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1
Q
A
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2
Q

What is the difference between a pharmacophore and auxacophore.

A

Pharmacophore- The Minimum structural unit required to interact, leading to a pharmacological response.

Auxacophore: Non essential portion of the drug, modulates the kinetics and selectivity of the drug.

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3
Q

WHat are the fundamentals of medicinal chemistry

A
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5
Q

pKa

A

9-11

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6
Q

What is it and what is its pKa

A

4-6

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7
Q

Name them and their pKas

A

Imidazole-7

Phenol- 9-11

Alkylthiol- 10-11

Guanidine-13-14

Amidine- 10-11

Alkyl Alcohol- 16

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8
Q

carboxylic acid pKa

A

4-6

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12
Q

Im a doll but shes a 7?

A

Imidazole has a pKa value of 7

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13
Q

What are some forces involved in drug interactions

A

Hydrogen bonds

Halogen bonds

Aryl-Aryl Interactions

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14
Q

As R1 increases what happens to physiological activity?

A

As R1 increases in size alpha activity decreases and Beta activity increases

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15
Q

What is this?

A

Alpha 1 agonist

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16
Q
A

Alpha 1 agonist

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17
Q
A

Alpha 1 agonist

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18
Q

As R1 increases what happens to physiological activity?

A

As R1 increases in size alpha activity decreases and Beta activity increases

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19
Q

What is this?

A

Alpha 1 agonist

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20
Q
A

Alpha 1 agonist

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21
Q
A

Alpha 1 agonist

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22
Q
A
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27
Q
A
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28
Q
A

Alpha 1 Agonist

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29
Q
A

Alpha 1 Agonist

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30
Q
A

Alpha 1 agonist

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31
Q
A

Alpha 1 agonist

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32
Q
A

Alpha 1 agonist

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33
Q
A

Alpha 1 agonist

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34
Q
A

Alpha 2 agonist

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35
Q
A

Alpha 2 Agonist

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36
Q
A

Alpha 2 agonist

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37
Q
A

Alpha 2 agonist

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38
Q
A

Alpha 2 agonist

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39
Q
A

Alpha 2 agonist

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40
Q
A

Methyldopa alpha 2 agonist prodrug

Metabolized into Methylnorepinephrine

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41
Q
A

Beta 1 agonist dopamine short acting easily metabolized by COMT and MAO

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42
Q
A

Dobutamine

Methyl group can change selectivity and function

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43
Q
A

Beta 2 Agonist

Albuterol

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44
Q
A

Beta 2 agonist

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45
Q
A

Beta 2 agonist

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46
Q
A

Beta 2 agonist

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47
Q
A

Beta 2 agonist

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48
Q
A

Salmeterol

Beta 2 agonist super long chain

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49
Q
A

Beta 2 agonist

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50
Q
A

Beta 2 agonist

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51
Q
A

beta 2 agonist

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52
Q
A

Causes release of NE

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53
Q
A

Causes release of NE

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54
Q
A

Causes release of NE

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55
Q
A

Amphetamine causes release of NE

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56
Q
A

meth Releas NE

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57
Q
A

Release NE

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58
Q
A

Release NE

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59
Q
A

Release NE

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60
Q
A

Some what selective for alpha

Covalent bond causes it to be an irreversible antagonist

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61
Q
A

Non selective antagonist

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62
Q
A

Alpha 1 antagonist

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63
Q
A

Alpha 1 antagonist

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64
Q
A

Alpha 1 Antagonist

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65
Q
A

Alpha 1 antagonist

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66
Q
A

Alpha 1 antagonist

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67
Q
A

Nonselective B antagonist

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68
Q
A

Nonselective B antagonist

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69
Q
A

Proptanolol Nonselective B antagonist

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70
Q
A

B1 antagonist

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71
Q
A

B1 antagonist

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72
Q
A

B1 antagonist

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73
Q

What does it do?

A

Carbidopa

Inhibitor of AAD

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74
Q

What the give away that makes it an inhibitor

A

Talcapone

COMT I

Nitro group with catechol system

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75
Q
A

Propargel group

MAO I irreversible

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76
Q

Its a potent?

A

Dopamine agonist

Emetic

Dopamine in locked conformation

Previagra

Apomorphine

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81
Q

In parkinsons there are two receptors in the striatum?

Which one is decreased which one is increased?

A

D1-Excitatory decreased

D2- Inhibitory increased

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82
Q

Direct pathway?

A

D1

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83
Q

Indirect pathway

A

D2

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84
Q

tyrosine, tyrosine epoxide

DA semiquinone and DA quinone are all?

A

Compounds indicated in neuronal cell death

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85
Q

D1, 5 receptor increases levels of?

A

cAMP

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86
Q

D2-4 receptor decrease levels of?

A

cAMP

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87
Q

Tyrosine is converted into _____ then in the presence of _____ is coverted to?

A

L-dopa (BBB+)

MAO

Dopamine (BBB-)

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88
Q

How does L-dopa cross the BBB?

A

It is actively transported and the presence of both the Amino and Carboxylic acid group forms a zwitter ion and cause less unionizable things

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89
Q

MPPP —-> ____ —- MPDP—>MPP

Causing?

A

Nigrostriatal cell death

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90
Q

Apomorphine locks dopamine in what conformation which is?

A

Locked into trans alpha rotamer which is favorable to the receptor

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91
Q

L-dopa is used in combination with?

Which is?

A

Carbidopa

Aromatic AA Decarboxylase Inhibitor

and COMPT

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92
Q

Adverse effects of combination L-dopa and carbidopa therapy?

A

Dose related dyskinesia (Impairement of voluntary movement)

Pathological gambling

CNS effects simialr to Schizo

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93
Q

Tolcapone and Entacapone are?

A

Compt I

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94
Q

Entacapone has a?

A

Short T1/2 and should be taken with every dose of L-dopa

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95
Q

Amantadine is a?

A

DA releaser

ClogP = 2.0

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96
Q

MAO-B inhibitors have a? bond

A

Ctriple bond CH

Irreversible inhibitor of MAO-B

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97
Q

Rasagiline has?

A

Fewer adverse effects compared to L-deprenyl (Selegiline)

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98
Q

Sofinamide is a?

A

Reersible and selective MAO-B I

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99
Q

DA receptor agonists

they all have?

A

Can lower required dose of l-dopa

Locked confomer of DA

S-enatiomer has post synaptic D2 antagonism

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100
Q

Anticholinergics do what for parkinsons?

A

Help reduce drooling and tremors

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101
Q

Dopa Scan is?

A

Longer acting

tropone ring

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102
Q

Trancypramine

MOA

Prototype Structure

What is the irreversible portion of this drug?

Since this is irreversible what is more likely to take place?

A
  • Irreversible MAO- Inhibitor
  • Triangle banana bond give it the irreversible nature
  • More likely to have toxic effects due to the covalent bond that is formed
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103
Q

Imipramine

MOA

Prototype

Class

Causes more what in comparison to other drugs in this class?

Metabolism

Presence of tertiary nitrogen gives it more?

