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Medicinal Chemistry > Lectures 8, 9, 10, and 11 > Flashcards

Lectures 8, 9, 10, and 11 Flashcards

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1
Q

What is the permeability of peripheral blood capillaries?

A

Relatively free exchange of substances between/across cells

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2
Q

What is the permeability of brain blood capillaries?

A

Strictly limit transport of substances into brain

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3
Q

What is the function of astrocytes?

A

Form a sheath around capillary

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4
Q

What acts as a barrier for drugs into the BBB?

A

Tight junctions and astrocytes

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5
Q

When would the BBB be ineffective and when would this be advantagous?

A
  • Brain infections that increase permeability

- Allows water soluble antibiotics to cross that normally wouldn’t cross

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6
Q

Which mechanisms allow drugs to cross the BBB?

A
  • Same mechanisms as crossing biological membranes
  • Passive diffusion through aqueous channels (not common)
  • Passive diffusion through lipid (most important)
  • Taken up by endocytosis
  • Facilitated transport via transporters
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7
Q

When is passive diffusion through the BBB most optimal?

A
  • Drug is mostly unionized at pH 7.4 (except quaternary amines; don’t normally cross BBB)
  • Drug has MW < 400
  • Drug has logP between 1-4
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8
Q

Succinylcholine is a ______ NM blocking agent

A

Depolarizing

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9
Q

What are used to reverse the effects of non-depolarizing NM blocking agents?

A

Acetylcholinesterase inhibitors

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10
Q

Are acetylcholinesterase inhibitors used w/ succinylcholine?

A

No, succinylcholine already has a short duration of action

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11
Q

What type of antagonist is a non-depolarizing NM blocker and what does this mean?

A
  • Is a competitive antagonist

- Excess agonist (ACh) can overcome its effect

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12
Q

What is edrophonium used for?

A

Diagnostic test for myasthenia gravis

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13
Q

What is the most common anticholinesterase used in anaethesia?

A

Neostigmine

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14
Q

What does neostigmine do to AChE?

A

Reversibly alkylates it, making it inactive for about 30 mins

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15
Q

What is pyridostigmine used to treat?

A

Myasthenia gravis

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16
Q

Which anticholinesterase crosses the BBB?

A

Physostigmine

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17
Q

What occurs in myasthenia gravis?

A

Autoimmune disease characterized by production of antibodies to ACh receptors => decrease in receptor density at NMJ (no morphological changes at NMJ) => less ACh will bind

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18
Q

What can be used to treat myasthenia gravis?

A
  • Anticholinesterases to increase ACh at NMJ to restore muscle contraction upon stimulus
  • Can use pyridostigmine or other anticholinesterases that are orally absorbed, longer acting, and do not cross BBB
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19
Q

What is cholinergic crisis?

A

When the effect of anticholinesterases decreases with increasing dose b/c of depolarizing NM block

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20
Q

What are side effects to anticholinesterases?

A
  • Salivation
  • Sweating
  • Decreased heart rate
  • Increased GI motility
  • Bronchospasm
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21
Q

What can be used to treat Alzheimer’s?

A

Anticholinesterase w/o a quaternary amine b/c need to cross BBB

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22
Q

What must happen to the tertiary amine of an anticholinesterase after it crosses the BBB?

A

Must ionize so it can bind to anionic site of AChE

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23
Q

What is important about the AChE active site?

A

Asp-His-Ser form a catalytic triad to make the alcohol of serine a better nucleophile

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24
Q

Is AChE a fast enzyme?

A

Yes, very fast

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25
Q

Which 2 anticholinesterases work via the same mechanism?

A

Pyridostigmine and physostigmine

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26
Q

Why are organophosphates nerve toxins?

A

Have the ability to increase ACh at NMJ and synapse, which eventually leads to persistent activation of ACh receptor, depolarizing the NM block and death by asphyxia

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27
Q

What are symptoms of organophosphate poisoning?

A
  • Pinpoint pupils
  • Bronchospasm
  • Decreased heart rate
  • Frothy salivation, profuse sweating
  • Increased GI motility
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28
Q

What is the only treatment for organophosphate poisoning and what does it do?

