OFF FOR MIDTERM Flashcards by Sam Myers

Q

BP must be more stringently controlled in _____

A

diabetics

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Q

As you get older than 65, the ____ pressure will rise

A

systolic

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Q

Shorter people will tend to have ____ BP than taller people

A

lower

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Q

Does a single high reading mean you have high blood pressure?

A

no way man

*need a few readings of consistently high BP to be diagnosed with hypertension

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Q

formula for BP

A

BP = CO x TPR
or
BP = CO x SVR

TPR = SVR
total peripheral resistance = systemic vascular resistance

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Q

formula for CO

A

CO = HR x SV

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Q

NA and A on alpha 1 receptors do what?

A

increase SVR and therefore BP

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Q

NA and A on B1 receptors do what?

A

increase CO and therefore BP

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Q

A on B2 receptors do what?

A

decrease SVR and therefore BP

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Q

What are the 2 main ways of controlling blood pressure?

A

1) decrease SVR/TPR

2) decrease CO

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Q

Explain how decreasing SVR/TPR decreases BP

List 4 possible ways to decrease SVR/TPR

A

it causes vasodilation

if we block alpha 1 receptors to prevent NA and A induced vasoconstriction: Decrease SVR
block AT1 receptor with AT1 receptor antagonists
production of NO, hydrochlorothiazide, hydralazine
Ca2+ channel blockers (nifedipine, felodipine, and amlodipine only)

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Q

Explain how Decreasing CO will decrease BP

List 2 possible ways to decrease CO

A

decrease HR
decrease SV or contractile force
Block B1 receptors to prevent NA and A induced increase in HR and contractile force: decrease HR and or SV
Ca2+ channel blockers (verapamil and diltiazem only)

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Q

List 3 uses of alpha receptor antagonists

A

used for hypertension
benign prostatic hyperplasia (BPH)
raynaud’s disease

*hypertension and BPH are the major uses

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Q

A major problem with alpha receptor antagonists is much like ?

A

antimuscarinics

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Q

What is the major problem with alpha receptor antagonists?

A

many drugs that are otherwise targeted to other receptor groups have some alpha receptor antagonist activity

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Q

What is the reason for many drugs targeted to other receptor groups having some alpha receptor antagonist activity?

A

alpha receptor antagonists have a very flexible and generic SAR which means that many drugs have unintended alpha receptor antagonist activity

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Q

many drugs have unintended ??

A

alpha receptor antagonist activity

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Q

Alpha adrenergic antagonists minimum SAR:

N must be ____ for affinity

A

charged

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Q

Alpha adrenergic antagonists minimum SAR:

N is often a _____ amine

A

tertiary, but sometimes R1 may be H

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Q

Alpha adrenergic antagonists minimum SAR:

R1 and R2 must be what?

A

CH3 or larger than t-butyl

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Q

Alpha adrenergic antagonists minimum SAR:

C(n) may be _ to _ heavy atoms

A

1 to 3 (normally carbon)

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Q

Alpha adrenergic antagonists minimum SAR:

X may not be present but if it is it is usually capable of forming ?

A

H-bonds

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Q

Alpha adrenergic antagonists minimum SAR:

There may be two rings attached to X but only one is needed. If two are present, at least one is _______

A

aromatic

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Q

Alpha adrenergic antagonists minimum SAR:

Second ring increases ?

A

antagonist potency

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Alpha adrenergic antagonists minimum SAR: The aromatic ring substitutions (R3) may not be present, however if they are, having para and meta substituents will favour binding to ___ receptors over ___ receptors

will favour alpha 1 over alpha 2 alpha 1 > alpha 2

What are the 2 types of alpha adrenergic antagonists?

Non-selective: - not used much anymore ex. phenoxybenazmine (irreversible) ex. phentolamine (reversible) Selective: - most important are alpha 1 quinazolines ex. prazosin ex. terazosin ex. doxazosin - tamsulosin for BPH

T or F: tamsulosin doesn't effect blood pressure at any dose

False: - it doesn't affect BP at clinically used doses - at higher doses tho, it will have an effect on BP

Phenoxybenazmine is an ____ antagonist

irreversible

Phenoxybenzamine: | _____ form of drug is stable

ionized

Phenoxybenzamine: | At physiological pH it becomes ____

unionized (and it is unstable)

Does Phenoxybenzamine have the basic SAR needed to bind to a1 and a2 receptors

yes man

Phenoxybenzamine: | once bound to the alpha receptor, what can happen?

-the drug can dissociate as a reversible competitive antagonist OR -can react with a nucleophile (Nu) in the receptor

Phenoxybenzamine: | Nu is typically ?

Cys or Ser residue

Phenoxybenzamine: | when it is covalently bound to the receptor, it is now ?

an irreversible non-competitive inhibitor

Reflex tachycardia

you're reducing BP so sometimes what you get is that the HR will try to increase the BP back to normal

Phenoxybenzamine: | t1/2

5 hours

Phenoxybenzamine: | why do the effects last for days?

because the receptors are irreversibly alkylated resulting in long term antagonist activity

What is Phenoxybenzamine used for?

used to treat pheochromocytoma

What is pheochromocytoma

adrenal gland tumor producing increased NA and A

Reflex tachycardia is an adverse effect for?

non selective receptor antagonists

Phenoxybenzamine can also decrease the effectiveness of the ______ ____because of inhibition of alpha1 receptors in vasculature

baroreceptor reflex

Phenoxybenzamine also has _____ activity and increases the release of histamine

antimuscarinic

Phentolamine has a small N substituent which favours?