A
  • TCA
  • inhibits reuptake of S > NE
  • more orthostatic hypotension than amitriptyline
  • Dealkylation will give active metabolites
  • Tertiary > Anticholinergic SEs, But less than amitriptyline
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104
Q

Fluoxetine

MOA

Metabolism

Dont use with?

A
  • SSRI
  • 2D6
  • Dont use with TCAs or MAOIs
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105
Q

EsKetamine

MOA

This has been known to ____ compared to SSRIs or SNRIs

A
  • NMDA antagonist
  • Known to be faster acting compared to SSRIs and SNRIs this can be benficial because they take so long to take effect
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106
Q

Duloxetine

MOA

What else can this be used to treat?

A
  • SNRI
  • Can be used to treat:
    • Diabetic Nueropathy
    • pain control in fibromyalgia
    • Chronic musculoskeletal pain
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107
Q

Phenelzine

What group is present?

MOA?

A
  • Irreversible non-selective MAO I
  • Hydrazine group present
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108
Q

Isocarboxazid

MOA?

A
  • Irreversible MAO I
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109
Q

Selegiline

MOA?

A
  • Irreversible non selective MAO I
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110
Q

Moclobemide

MOA?

Has less?

A
  • Reversible MAO-A Inhibitor
  • Less toxic effects compared to irreversible
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111
Q

Moclobemide

MOA?

Has less?

A
  • Reversible MAO-A Inhibitor
  • Less toxic effects compared to irreversible
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112
Q

Desipramine

R=H

MOA?

Activity at?

A
  • TCA
  • Activity more at NE
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113
Q

Trimipramine

MOA?

A
  • Inhibits reuptake of both NE and S
  • Alkylation on the 3 carbon provides less anticholinergic SEs
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114
Q

Clomipramine

MOA?

A
  • Mainly inhibits 5HT reuptake
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115
Q

Amitriptyline

MOA?

Whats the difference with this one compared to others in this class?

R=CH3

A
  • S>NE
  • TCA
  • Does not contain a Nitrogen in ring instead has a C=C these have the same geometry though so they can be interchanged but steriochemistry becomes important
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116
Q

Nortriptyline

R=H

MOA

Class

A
  • TCA
  • S and NE equally
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117
Q

Protriptyline

Isomer of nortriptyline

MOA?

Class

Contains what? Possible?

A
  • TCA
  • NE more
  • C=C possible epoxidation
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118
Q

Doxepin

MOA?

Only used?

Class?

A
  • TCA
  • NE and S
  • Used topically as H1 antagonist
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119
Q

Amoxapine

R=H

MOA

Similar to?

Antagonist at what receptors?

Class?

Metabolite of?

A
  • EPS
  • TCA
  • 51C - 2 and 3
  • Similar to desipramine
  • Metabolite of Loxapine
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120
Q

Amoxapine

R=H

MOA

Similar to?

Antagonist at what receptors?

Class?

Metabolite of?

A
  • EPS
  • TCA
  • 51C - 2 and 3
  • Similar to desipramine
  • Metabolite of Loxapine
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121
Q

Trazodone

MOA

what gives it the Serotonin activity?

Class?

A
  • phenylpiperazine
  • 5HT uptake inhibitor
  • 5HT2A antagonist
  • Sedation
  • Piperazine with phenyl CL gives serotonin activity
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122
Q

Nefazodone

Class

MOA

Less sedation than?

A
  • Phenylpiperazine
  • 5HT uptake inhibition
    • Some NE uptake inhibition
  • 5HT2 antagonist
  • Less sedation compared to TCAs and Trazodone
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123
Q

Bupropion

Class

MOA

Looks like?

Minimal what SE?

A
  • Phenylethylamines
  • Weak dopamine uptake inhibitor
  • Very weak NE and S uptake inhibitor
  • Looks like amphetamine so the dopamine part makes sense
  • Less Sexual AEs
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124
Q

Nisoxetine

MOA

Class

A
  • SNRI
  • Contains chiral center
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125
Q

Reboxetine

MOA

A
  • SNRI
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126
Q

Mirtazepine

MOA

Class

Antagonism where else?

A
  • NE/S reuptake inhibitor
  • a1 and H1 antagonist
  • 5HT2 and 3 not 1
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127
Q

Venlafaxine

MOA

what SEs are low?

R=CH3

A
  • NE/S reuptake inhibitor
  • Low anticholinergic, sedation, and orthostatic hypo
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128
Q

Venlafaxine

MOA

what SEs are low?

R=CH3

A
  • NE/S reuptake inhibitor
  • Low anticholinergic, sedation, and orthostatic hypo
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129
Q

Sertraline MOA class

Fewer interactions than?

A
  • SSRI
  • less 2D6 so less interactions
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130
Q

Paroxetine

MOA

What about toxicity?

A
  • SSRI
  • methylenedioxy ring—> more toxic
  • Michael acceptor
  • Quinone formation from methylene
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131
Q

Citalopram

MOA

What needs to be watched?

Escitalopram

A
  • SSRI
  • QT prolongation
  • Escitalopram is the S-enantiomer less prolongation
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132
Q

Vilazodone

MOA

A
  • Agonist at 5 HT 1A partial
  • SSRI
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133
Q

Vortioxetine

MOA

whats special about it?

A
  • SSRI
  • active at many receptors
  • antagonist at: HT1D, HT3, HT7
  • Steric hinderance of ring decreases rate of metabolism
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134
Q

Bath salts

MOA

4 x more potent as a stimulant than ritalin

A
  • NE and dopamine reuptake inhibitor
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135
Q

Bath salts

MOA

4 x more potent as a stimulant than ritalin

A
  • NE and dopamine reuptake inhibitor
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136
Q

Vortioxetine

MOA

whats special about it?

A
  • SSRI
  • active at many receptors
  • antagonist at: HT1D, HT3, HT7
  • Steric hinderance of ring decreases rate of metabolism
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137
Q

Vilazodone

MOA

A
  • Agonist at 5 HT 1A partial
  • SSRI
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138
Q

Citalopram

MOA

What needs to be watched?

Escitalopram

A
  • SSRI
  • QT prolongation
  • Escitalopram is the S-enantiomer less prolongation
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139
Q

Paroxetine

MOA

What about toxicity?

A
  • SSRI
  • methylenedioxy ring—> more toxic
  • Michael acceptor
  • Quinone formation from methylene
140
Q

Sertraline MOA class

Fewer interactions than?

A
  • SSRI
  • less 2D6 so less interactions
141
Q

Mirtazepine

MOA

Class

Antagonism where else?

A
  • NE/S reuptake inhibitor
  • a1 and H1 antagonist
  • 5HT2 and 3 not 1
142
Q

Reboxetine

MOA

143
Q

Nisoxetine

MOA

Class

A
  • SNRI
  • Contains chiral center
144
Q

Bupropion

Class

MOA

Looks like?

Minimal what SE?

A
  • Phenylethylamines
  • Weak dopamine uptake inhibitor
  • Very weak NE and S uptake inhibitor
  • Looks like amphetamine so the dopamine part makes sense
  • Less Sexual AEs
145
Q

Nefazodone

Class

MOA

Less sedation than?

