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Med Chem > Lecture 11 (The Adrenergic System 3) *CUT OFF FOR MIDTERM > Flashcards

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

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1
Q

BP must be more stringently controlled in _____

A

diabetics

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2
Q

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

A

systolic

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3
Q

Shorter people will tend to have ____ BP than taller people

A

lower

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4
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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5
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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6
Q

formula for CO

A

CO = HR x SV

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7
Q

NA and A on alpha 1 receptors do what?

A

increase SVR and therefore BP

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8
Q

NA and A on B1 receptors do what?

A

increase CO and therefore BP

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9
Q

A on B2 receptors do what?

A

decrease SVR and therefore BP

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10
Q

What are the 2 main ways of controlling blood pressure?

A

1) decrease SVR/TPR

2) decrease CO

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11
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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12
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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13
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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14
Q

A major problem with alpha receptor antagonists is much like ?

A

antimuscarinics

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15
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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16
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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17
Q

many drugs have unintended ??

A

alpha receptor antagonist activity

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18
Q

Alpha adrenergic antagonists minimum SAR:

N must be ____ for affinity

A

charged

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19
Q

Alpha adrenergic antagonists minimum SAR:

N is often a _____ amine

A

tertiary, but sometimes R1 may be H

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20
Q

Alpha adrenergic antagonists minimum SAR:

R1 and R2 must be what?

A

CH3 or larger than t-butyl

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21
Q

Alpha adrenergic antagonists minimum SAR:

C(n) may be _ to _ heavy atoms

A

1 to 3 (normally carbon)

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22
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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23
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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24
Q

Alpha adrenergic antagonists minimum SAR:

Second ring increases ?

A

antagonist potency

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25
Q

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

A

will favour alpha 1 over alpha 2

alpha 1 > alpha 2

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26
Q

What are the 2 types of alpha adrenergic antagonists?

A

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
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27
Q

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

A

False:

  • it doesn’t affect BP at clinically used doses
  • at higher doses tho, it will have an effect on BP
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28
Q

Phenoxybenazmine is an ____ antagonist

A

irreversible

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29
Q

Phenoxybenzamine:

_____ form of drug is stable

A

ionized

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30
Q

Phenoxybenzamine:

At physiological pH it becomes ____

A

unionized (and it is unstable)

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31
Q

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

A

yes man

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32
Q

Phenoxybenzamine:

once bound to the alpha receptor, what can happen?

A

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

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33
Q

Phenoxybenzamine:

Nu is typically ?

A

Cys or Ser residue

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34
Q

Phenoxybenzamine:

when it is covalently bound to the receptor, it is now ?

A

an irreversible non-competitive inhibitor

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35
Q

Reflex tachycardia

A

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

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36
Q

Phenoxybenzamine:

t1/2

A

5 hours

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37
Q

Phenoxybenzamine:

why do the effects last for days?

A

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

38
Q

What is Phenoxybenzamine used for?

A

used to treat pheochromocytoma

39
Q

What is pheochromocytoma

A

adrenal gland tumor producing increased NA and A

40
Q

Reflex tachycardia is an adverse effect for?

A

non selective receptor antagonists

41
Q

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

A

baroreceptor reflex

42
Q

Phenoxybenzamine also has _____ activity and increases the release of histamine

A

antimuscarinic

43
Q

Phentolamine has a small N substituent which favours?

A

alpha receptor affinity

44
Q

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

A

enhances alpha-receptor affinity and makes it an antagonist

45
Q

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

A

yeah

46
Q

Phentolamine has receptor affinity enhanced by ?

A

additional aromatic ring substitution to N

47
Q

Phentolamine slightly more receptor selective for ?

A

alpha 1 versus alpha 2

alpha 1 > alpha 2

48
Q

Phentolamine has ______ activity and causes release of histamine

A

antimuscarinic

49
Q

What is Phentolamine used to treat?

A

cocaine and amphetamine induced hypertensive crisis

50
Q

Quinazolines have an __ in the X position

A

N

51
Q

Quinazolines:

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

A

a1 >a2

52
Q

Quinazolines:

R is typically a ?

A

heterocyclic ring

53
Q

Quinazolines:

Guanidine like group important for increasing affinity for __ receptors

A

alpha

54
Q

Quinazoline uses:

Decrease BP without increasing ?

A

HR or CO

55
Q

Quinazoline uses:

Do not bind to ______ or ______ receptors

A

muscarinic or histamine

56
Q

Quinazoline uses:

do not increase release of ______

A

histamine

57
Q

Quinazoline uses:

very selective for ____

A

alpha 1

58
Q

Quinazoline uses:

they do not block _____-

A

alpha 2

59
Q

Quinazoline uses

A
  • used to treat hypertension

- used to treat BPH (esp terazosin and doxazosin)

60
Q

3 examples of quinazolines

A

prazosin
terazosin
doxazosin

61
Q

Describe Prazosin (Minipress)

A
  • highly metabolized by liver
  • very high first pass metabolism which results in low bioavailability
  • planarity of molecule results in increase in metabolism
62
Q

Describe Terazosin (Hytrin)

A
  • 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
63
Q

Describe Doxazosin (Cardura)

A
  • like terazosin, induces apoptosis of prostate smooth muscle cells , not dependent on alpha 1 blockade
  • also more useful than prazosin for BPH
64
Q

Explain dose titrating

A
  • 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
65
Q

Should you take quinazolxines with food?

A

no, bioavailability with food <50%

66
Q

What is the quinazoline starting dose?

A

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

67
Q

see slide 21 for quinazoline PK and dosing

A

okay man

68
Q

Describe the metabolism of quinazolines

A

Phase 1 includes O-dealkylation and N-dealkylation

Phase 2 includes conjugation and or elimination

69
Q

O-dealkylation of a quinazoline causes an ?

A

active metabolite

70
Q

N-dealkylation of a quinazoline causes an ?

A

no longer active

71
Q

Anything that relaxes blood vessels can cause ?

A

orthostatic hypotension (low BP)

72
Q

Quinazolines used to treat BP?

A

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

73
Q

Syncope

A

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

74
Q

Why do you give the first dose at night?

A

so Pt reaches Cmax when they are asleep

75
Q

Orthostatic hypotension is also called ?

A

postural hypotension

76
Q

When are people most at risk for postural/orthostatic hypotension

A

Most at risk a few hours to days after:

  • initiating a dose
  • dose changes
  • adding another antihypertensive drug
77
Q

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

A

large

78
Q

Tamsulosin:

-meta and para substitution enhance ______ receptor affinity and reduces _____ affinity

A

alpha 1

alpha 2

79
Q

Tamsulosin is an ?

A

alpha 1 receptor antagonist

80
Q

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

A

alpha 1A > alpha 1B

81
Q

Tamsulosin selectivity favours blockade of _____ receptors in prostate.

A

alpha 1A

82
Q

Tamsulosin is used in the treatment of ____

A

BPH

83
Q

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

A

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

84
Q

How do alpha 1 antagonists work on BPH

A

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

85
Q

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

A

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

86
Q

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

A

terazosin and doxazosin

87
Q

List 4 examples of unintended alpha antagonists

A

chlorpromazine
haloperidol
imipramine
promethazine

88
Q

chlorpromazine
haloperidol
imipramine
promethazine

all either have what two N substituents?

A

small, CH3 N substituents
or
Large, N substituent

89
Q

General alpha adrenergic antagonists side effects.

Memorize these

A
  • 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)
90
Q

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

A

no

91
Q

Recommendations for syncope

A
  • 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.

Med Chem (11 decks)

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