A

2-PAM binds to anionic site to position itself for reaction and removes the initial phosphorylated enzyme which would otherwise cause permanent AChE inactivation

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29
Q

What AChE inhibitors do not covalently bind to enzyme , do not alkylate AChE and are completely reversible?

A
  • Donepezil
  • Edrophonium
  • Galantamine
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30
Q

Which AChE inhibitors covalently bind to enzyme but do not permanently inactivate it?

A
  • Neostigmine
  • Pyridostigmine
  • Physostigmine
  • Rivastigmine
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31
Q

Which AChE inhibitors covalently bind to enzyme and permanently inactivate it?

A
  • Organophosphates

- Anticholinesterases

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32
Q

Where do R1 and R2 of an antimuscarinic bind in the binding site?

A

Large hydrophobic binding pockets

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33
Q

Where does R3 of an antimuscarinic bind in the binding site?

A

Secondary H-bonding site

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34
Q

Where does X of an antimuscarinic bind in the binding site?

A

Primary H-bonding site

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35
Q

Where does N of an antimuscarinic bind in the binding site?

A

Anionic binding site (must be positively charged amine)

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36
Q

What are common uses of antimuscarinic drugs?

A
  • Dilation of pupil
  • Frequent urination or abdominal pain caused by GI spasms
  • Bronchodilation (asthma or COPD)
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37
Q

What is atropine used for?

A
  • Painful urethral spasm or intestinal cramping
  • Given w/ 2-PAM for organophosphate anticholinesterase toxicity and sometimes w/ neostigmine after surgery when recovering from NM block
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38
Q

What is benztropine?

A

Dopamine blocker

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39
Q

What is scopolamine used for?

A

To prevent motion sickness

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40
Q

What is hyoscine used for and what is important about its structure?

A
  • Used to stop spasms in GI tract that produce abdominal pain
  • Quaternary amine means it has a permanent positive charge so little of it is absorbed from GI tract
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41
Q

What is ipratropium used for and what is important about its structure?

A
  • Reduce bronchospasms from COPD

- Quaternary amine decreases systemic absorption from lungs and prevents crossing BBB, so no CNS side effects

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42
Q

What is important about the structure of tiotropium?

A

Quaternary amine decreases systemic absorption from lungs and prevents crossing BBB, so no CNS side effects

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43
Q

What is tiotropium used for and what is its advantage over ipratropium?

A
  • Used for COPD

- Longer half-life than ipratropium

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44
Q

What are some side effects from antimuscarinics?

A
  • Dry mouth
  • Pupil dilation, blurred vision
  • Hot, flushed, dry skin
  • Increased heart rate
  • Urinary retention and constipation
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45
Q

Alpha 1 is G alpha __

A

q

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46
Q

Alpha 2 is G alpha __

A

i

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47
Q

Beta 1, 2, and 3 are G alpha __

A

s

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48
Q

What are 3 ways to eliminate signal for noradrenaline?

A

1) Reuptake at synapse (most important)
2) Catechol-o-methyl transferase (COMT)
3) Monoamine oxidase (MOA)

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49
Q

Where is noradrenaline very potent?

A

Alpha 1, alpha 2, and beta 1

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50
Q

Where is adrenaline very potent and where is it moderately potent?

A
  • Very potent at beta 1 and 2

- Moderately potent at alpha 1 and 2

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51
Q

What does biosynthesis of adrenaline and noradrenaline produce?

A

DOPA, dopamine, and tyramine

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52
Q

What is the function of amphetamine and amphetamine-like drugs?

A

Cause release of noradrenaline, serotonin, and dopamine from presynaptic vesicles into synaptic cleft

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53
Q

What is the mechanism of amphetamine?

A
  • Blocks VMAT2 which decreases vesicular uptake of monoamine
  • Binds to and inhibits MAO which increases non-vesicular [monoamine] causing the increase of non-vesicular [NA], [dopamine] and [serotonin]
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54
Q

What is the mechanism of cocaine?