A
  • Phenylpiperazine
  • 5HT uptake inhibition
    • Some NE uptake inhibition
  • 5HT2 antagonist
  • Less sedation compared to TCAs and Trazodone
146
Q

Trazodone

MOA

what gives it the Serotonin activity?

Class?

A
  • phenylpiperazine
  • 5HT uptake inhibitor
  • 5HT2A antagonist
  • Sedation
  • Piperazine with phenyl CL gives serotonin activity
147
Q

Doxepin

MOA?

Only used?

Class?

A
  • TCA
  • NE and S
  • Used topically as H1 antagonist
148
Q

Protriptyline

Isomer of nortriptyline

MOA?

Class

Contains what? Possible?

A
  • TCA
  • NE more
  • C=C possible epoxidation
149
Q

Nortriptyline

R=H

MOA

Class

A
  • TCA
  • S and NE equally
150
Q

Amitriptyline

MOA?

Whats the difference with this one compared to others in this class?

R=CH3

A
  • S>NE
  • TCA
  • Does not contain a Nitrogen in ring instead has a C=C these have the same geometry though so they can be interchanged but steriochemistry becomes important
151
Q

Clomipramine

MOA?

A
  • Mainly inhibits 5HT reuptake
152
Q

Trimipramine

MOA?

A
  • Inhibits reuptake of both NE and S
  • Alkylation on the 3 carbon provides less anticholinergic SEs
153
Q

Desipramine

R=H

MOA?

Activity at?

A
  • TCA
  • Activity more at NE
154
Q

Selegiline

MOA?

A
  • Irreversible non selective MAO I
155
Q

Isocarboxazid

MOA?

A
  • Irreversible MAO I
156
Q

Phenelzine

What group is present?

MOA?

A
  • Irreversible non-selective MAO I
  • Hydrazine group present
157
Q

Duloxetine

MOA

What else can this be used to treat?

A
  • SNRI
  • Can be used to treat:
    • Diabetic Nueropathy
    • pain control in fibromyalgia
    • Chronic musculoskeletal pain
158
Q

EsKetamine

MOA

This has been known to ____ compared to SSRIs or SNRIs

A
  • NMDA antagonist
  • Known to be faster acting compared to SSRIs and SNRIs this can be benficial because they take so long to take effect
159
Q

Fluoxetine

MOA

Metabolism

Dont use with?

A
  • SSRI
  • 2D6
  • Dont use with TCAs or MAOIs
160
Q

Imipramine

MOA

Prototype

Class

Causes more what in comparison to other drugs in this class?

Metabolism

Presence of tertiary nitrogen gives it more?

A
  • TCA
  • inhibits reuptake of S > NE
  • more orthostatic hypotension than amitriptyline
  • Dealkylation will give active metabolites
  • Tertiary > Anticholinergic SEs, But less than amitriptyline
161
Q

Trancypramine

MOA

Prototype Structure

What is the irreversible portion of this drug?

Since this is irreversible what is more likely to take place?

A
  • Irreversible MAO- Inhibitor
  • Triangle banana bond give it the irreversible nature
  • More likely to have toxic effects due to the covalent bond that is formed
171
Q

In general TCAs what is the difference betwen secondary and tertiary nitrogens?

A
  • Tertiary S > NE
  • Secondary NE > S
172
Q

In general TCAs what is the difference betwen secondary and tertiary nitrogens?

A
  • Tertiary S > NE
  • Secondary NE > S
180
Q

SAR for TCAs

  1. Amine substitution
  2. _ carbons between tricyclic ring and amine
  3. _____ on tricyclic ring increses affinity for?
A
  • Tertiary
    • S reuptake > NE reuptake
    • More orthostatic hypotension than secondary
    • Generally more anticholinergic SEs
  • Secondary
    • NE reuptake > S
    • less sedation compared to tertiaty
  • 3 carbons between tricyclic ring system and amine
  • Halogen on tricyclic system increases affinity for 5-HT transporter
181
Q

SAR for TCAs

  1. Amine substitution
  2. _ carbons between tricyclic ring and amine
  3. _____ on tricyclic ring increses affinity for?
A
  • Tertiary
    • S reuptake > NE reuptake
    • More orthostatic hypotension than secondary
    • Generally more anticholinergic SEs
  • Secondary
    • NE reuptake > S
    • less sedation compared to tertiaty
  • 3 carbons between tricyclic ring system and amine
  • Halogen on tricyclic system increases affinity for 5-HT transporter
188
Q

What are the advantages and AEs of SSRIs

A
  • Less cardiavascular toxicity than TCAs
  • Less sedation
  • Lower toxicity in OD compared to MAOIs and TCAs
  • AEs: Anxiety, sexaul dysfunction, nausea
189
Q

What are the advantages and AEs of SSRIs

A
  • Less cardiavascular toxicity than TCAs
  • Less sedation
  • Lower toxicity in OD compared to MAOIs and TCAs
  • AEs: Anxiety, sexaul dysfunction, nausea
190
Q

Explaine the phases of Cardia action potential

192
Q

Cardia glycosides inhibit what phase of the cardiac action potential?

A
  • Na+/KATPase Phase 4
  • Contain a carbohydrate and a steriodal group
193
Q

2 types of nonglycoside drugs

A

PDE- block cAMP –> AMP

B-adrenergic increase cAMP

194
Q

Inamrinone

Milrinone

MOA

which one is longer acting

Dose adjustments for?

A

Inamrinone is longer acting - inhibition of PDE

Milrinon- Greater selectivity

Dose adjustment in renal impairment

195
Q

Dobutamine

A

Dopamine analog, B1 agonist

Active only with IV

Short half life

196
Q

3 classes for IHD

A

Organic nitrates

CCBs

B BLOCKERs

197
Q

Production of Nitric oxide in body

Produced from

by?

What does the precursor contain?

A
  • From L-arginine
  • NOS
  • Guanidine H bonding and Ionic
  • Stimulates cGMP
198
Q

Effect of NO

A

decreases myocardial workload

this is very reactive

Causes reduced O demand

199
Q

AMyl nitrite

A

Ester, Inhalation

Fastest acting in class

Short duration

200
Q

Glyceryl Trinitrate

3 ns

A

Sublingual - most useful

Prophylactic and acute pain

Rapid onset not as fast at Amyl

201
Q

Isosorbide Dinitrate

Ring system

A

Sub, chew, SR

Slowest onset but longest DOA

Metabolite 5-isosorbide mononitrate is active

202
Q

DIs with Organic Nitrates

A

INteraction with other vasodilators, alcohol

Avoid Viagra fall Bp

203
Q

AEs of organic

My head hurts, I get dizzy when I stand up, my body is all red, I cant tolerate it anymore

204
Q

CCB structural classes

A

Dihydropyridine

Benxothiapine

Aralkylamine

CCBS inhibit Ca influx negative inotropic effects, vasodilation, Smooth muscle

205
Q

Nifedipine is a?

Potent?

Highly?

Metabolism to?