alpha receptor affinity

Phentolamine has a phenol ring with CH3 - what does this do?

enhances alpha-receptor affinity and makes it an antagonist

Phentolamine has no alpha-agonist activity!!!! (just like xylometazoline and clonidine)

yeah

Phentolamine has receptor affinity enhanced by ?

additional aromatic ring substitution to N

Phentolamine slightly more receptor selective for ?

alpha 1 versus alpha 2 alpha 1 > alpha 2

Phentolamine has ______ activity and causes release of histamine

antimuscarinic

What is Phentolamine used to treat?

cocaine and amphetamine induced hypertensive crisis

Quinazolines have an __ in the X position

N

Quinazolines: | The meta and para substituents on the aromatic ring increase affinity for ?

a1 >a2

Quinazolines: | R is typically a ?

heterocyclic ring

Quinazolines: | Guanidine like group important for increasing affinity for __ receptors

alpha

Quinazoline uses: | Decrease BP without increasing ?

HR or CO

Quinazoline uses: | Do not bind to ______ or ______ receptors

muscarinic or histamine

Quinazoline uses: | do not increase release of ______

histamine

Quinazoline uses: | very selective for ____

alpha 1

Quinazoline uses: | they do not block _____-

alpha 2

Quinazoline uses

- used to treat hypertension | - used to treat BPH (esp terazosin and doxazosin)

3 examples of quinazolines

prazosin terazosin doxazosin

Describe Prazosin (Minipress)

- highly metabolized by liver - very high first pass metabolism which results in low bioavailability - planarity of molecule results in increase in metabolism

Describe Terazosin (Hytrin)

- less potent than prazosin but same maximal efficacy - more soluble in water than prazosin, with higher bioavailability and longer t1/2 - induces apoptosis of prostate smooth muscle cells, not dependent on alpha 1 blockage - more useful for prazosin for BPH

Describe Doxazosin (Cardura)

- like terazosin, induces apoptosis of prostate smooth muscle cells , not dependent on alpha 1 blockade - also more useful than prazosin for BPH

Explain dose titrating

- start with low dose - Pt comes back and check BP - if it doesn't work, give them a slightly higher dose - Pt comes back to se if it is now being controlled

Should you take quinazolxines with food?

no, bioavailability with food <50%

What is the quinazoline starting dose?

1mg, hs to reduce the incidence of postural hypotension (AKA orthostatic hypotension). Dose is titrated to BP

see slide 21 for quinazoline PK and dosing

okay man

Describe the metabolism of quinazolines

Phase 1 includes O-dealkylation and N-dealkylation Phase 2 includes conjugation and or elimination

O-dealkylation of a quinazoline causes an ?

active metabolite

N-dealkylation of a quinazoline causes an ?

no longer active

Anything that relaxes blood vessels can cause ?

orthostatic hypotension (low BP)

Quinazolines used to treat BP?

not usually - due to the hypotensive side effect (orthostatic hypotension)

Syncope

Passing out (fainting) = can happen because of orthostatic hypotension

Why do you give the first dose at night?

so Pt reaches Cmax when they are asleep

Orthostatic hypotension is also called ?

postural hypotension

When are people most at risk for postural/orthostatic hypotension

Most at risk a few hours to days after: - initiating a dose - dose changes - adding another antihypertensive drug

Tamsulosin has a _____ hydrophobic substituent enhance alpha receptor affinity eliminate intrinsic activity

large

Tamsulosin: | -meta and para substitution enhance ______ receptor affinity and reduces _____ affinity

alpha 1 alpha 2

Tamsulosin is an ?

alpha 1 receptor antagonist

Tamsulosin is 10 to 40 times more potent at ___>___

alpha 1A > alpha 1B

Tamsulosin selectivity favours blockade of _____ receptors in prostate.

alpha 1A

Tamsulosin is used in the treatment of ____

BPH

T or F: Tamsulosin has lots of effect on BP.

False - little or no effect on BP at clinically used doses

How do alpha 1 antagonists work on BPH

alpha 1 antagonists efficacy in BPH results from relaxation of smooth muscle via alpha 1 receptor antagonism in the bladder and prostate.

Because of the distribution of alpha 1 receptors in the bladder and prostate, what happens?

alpha 1 antagonists reduce bladder obstruction, possibly by affecting the tone in the sphincters, without affecting muscular contractility of the bladder

What 2 drugs have direct effect on prostate smooth muscle by inducing apoptosis of smooth muscle cells that is independent of it's alpha 1 antagonist properties? Note**no other alpha 1 antagonists do this

terazosin and doxazosin

List 4 examples of unintended alpha antagonists

chlorpromazine haloperidol imipramine promethazine

chlorpromazine haloperidol imipramine promethazine all either have what two N substituents?

small, CH3 N substituents or Large, N substituent

General alpha adrenergic antagonists side effects. Memorize these

- orthostatic hypotension and syncope - hypotension - dizziness, lightheadedness - nasal congestion (dilation of blood vessels in nasal mucosal) - headache - reflex tachycardia (especially with non-selective alpha-blockers)

Are any of these general alpha adrenergic antagonist side effects likely to be caused by tamsulosin at normal doses?

no

Recommendations for syncope

* these recommendations are more important for those taking quinazolines for high BP - ask pt to be careful for the first few days after initiation or increasing dose of alpha adrenergic antagonists - when sitting or lying down, get up slowly and steady yourself with something like the arm rests of the chair you were sitting on or a table, etc.