A

Competitive inhibitor of MA reuptake transporter, causing increased concentration of NA, dopamine, and 5-HT in synaptic cleft

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55
Q

What causes the psychological effects of amphetamine and cocaine?

A

Their effects on dopamine, including euphoria, addiction, and psychotic symptoms

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56
Q

Tyramine has ____ activity

A

Amphetamine

57
Q

What is contraindicated w/ foods that contain high levels of tyramine?

A

Irreversible MAO inhibitors, b/c inhibition of MAO while taking tyramine increases [NA], [dopamine], and [5-HT] in synapse

58
Q

What are the 3 basic types of sympathomimetics?

A

1) Drugs that bind to receptors of symp NS, aka agonists or direct acting (most important for therapeutic drugs)
2) Drugs that have amphetamine-like actions, called indirect acting
3) Drugs that do both (mixed acting)

59
Q

Which structure do all sympathomimetics have?

A

Phenethylamine

60
Q

What is dexamphetamine used for?

A
  • Treatment of ADHD and possibly narcolepsy

- High doses cause hallucinations and psychotic symptoms that are schizophrenia-like

61
Q

Which isomer of NA and A is preferred?

A

(R)

62
Q

Can clonidine be inactivated by COMT?

A

No b/c it has no meta OH

63
Q

Does clonidine cross the BBB? Why or why not?

A

Does cross b/c it is hydrophobic and has a low enough pKa that a portion is in the unionized form at pH 7.4

64
Q

What is clonidine used for?

A

Treatment of symptoms of menopause

65
Q

What is methyldopa used for?

A

Occasionally to treat hypertension in pregnancy

66
Q

What are imidazoles used for?

A

Topical decongestants, which cause vasoconstriction of arterioles causing decreased appearance of red eyes and decreased swelling in nasal membranes

67
Q

What is phenylephrine used for?

A

In many cough and cold preparations

68
Q

What is a side effect of pseudoephedrine, so what does this mean for recommending products?

A
  • Decreased sleep

- Recommend tablets that work for 6 hours and make sure last dose is 3-4 hours before bed

69
Q

What are side effects for phenylephrine and pseudoephedrine?

A
  • Peripheral vasoconstriction and increased heart rate

- Only a problem in people w/ existing hypertension

70
Q

What is sinusitis?

A

Inflammation or swelling of the tissue lining the sinus

71
Q

Are oral or nasal decongestants preferred and why?

A

Oral b/c don’t cause rebound congestion

72
Q

When should oral decongestants not be used?

A

Those w/ high BP

73
Q

What are beta 1 agonists used for?

A

Acute heart failure or decreased cardiac output that can occur after heart surgery

74
Q

What are beta 2 agonists used for?

A

Treatment of asthma and COPD

75
Q

Most therapeutically used beta agonists are _____

A

Secondary amines

76
Q

The majority of beta agonists are _____

A

Phenylethylamines

77
Q

Since the SAR for alpha agonists and beta agonists are the same, what method is used for selectivity at beta receptors and why?

A
  • Large R substituents on N
  • Increase affinity at both alpha and beta receptors
  • Decrease intrinsic activity at alpha receptors but increase or keep intrinsic activity the same at beta receptors
78
Q

What does the structure of potent beta 2 agonists suggest about binding sites?

A
  • Suggests there are 2 binding sites beyond the Asp-COO- on TM3 to which the N ion pairs
  • Nearest site to N accommodates a t-butyl group and distal to this is a hydrophobic binding pocket that seems to require a phenolic OH or a longer hydrophobic chain for optimal binding
79
Q

What is isoproterenol used for?

A
  • Sometimes used to treat heart block or shock
  • Decreases vascular resistance by causing vasodilation in muscular blood vessels and also increases CO and force of contraction
80
Q

What is dobutamine used for?

A
  • In acute heart failure, cardiogenic shock, septic shock, and for cardiac insufficiency after heart surgery
  • Modestly increases heart rate but increases contractile force more
81
Q

Which beta agonists have a short half life and are rapidly metabolized by MAO and COMT?