A

Dihydropyridine

Peripheral vasodilation

Protein bound

Inactive metabolites in urine

206
Q

Amlodipine is a?

Greater?

long?

Metabolized?

A

Dihydropyridine

Selective for vascualr SM vs Myocardial

Long DOA

Inactive metabolites, Urine

207
Q

SAR of Dihydropyridines

1,4?

C4 position ring with?

C3/5 What functional group?

C2 bulkier?

Free __ group at 1 position

A

Dihydromoeity essential

Aromatic ring with ortho or meta required

Ester functional group

Can increase potency (amlodipine)

Free NH at one position is REQUIRED

208
Q

Clevidipine is a?

how to take it?

Onset?

Rapid hydrolysis of?

A

Dihydropyridine

IV

Fast short acting shortest

of ester inactive

210
Q

CCBS dose adjustment for?

dont give with?

High protein binding causes?

DI with?

A

Chronic liver disease

Grapefruit

Azole fungal and CYp3A4

Displacement of protein binding with other drugs that protein bind

211
Q

Diltiazem is a?

Active?

deacetylation is?

O and N demethylation?

A

Benzothiazepine

Somea activity with the weird one

O and N inactive

212
Q

Verapamil is a?

Ca2+ ____

Liver dysfunction

Grapefruit

Commone SEs

A
  • Phenylalkylamine
  • Ca2+ antagonist
  • Intry into Myocardial
  • CYP3A4 interaction
  • increase verapamil
  • Brady, Hypo, Edema
213
Q

Classes of Anti arrythmics

A
  • 1 Membrane depressant, act on fast Na+ channels prevent conductance
  • B blockers
  • Repolarization prolongers blocking K+
  • CCBS inward slow Ca2+
214
Q

1 A examples

Slows?

A

Quinidine, Procainamide, Disopyramide

Quinide

Phase 0 depol

215
Q

Quinidine is a substrate for P-gp and can inhibit?

A

Tubular excretion of DIgoxin leading to toxic

Substrate for CYP3A4

unchanges urine

216
Q

Contamination of Quinidine with? Can be?

A

Dihydroquinidine more potent but toxic

217
Q

Procainamide

Bioisosteric drug design

Treats?

analog of?

Dose adjustment in?

Metabolized into?

A

analog of procain

Ventricular arrythmias

N-acetyl procainamide is active

Unchanges in urine 50%

Leukopenia and agranulocytosis

218
Q

Disopyramide

Metabolized?

Weak

AEs

A

Cardiac activity like procainamide

weak Anticholinergic

AE- Anticholinergic SEs

219
Q

1 A examples

Slows?

A

Quinidine, Procainamide, Disopyramide

Phase 0 depol

220
Q

Quinidine is a substrate for P-gp and can inhibit?

A

Tubular excretion of DIgoxin leading to toxic

Substrate for CYP3A4

unchanges urine

221
Q

Procainamide

Bioisosteric drug design

Treats?

analog of?

Dose adjustment in?

Metabolized into?

A

analog of procain

Ventricular arrythmias

N-acetyl procainamide is active

Unchanges in urine 50%

Leukopenia and agranulocytosis

222
Q

Class IB drugs and what they do?

A
  • Rapid rate of dissociation from Na+-ion channels. Shortens ‘Phase 3’ repolarization and action potential duration. Drug examples include: Lidocaine, and Phenytoin etc.
223
Q

Procainamide

A
  • Synthetic drug. An amide analog of the local anesthetic Procaine (example of bioisosteric drug design principle!)
  • Orally bioavailable. Parenteral (IV and IM) formulation also available.
  • Indicated for the treatment of ventricular arrythmias
  • Hepatic metabolism. Metabolites include N-acetyl procainamide (active) and p-aminobenzoic acid. Renal excretion of unchanged drug (~50%) and the metabolites.
  • Might require dose adjustment in hepatic and renal impaired patients
  • SEs- Drug induced lupus syndrome. Can also cause (0.5%) serious hematological disorders, particularly leukopenia and agranulocytosis.
224
Q

Disopyramide

A
  • Synthetic drug. Cardiac activity similar to Procainamide, Also exhibit weak anticholinergic activity.
  • Good oral availability. T1/2= 5-7 hr.
  • Partially metabolized in liver (CYP3A4), mostly to a mono-N-dealkylated product. Renal excretion of unchanged drug (~50%) and metabolites.
  • Dose adjustment might be required in patients with liver/renal impairment
  • SEs- are primarily related to anticholinergic activities of the drug, and can include dry mouth, blurry vision, constipation, and urinary retention.
225
Q

Lidocaine

A
  • Original use as a local anesthetic (Procaine-like).
  • Drug of choice for emergency treatment of ventricular arrythmia (IV). Also used parenterally for suppression of arrythmias associated with acute myo cardial infraction and cardiac surgery.
  • Rapid onset (1-2 min) and short duration of action (T1/2 = < 30 min).
  • Liver metabolized (N-Deethylation and amidase hydrolysis). Renal excretion.
  • SEs- Dizziness, paresthesis and seizure in severe cases.
226
Q

Phenytoin

A
  • Structurally analogous to barbiturates, but does not possess sedative properties.
  • Long history of use for the treatment of epileptic seizures.
  • Useful antiarrythmic agent for the treatment of digitalis induced arrythmias.
  • Orally active. Also available for parenteral (IV) use.
  • High plasma protein binding (~ 90%). T1/2 = 15 -30 hrs.
  • Slow hepatic (CYP450) metabolism to mono-p-hydroxyphenyl derivative, followed by glucuronide conjugation and excretion in urine.
  • Prevention of metabolism, or the presence of other plasma protein bound drugs can cause toxicity.
227
Q

Flecainide

A
  • Potent antiarrythmic drug with local anesthetic activity.
  • Orally administered for the treatment of ventricular arrythmias.
  • Plasma half-life ~14 hrs.
  • Part of the drug (~50%) is metabolized in liver (CYP2D6). Metabolism involves m-O-dealkylation. Urinary excretion of unchanged drug and the metabolites.
  • New or worsened arrythmias have been reported with the use of this drug.
  • Other adverse effects: Dizziness, blurred vision, nausea, and headache etc.
228
Q

Propafenone

A
  • Structural resemblance to class 1C antiarryhmics, as well as β-blockers
  • Used primarily for ventricular and supraventricular arrythmias
  • Oral drug. Metabolized in liver (CYP2D6; CYP3A4; CYP1A2). Dose adjustment might be required with simultaneous use of other drugs interacting with the above metabolic enzymes.
  • New or worsened arrythmias have been reported with the use of this drug.
  • Other adverse effects: Agranulocytosis, taste disturbance, dizziness, nausea, and constipation etc.
229
Q

Class II drugs

A

β-Adneregic blockers. Suppresses sympathomimetic activity. Slows ‘Phase 4’ depolarization.

Propranolol

230
Q

Class III drugs

A
  • K+-ion channel blockers. Prolongs ‘Phase 3’ repolarization and duration of action potential.
  • A quaternary ammonium salt. Originally developed as an antihypertensive.
  • Use limited for the treatment of emergency life threatening ventricular arrythmias resistant to other therapy.
  • Usually administered iv or im.
  • Adverse Effects : Hypotension (most common), nausea, and dizziness etc.
231
Q

Class III cont..

A
  • Antiarrythmic effects similar to Bretylium. Approved for the treatment of life-threatening ventricular arrythmias refractory to other drugs.
  • Oral and parenteral formulations. Long half-life (several weeks)
  • Hepatic metabolism involving N-deethylation (active metabolite).
  • Severe toxicity limits the use of this drug (used in hospital setting only)
232
Q

Class III cont..

A
  • Used orally for tachyarrythmias (esp. AF). T1/2 ~ 10 hr.
  • Due to the pro-arrhythmic potential of dofetilide, to be prescribe by physicians who have undergone specific training in the risks of treatment with dofetilide.
  • Hepatic metabolism (20%). Metabolites and unchanged drug excreted in urine. Dose adjustment in renal impairment.
  • Adverse effects: Induced arrythmia, headache, dizziness, nausea, rash, flu-like syndrome etc.
233
Q

Summary of Cardiac effects table

234
Q

Class IC drugs and what they do

A
  • Slows rate of dissociation from Na+-ion channels. Markedly slow ‘Phase 0’ depolarization
  • Flecainide, Propafenone
235
Q

Class IV

Examples

A
  • Ca2+-ion channel blockers. Slows ‘Phase 4’ depolarization and duration.
  • Prototypical drug examples are Verapamil, and Diltiazem etc.
236
Q

Diuretics

  1. Agents which _____ the rate of urine formation.
  2. Diuretic usage leads to _____ excretion of _____ (especially Na+ and Cl- ions) and water.
  3. Useful in the treatment of _____ conditions caused by?
  4. Diuretics are also used as the ____ agent or as ____therapy in the treatment of?
  5. The primary site of action for the diuretics is?
A
  1. Agents which increase the rate of urine formation.
  2. Diuretic usage leads to increased excretion of electrolytes (especially Na+ and Cl- ions) and water.
  3. Useful in the treatment of edematous conditions caused by congestive heart failure, nephritic syndrome, chronic liver disease etc., and in the management of hypertension.
  4. Diuretics are also used as the sole agent or as adjunctive therapy in the treatment of glaucoma, hypercalcemia, mountain sickness etc.
  5. The primary site of action for the diuretics is the kidney, where these drugs interfere with the reabsorption of sodium and other ions.
237
Q

Average GFR?

Urine formation represents how much of total filtration?

What percentage of water is reabsorbed?

A
  • 120
  • 1-2%
  • 98%
238
Q

Diuretic drug classes are classified by?

A
  • Chemical Class (eg. thiazides);
  • Mechanism of Action (eg. Carbonic Anhydrase Inhibitors);
  • Site of Action within the nephron (eg. Loop Diuretics);
  • Effects on Urine contents (Potassium- Sparing Diuretics) etc.
239
Q

Osmotic Diuretics?

A
  • Low molecular weight compounds
  • Passively filtered through Bowman’s capsule into renal tubule.
  • Limited reabsorption.
  • Undergoes negligible metabolism
  • Forms hypertonic solution, causing water to secrete into renal tubule, producing a diuretic effect
240
Q

Diuretic Sites of Action

A

Proximal Tubule; Loop of Henle; Collecting Tubule

241
Q

Diuretics

  1. Agents which _____ the rate of urine formation.
  2. Diuretic usage leads to _____ excretion of _____ (especially Na+ and Cl- ions) and water.
  3. Useful in the treatment of _____ conditions caused by?
  4. Diuretics are also used as the ____ agent or as ____therapy in the treatment of?
  5. The primary site of action for the diuretics is?
A
  1. Agents which increase the rate of urine formation.
  2. Diuretic usage leads to increased excretion of electrolytes (especially Na+ and Cl- ions) and water.
  3. Useful in the treatment of edematous conditions caused by congestive heart failure, nephritic syndrome, chronic liver disease etc., and in the management of hypertension.
  4. Diuretics are also used as the sole agent or as adjunctive therapy in the treatment of glaucoma, hypercalcemia, mountain sickness etc.
  5. The primary site of action for the diuretics is the kidney, where these drugs interfere with the reabsorption of sodium and other ions.
242
Q

Average GFR?

Urine formation represents how much of total filtration?

What percentage of water is reabsorbed?

A
  • 120
  • 1-2%
  • 98%
243
Q

Diuretic drug classes are classified by?

A
  • Chemical Class (eg. thiazides);
  • Mechanism of Action (eg. Carbonic Anhydrase Inhibitors);
  • Site of Action within the nephron (eg. Loop Diuretics);
  • Effects on Urine contents (Potassium- Sparing Diuretics) etc.
244
Q

Osmotic Diuretics?

A
  • Low molecular weight compounds
  • Passively filtered through Bowman’s capsule into renal tubule.
  • Limited reabsorption.
  • Undergoes negligible metabolism
  • Forms hypertonic solution, causing water to secrete into renal tubule, producing a diuretic effect
245
Q

Diuretic Sites of Action

A

Proximal Tubule; Loop of Henle; Collecting Tubule

246
Q

Osmotic Diuretic Examples

Which one has greater absorption? Longer half life? Duration of action?

A
  • Isosorbide greater absorption longer t half
  • Mannitol greater DOA
  • Not a frequently used class of diuretics in current practice, except in the prophylaxis of acute renal failure to inhibit water reabsorption and maintain urine flow.
  • Mannitol is the agent most commonly used as an osmotic diuretic.
  • Administered as an intravenous solution.
  • Isosorbide (a bicyclic form of sorbitol!) is primarily used for the treatment of glaucoma.
247
Q

Carbonic Anyhydrase?

A
  • Carbonic anhydrase (CA), a metalloenzyme (Zn2+-ion at active site), catalyzes the formation of carbonic acid (H2CO3) from carbon dioxide and water.
  • At least seven CA isozymes in human, present mainly in blood cells, gastric mucosa, pancreatic cells, and renal tubules.
  • In the proximal tubule, promotes reabsorption of Na+ and HCO3 – ions from the glomerular filtrate, and excretion of H+ ions. (Acidic nature of urine and alkalinity of blood)
  • Inhibition of carbonic anhydrase induces diuresis via excretion of sodium and bicarbonate ions, and associated water molecules.
  • Accidental initial discovery of carbonic anhydrase inhibitory activity (in dog urine!) of Sulfanilamide, a sulfonamide antibacterial.
248
Q

Carbonic Anhydrase Inhibitors?

A
  • Presence of an acidic sulfonamide group (pKa= 7–9). Free N–H required for activity.
  • Site of Action: Proximal Convoluted Tubule
  • Not very efficacious (increases renal excretion of sodium only by 2%–5%)
  • Limited use, mostly for the treatment of glaucoma (oral and topical formulations)
  • First orally effective CA inhibitor diuretic in clinical use § Diuretic effect lasts for 8 – 12 hrs § Limited use because of systemic acidosis
  • AEs-
    • Development of metabolic acidosis on prolonged use
    • Can cause electrolyte disturbance (hypokalemia) and renal effects (kidney stone)
    • Hypersensitivity reactions possible (attributable to sulfonamide group)
249
Q

Osmotic Diuretic Examples

Which one has greater absorption? Longer half life? Duration of action?