A

Dobutamine and isoproterenol

82
Q

Why is isoproterenol not appropriate as a bronchdilator?

A

Targets beta 2 and beta 1 receptors, so it has effects on the heart

83
Q

How can the short half life of dobutamine be worked around?

A

By given by continuous infusion

84
Q

What is important to remember when making substitutions to block COMT metabolism?

A

Some part of the substitution should be capable of forming H-bonds or affinity will decrease

85
Q

Why are resorcinol derivatives good for resisting COMT methylation?

A

Do not form the right geometry for Mg2+ coordination complex

86
Q

What are short-acting beta 2 agonists used for?

A

Fast bronchodilation in the event of an acute asthmatic attack

87
Q

Asthma treatment should include a short-acting beta 2 agonists and a ______

A

Inhaled glucocorticoid to decrease frequency and severity of asthmatic attacks

88
Q

When are long-acting beta 2 agonists used?

A
  • When asthma is not controlled w/ short-acting beta 2 agonists and inhaled glucocorticoids
  • Used in COPD
89
Q

What is the most common short-acting beta 2 agonist?

A

Salbutamol

90
Q

Why is orciprenaline used less often than salbutamol?

A

Has an isopropyl group, which makes it less beta 2 selective

91
Q

What are some side effects of beta 2 agonists?

A
  • Muscle tremors

- Increased or irregular heart rate

92
Q

What is a sign that shows a patient is using their rescue inhaler too often and what should be done when you notice this symptom?

A
  • Muscle tremors

- Add a long-acting beta 2 agonist or increase dose of glucocorticoid

93
Q

LABA’s are highly _____

A

Lipophilic

94
Q

What does an increased logP for a LABA generally mean and what is the exception to this?

A
  • Longer duration and slower onset

- Exception is indacaterol which has the same logP as salmeterol, but has a longer duration and a faster onset

95
Q

Can salmeterol or formoterol be used for asthmatic attacks?

A

No b/c onset is too slow

96
Q

What is indacaterol used for?

A

COPD, but could be used for asthma

97
Q

Why does indacaterol have a short onset and a long duration?

A

Charged at 2 sites, but exists as a zwitterion at physiological pH, which gives it the properties of lower and higher logP beta 2 agonists (it can partition through membranes and bind to receptors)

98
Q

What is systolic blood pressure?

A

Maximum pressure in the arteries after the ventricles contract

99
Q

What is diastolic blood pressure?

A

Minimum pressure between ventricular contractions

100
Q

BP must be more stringently controlled in _____

A

Diabetics

101
Q

What effect does age have on systolic blood pressure?

A

Increased age means increased systolic blood pressure, so a person w/ a high systolic pressure does not have high blood pressure

102
Q

What is hypertensive crisis?

A

Systolic > 180 or diastolic > 110

103
Q

What are the 2 formulas for blood pressure?

A
  • BP = CO * SVR

- BP = HR * SV * SVR

104
Q

What effect do transient increases in blood volume have on blood pressure?

A

Will increase BP b/c increase stroke volume

105
Q

What do noradrenaline and adrenaline on alpha 1 receptors do to blood pressure?

A

Increase SVR (systemic vascular resistance), so increase BP

106
Q

What do noradrenaline and adrenaline on beta 1 receptors do to blood pressure?

A

Increase cardiac output, so increase BP

107
Q

What does adrenaline on beta 2 receptors do to blood pressure?

A

Decreases SVR, so decreases BP

108
Q

What are the 2 main ways to control BP?

A

1) Decrease SVR w/ vasodilation (block alpha 1 receptors to prevent noradrenaline and adrenaline-induced vasoconstriction)
2) Decrease cardiac output

109
Q

What are other ways to decrease SVR besides blocking alpha 1 receptors?

A
  • Block AT1 receptor w/ AT1 antagonists
  • Production of NO, hydrochlorothiazide, or hydralazine
  • Calcium channel blockers
110
Q

How can you decrease cardiac output?

A
  • Decrease heart rate

- Decrease stroke volume or contractile force

111
Q

How do you decrease stroke volume or contractile force?