A
  • Isosorbide greater absorption longer t half
  • Mannitol greater DOA
  • Not a frequently used class of diuretics in current practice, except in the prophylaxis of acute renal failure to inhibit water reabsorption and maintain urine flow.
  • Mannitol is the agent most commonly used as an osmotic diuretic.
  • Administered as an intravenous solution.
  • Isosorbide (a bicyclic form of sorbitol!) is primarily used for the treatment of glaucoma.
250
Q

Thiazide examples

A
  • Used in the treatment of edema caused by congestive heart failure as well as in hepatic or renal disease. Also useful in the treatment of hypertension (reduction in blood volume)
  • Compared to Chlorothiazide, the double bond reduced analog Hydrochlorothiazide (HCT) is more potent and has a longer half-life.
  • Adverse Effects: Gastric irritation, hypersensitivity, nausea, and electrolyte disturbance. Long-term use may also result in decreased glucose tolerance and increased blood lipid content (TC, LDL, TG).
251
Q

SAR of Thiazide Diuretics?

A
  • C7-position: Sulfonamide group is required for activity
  • C6-position (R1): Electron-withdrawing group (e.g. Cl, CF3 etc) required for activity
  • 3–4-position: Saturation of the double bond results in more potent (~ 10-fold) analogs
  • C3-position (R2): Lipophilic group improves diuretic potency
  • 2-position (R3): N-alkyl substitution increases the duration of diuretic action
252
Q

Thiazide-like Diuretics

Quinazolinone

A
  • Contains a quinazolin-4-one structural core (ring-SO2 of thiazides replaced with a CO group)
  • Diuretic effects similar to the thiazide class of compounds
  • Orally active. Long duration of action (upto 24 hrs)
  • Adverse effects similar to the thiazide diuretic class
253
Q

Carbonic Anyhydrase?

A
  • Carbonic anhydrase (CA), a metalloenzyme (Zn2+-ion at active site), catalyzes the formation of carbonic acid (H2CO3) from carbon dioxide and water.
  • At least seven CA isozymes in human, present mainly in blood cells, gastric mucosa, pancreatic cells, and renal tubules.
  • In the proximal tubule, promotes reabsorption of Na+ and HCO3 – ions from the glomerular filtrate, and excretion of H+ ions. (Acidic nature of urine and alkalinity of blood)
  • Inhibition of carbonic anhydrase induces diuresis via excretion of sodium and bicarbonate ions, and associated water molecules.
  • Accidental initial discovery of carbonic anhydrase inhibitory activity (in dog urine!) of Sulfanilamide, a sulfonamide antibacterial.
254
Q

Furosemide

A
  • Contains a carboxylic acid functional group (pKa ~4)
  • 8 – 10 Times stronger saluretic action than the thiazides.
  • Causes excretion of Na+, K+, Ca2+, Mg2+, Cl- and HCO3 - ions
  • Orally active. Parenteral form for faster onset of action.
  • Extensive plasma protein binding (> 90%). Mostly excreted unchanged (kidney).
  • Uses-Most important use in the treatment of pulmonary edema. Additional uses include, treatment of edemas associated with cardiac, hepatic and renal malfunctions. Also useful in the treatment of hypertension.
  • Side-Effects: Electrolyte Imbalance; Hyperuricemia; Gastrointestinal side-effects, and hypersensitivity etc. Can also cause ototoxicity (temporary hearing loss). This effect can be additive with concurrent usage of aminoglycoside antibiotics.
255
Q

Bumetanide

A
  • Ring substitution pattern different than furosemide
  • Greater bioavailability than furosemide
  • Marked increase in diuretic potency (~ 40 times of furosemide)
  • Uses and side effect profile similar to furosemide
256
Q

Torsemide

A
  • Sulfonylurea side-chain instead of sulfonamide
  • Same site / mechanism of action as furosemide and bumetanide
  • Available in oral and parenteral (IV) forms
  • Partially metabolized by hepatic cytochrome P450 enzymes. A major metabolic route involves oxidn of the Ar-Me group to carboxylic acid.
  • Uses: Treatment of hypertension; Congestive heart failure and cirrhosis associated edema.
  • Adverse Effects : Fatigue, dizziness, muscle cramps, nausea and orthostatic hypotension.
257
Q

Ethacrynic

A
  • A phenoxyacetic acid derivative. Lacks a sulfonamide group.
  • Same site / mechanism of action as the above loop diuretics
  • Rapid onset (~ 30 min) and long duration of action (6 – 8 hr)
  • Oral and parenteral. Highly plasma protein bound (> 95%)
  • Relatively less potent than the other drugs in this category. However, useful in patients who are allergic to the sulfonamides.
  • Adverse effects: Greater incidences of ototoxicity and more serious gastrointestinal effects
258
Q

Properties of loop di table

259
Q

K sparing Diuretics

Mineralcorticoid Receptor Antagonists

A
  • Aldosterone, a steroid hormone, is secreted by the adrenal cortex, and is a potent mineral corticoid.
  • Acting on the distal tubule and collecting ducts of the nephron, it causes increased reabsorption of Na+ and Cl– ions and water, while increasing K+-ion ion excretion
  • Aldosterone action leads to increase in water retention, and increased blood pressure / volume.
  • The biologic effect of Aldosterone is caused by its binding to the mineralcorticoid receptor (MR), a nuclear transcription factor
  • Inhibition (antagonism) of aldosterone function can lead to diuresis (excretion of Na+, and Cl– ions and water)
  • Such inhibitors are also classified as Potassium-Sparing Diuretics
260
Q

Spironolactone

A
  • A semi-synthetic drug. Prevents aldosterone binding (antagonist) to the MR in the distal convoluted tubule and the collecting system.
  • Causes increased amount of Na+ / water excretion, and retention of K+-ion.
  • Oral drug (90% availability). Undergoes significant first-pass metabolism to form Canrenone (loses Me–CO–SH), an active metabolite. Excretetion mainly in urine.
  • Adverse effects: Can cause hyperkalemia. Use of other K+-sparing diuretics, potassium supplements and food rich in potassium should be avoided. Anti-androgenic effects, hypersensitivity reactions, GI disturbances, and peptic ulcer have also been reported.
261
Q

Eplerenone

A
  • An aldosterone antagonist. Compared to Spironolactone, lower affinity for MR, however a more selective inhibitor (does not inhibit AR, PR, and GR)
  • Oral drug (~70% availability). T1/2≃ 5 hr. Hepatic metabolism (CYP3A4). Metabolites inactive and excreted in urine and feces.
  • Adverse effects: Can cause hyperkalemia. However, unlike spironolactone, limited/fewer sexual side effects.
262
Q

Comparison Table of K sparing Diuretics

263
Q

Triametrene

A
  • Contains a pteridine sturctural core.
  • Renal epithelial Na+ channel blocker. Blocks the reabsorption of Na+ ion and prevents excretion of K+ ion in the distal tubule (but no effect on aldosterone action).
  • Oral drug (~70% absorption). Metabolized extensively (4’-OH analog and its sulfate conjugate). Excreted in the urine
  • Adverse Effects: Can cause hyperkalemia, nausea, vomiting and headache. Potassium supplements are contraindicated, and serum potassium levels should be monitored.
264
Q

Amiloride

A
  • An aminopyrazine derivative.
  • Renal epithelial Na+ channel blocker. Blocks the reabsorption of Na+- ion and secretion of K+-ion in DCT. No effect on aldosterone action.
  • Oral drug (~50% absorption). Excreted (mostly unchanged) in urine and feces. Renal impairment can increase half-life.
  • Adverse Effects: Similar to triamterene.
265
Q

Comparison of Triametrene and Amiloride

266
Q

Site of Mechanism of Action of Diuretics Summary

267
Q

Overview of Site of Mechanism of Action Picture

268
Q

Carbonic Anhydrase Inhibitors?

A
  • Presence of an acidic sulfonamide group (pKa= 7–9). Free N–H required for activity.
  • Site of Action: Proximal Convoluted Tubule
  • Not very efficacious (increases renal excretion of sodium only by 2%–5%)
  • Limited use, mostly for the treatment of glaucoma (oral and topical formulations)
  • First orally effective CA inhibitor diuretic in clinical use § Diuretic effect lasts for 8 – 12 hrs § Limited use because of systemic acidosis
  • AEs-
    • Development of metabolic acidosis on prolonged use
    • Can cause electrolyte disturbance (hypokalemia) and renal effects (kidney stone)
    • Hypersensitivity reactions possible (attributable to sulfonamide group)
269
Q

Thiazide Diuretics?

A
  • Further modified sulfonamides, characterized by the presence of a benzothiadiazine 1,1-dioxide core
  • Weakly acidic compounds (pKa ~ 7). Actively secreted into the proximal tubule and are carried to the site of action.
  • Site of Action: Thick ascending loop of Henle and distal convoluted tubule
  • Mechanism of Diuretic Action: Binds to the Na+/Cl– symporter and inhibits the reabsorption of sodium and chloride ions (saluretic agents)
  • Used alone, or as add-on therapy. Rapid oral absorption. Excreted mainly unchanged (urine)
271
Q

Thiazide examples

A
  • Used in the treatment of edema caused by congestive heart failure as well as in hepatic or renal disease. Also useful in the treatment of hypertension (reduction in blood volume)
  • Compared to Chlorothiazide, the double bond reduced analog Hydrochlorothiazide (HCT) is more potent and has a longer half-life.
  • Adverse Effects: Gastric irritation, hypersensitivity, nausea, and electrolyte disturbance. Long-term use may also result in decreased glucose tolerance and increased blood lipid content (TC, LDL, TG).
272
Q

SAR of Thiazide Diuretics?

A
  • C7-position: Sulfonamide group is required for activity
  • C6-position (R1): Electron-withdrawing group (e.g. Cl, CF3 etc) required for activity
  • 3–4-position: Saturation of the double bond results in more potent (~ 10-fold) analogs
  • C3-position (R2): Lipophilic group improves diuretic potency
  • 2-position (R3): N-alkyl substitution increases the duration of diuretic action
273
Q

Loop Diuretics?

A
  • Diverse structural classes
  • The most efficacious among the various diuretic classes
  • Peak diuresis produced > other commonly used diuretics (High-Ceiling Diuretics)
  • Site of Action: Loop of Henle (thick ascending limb)
  • Inhibits the luminal Na+/ K+/ 2Cl- co-transporter
  • Characterized by quick onset (~ 30 min) and relatively short duration of action (~ 6 hrs)
274
Q

Thiazide-like Diuretics

Quinazolinone

A
  • Contains a quinazolin-4-one structural core (ring-SO2 of thiazides replaced with a CO group)
  • Diuretic effects similar to the thiazide class of compounds
  • Orally active. Long duration of action (upto 24 hrs)
  • Adverse effects similar to the thiazide diuretic class
276
Q

Furosemide

A
  • Contains a carboxylic acid functional group (pKa ~4)
  • 8 – 10 Times stronger saluretic action than the thiazides.
  • Causes excretion of Na+, K+, Ca2+, Mg2+, Cl- and HCO3 - ions
  • Orally active. Parenteral form for faster onset of action.
  • Extensive plasma protein binding (> 90%). Mostly excreted unchanged (kidney).
  • Uses-Most important use in the treatment of pulmonary edema. Additional uses include, treatment of edemas associated with cardiac, hepatic and renal malfunctions. Also useful in the treatment of hypertension.
  • Side-Effects: Electrolyte Imbalance; Hyperuricemia; Gastrointestinal side-effects, and hypersensitivity etc. Can also cause ototoxicity (temporary hearing loss). This effect can be additive with concurrent usage of aminoglycoside antibiotics.
277
Q

RAS a Bp Elevation picture

278
Q

RAS drug target?

279
Q

Bumetanide

A
  • Ring substitution pattern different than furosemide
  • Greater bioavailability than furosemide
  • Marked increase in diuretic potency (~ 40 times of furosemide)
  • Uses and side effect profile similar to furosemide
280
Q

Torsemide

A
  • Sulfonylurea side-chain instead of sulfonamide
  • Same site / mechanism of action as furosemide and bumetanide
  • Available in oral and parenteral (IV) forms
  • Partially metabolized by hepatic cytochrome P450 enzymes. A major metabolic route involves oxidn of the Ar-Me group to carboxylic acid.
  • Uses: Treatment of hypertension; Congestive heart failure and cirrhosis associated edema.
  • Adverse Effects : Fatigue, dizziness, muscle cramps, nausea and orthostatic hypotension.
281
Q

Ethacrynic

A
  • A phenoxyacetic acid derivative. Lacks a sulfonamide group.
  • Same site / mechanism of action as the above loop diuretics
  • Rapid onset (~ 30 min) and long duration of action (6 – 8 hr)
  • Oral and parenteral. Highly plasma protein bound (> 95%)
  • Relatively less potent than the other drugs in this category. However, useful in patients who are allergic to the sulfonamides.
  • Adverse effects: Greater incidences of ototoxicity and more serious gastrointestinal effects
282
Q

Captopril

A
  • First ACE inhibitor drug (1981); Contains a sulfhydryl (SH) group
  • Oral drug; Rapid absorption; Bioavailability ~ 75%; T1/2 = 2 hrs
  • Partially eliminated unchanged in urine (~50%), remainder as disulfide dimer and captopril-cysteine disulfide
  • Used for the therapy of hypertension and heart failure
  • Food reduces oral bioavailability by 25-30%
  • Sulfhydryl group implicated in skin rashes and taste disturbance
283
Q

Captopril Binding site interaction?