A
  • Block beta 1 receptors to prevent noradrenaline and adrenaline-induced increase in heart rate and contractile force
  • Calcium channel blocker
112
Q

What are alpha antagonists used for?

A
  • Controlling blood pressure

- Controlling benign prostatic hypertrophy

113
Q

Drugs tend to have unwanted ______ or ______ activity

A

Antimuscarinic or alpha antagonist

114
Q

Do all drugs w/ the minimum SAR for alpha antagonists actually have alpha antagonist activity?

A

No b/c sufficient affinity may not be there to have a significant alpha blocker effect, put the potential will exist

115
Q

What are the 2 examples of non-selective alpha antagonists and are they reversible or irreversible?

A
  • Phenoxybenzamine (irreversible)

- Phentolamine (reversible)

116
Q

What are 2 examples of selective alpha antagonists?

A

1) Alpha 1 selective (most important) – quinazolines

2) Tamsulosin for BPH

117
Q

What does phenoxybenzamine do once it is bound to the alpha receptor?

A

Can dissociate as a reversible competitive antagonist or can react w/ a nucleophile in the receptor (typically Cys or Ser residue)

118
Q

What happens when phenoxybenzamine is covalently bound to the receptor?

A

Is an irreversible non-competitive inhibitor

119
Q

Why does phenoxybenzamine have long-term antagonist activity?

A

Irreversibly alkylates receptors

120
Q

What is phenoxybenzamine used to treat and why?

A

Pheochromocytoma (adrenal gland tumour) b/c increases noradrenaline and adrenaline

121
Q

What are side effects for non-selective alpha antagonists?

A
  • Reflex tachycardia b/c of decrease in BP
  • Decreased effectiveness of baroreceptor reflex b/c of inhibition of alpha 1 receptors
  • Also has antimuscarinic activity and increased release of histamine
122
Q

What is phentolamine used to treat?

A

Cocaine and amphetamine induced hypertensive crisis

123
Q

What are quinazolines used for?

A
  • Decrease BP w/o increased HR or CO

- Used to treat hypertension and BPH

124
Q

Do quinazolines have antimuscarinic activity?

A

No and don’t release histamine

125
Q

Quinazolines are alpha ___ selective

A

1

126
Q

Why does prazosin have low bioavailability?

A

Highly metabolized by liver b/c of planarity

127
Q

What are terazosin and doxazosin used for?

A

Induces apoptosis of prostate smooth muscle cells, not dependent on alpha 1 blockade

128
Q

Is terazosin or perazosin more useful for BPH?

A

Terazosin

129
Q

What is the starting dose for all quinazolines?

A

1 mg at bedtime to decrease incidence of postural hypotension (dose is titrated to BP)

130
Q

What is the metabolism of quinazolines?

A

O-dealkylation produces active metabolite or N-dealkylation, then phase 2 reactions produce conjugation and/or elimination

131
Q

What is a serious side effect of quinazolines?

A

Orthostatic hypotension; most risk at few hours-days after initiating or changing dose or adding another antihypertensive drug
- No effect on BP

132
Q

What is syncope?

A

Passing out/fainting b/c of orthostatic hypotension

133
Q

Which receptor does tamsulosin have selectivity for?

A

Alpha 1 A

134
Q

What is tamsulosin used to treat?

A

BPH

135
Q

What is the most common side effect of tamsulosin?

A
  • Decreased urination

- At normal doses, does not cause any of the general side effects of alpha antagonists

136
Q

What causes the efficacy of alpha 1 antagonists in BPH?

A

Relaxation of smooth muscle via alpha 1 receptor antagonism in bladder and prostate

137
Q

What are some general alpha antagonist side effects?

A
  • Orthostatic hypotension and syncope
  • Hypotension b/c of decreased TPR
  • Dizziness, lightheadedness
  • Nasal congestion
  • Headache
  • Reflex tachycardia (especially w/ non-selective alpha blockers)
138
Q

Which patients are most at risk for syncope?

A

Those taking quinazolines for high BP (rather than for BPH)

Medicinal Chemistry (14 decks)

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