284
Q

Captopril Metabolic Pathway

285
Q

Enalapril

A
  • An ester prodrug. Hydrolyzed by hepatic esterase to the active carboxylic acid form. Dicarboxylate class of ACE inhibitor.
  • More potent than Captopril.
  • Oral drug; Readily absorbed; Oral bioavailability ~ 60%, not reduced by food. Eliminated unchanged in urine
  • Enalaprilat not absorbed orally. Available in IV formulation.
  • Used for the therapy of hypertension and heart failure; Only ACE inhibitor approved for pediatric use.
286
Q

Benzapril

A
  • A prodrug; Ester hydrolysis produces the active drug.
  • Belongs to the dicarboxylate class of ACE inhibitors
  • More potent than captopril or enalaprilat
  • Oral drug. Indicated for hypertension.
  • Readily but incompletely absorbed. Glucuronide conjugate excreted via urine and bile.
  • Also available in combination with Hydrochlorothoazide (Lotensin HCT®) or Amlodipine (Lotrel®)
287
Q

Fosinopril

A
  • Phosphinate group containing ACE inhibitor.
  • A prodrug. Cleavage of the ester moiety by hepatic esterases generates the active drug Fosinoprilat
  • Slowly and incompletely (36%) absorbed after oral administration.
  • Fosinoprilat and glucuronide conjugate excreted in urine and bile; Clearance not significantly altered by renal impairment.
  • Indicated for the treatment of hypertension and heart failure.
288
Q

Other examples of ACEs in Dicarboxylate group

289
Q

SAR of ACE Is

A
  • The N-ring carboxylic acid is essential (mimics the C-terminal carboxylate of ACE substrates)
  • Large hydrophobic functionalities in the N-ring increases potency
  • Zn-ion binding groups (sulfhydryl, carboxylate, phosphinic acid etc) required for potency
  • ‘X’ is usually methyl (mimics the side-chain of alanine), the exception being Lisinopril
  • For optimum activity, stereochemistry should be consistent with natural L-amino acid
290
Q

Properties of loop di table

291
Q

K sparing Diuretics

Mineralcorticoid Receptor Antagonists

A
  • Aldosterone, a steroid hormone, is secreted by the adrenal cortex, and is a potent mineral corticoid.
  • Acting on the distal tubule and collecting ducts of the nephron, it causes increased reabsorption of Na+ and Cl– ions and water, while increasing K+-ion ion excretion
  • Aldosterone action leads to increase in water retention, and increased blood pressure / volume.
  • The biologic effect of Aldosterone is caused by its binding to the mineralcorticoid receptor (MR), a nuclear transcription factor
  • Inhibition (antagonism) of aldosterone function can lead to diuresis (excretion of Na+, and Cl– ions and water)
  • Such inhibitors are also classified as Potassium-Sparing Diuretics
292
Q

Pharmacokinetic Properties of ACEs table

293
Q

Spironolactone

A
  • A semi-synthetic drug. Prevents aldosterone binding (antagonist) to the MR in the distal convoluted tubule and the collecting system.
  • Causes increased amount of Na+ / water excretion, and retention of K+-ion.
  • Oral drug (90% availability). Undergoes significant first-pass metabolism to form Canrenone (loses Me–CO–SH), an active metabolite. Excretetion mainly in urine.
  • Adverse effects: Can cause hyperkalemia. Use of other K+-sparing diuretics, potassium supplements and food rich in potassium should be avoided. Anti-androgenic effects, hypersensitivity reactions, GI disturbances, and peptic ulcer have also been reported.
294
Q

Losartan

A
  • The first clinically approved ARB drug (1995)
  • Highly protein bound (~98%); Adequate oral bioavailability (33%)
  • Approximately 14% of an oral dose is oxidized by the isozymes CYP2C9 and CYP3A4 to a more potent (10-40 times) carboxylic acid metabolite
    • (-CH2OH —-> -CO2H)
  • Primarily excreted by the fecal route.
295
Q

Candesartan cilexitil

A
  • Inactive ester prodrug. Completely hydrolyzed during absorption from the GI tract to form the active drug Candestran; High plasma protein binding (99%); Oral bioavailability = 15%; T1/2 = 9 hrs.
296
Q

Other ARBs in use

Features of all ARBs

A
  • All the ARBs are acidic drugs. The tetrazole ring has a pKa ≃ 6, and the carboxylic acid pKa = 3-4.
  • Azilsartan medomoxil and Olmesartan medomoxil are prodrugs that are completely hydrolyzed during absorption from the GI tract to generate the active carboxylic acid metabolites.
297
Q

Pharmacokinetics of ARBs

298
Q

Eplerenone

A
  • An aldosterone antagonist. Compared to Spironolactone, lower affinity for MR, however a more selective inhibitor (does not inhibit AR, PR, and GR)
  • Oral drug (~70% availability). T1/2≃ 5 hr. Hepatic metabolism (CYP3A4). Metabolites inactive and excreted in urine and feces.
  • Adverse effects: Can cause hyperkalemia. However, unlike spironolactone, limited/fewer sexual side effects.
299
Q

Renin

Only drug in class

A
  • Development of Aliskiren: The First (and only) Renin Inhibitor in Clinical Use
300
Q

Comparison Table of K sparing Diuretics

301
Q

Triametrene

A
  • Contains a pteridine sturctural core.
  • Renal epithelial Na+ channel blocker. Blocks the reabsorption of Na+ ion and prevents excretion of K+ ion in the distal tubule (but no effect on aldosterone action).
  • Oral drug (~70% absorption). Metabolized extensively (4’-OH analog and its sulfate conjugate). Excreted in the urine
  • Adverse Effects: Can cause hyperkalemia, nausea, vomiting and headache. Potassium supplements are contraindicated, and serum potassium levels should be monitored.
302
Q

Amiloride

A
  • An aminopyrazine derivative.
  • Renal epithelial Na+ channel blocker. Blocks the reabsorption of Na+- ion and secretion of K+-ion in DCT. No effect on aldosterone action.
  • Oral drug (~50% absorption). Excreted (mostly unchanged) in urine and feces. Renal impairment can increase half-life.
  • Adverse Effects: Similar to triamterene.
303
Q

Comparison of Triametrene and Amiloride

304
Q

HTN is a risk factor for?

A

Stroke, MI, Renal Failure, CHF, Progressive Atherosclerosis and Dementia

305
Q

What is the RAS?

A

Highly regulated pathway, integral in regulating arterial blood pressure, body fluid volume, and electrolyte balance

306
Q

What two major enzymes are involved in the RAS?

A

Renin and Angiotensin Converting Enzyme

307
Q

Angiotensin II is a?

What is its precursor?

Angiotensin II is also responsible for?

A
  • Potent vasodilator
  • Angiotensinogen
  • Production of Aldosterone which in turn contributes towards an increase in plasma volume and Bp.
308
Q

Angiotensinogen

Hydrolyzed by? to release?

A

Renin to release angiotensin I

309
Q

Renin?

Type of enzyme?

A

Protease

Angiotensinogen to form Angiotensin I

310
Q

Angiotensin I is converted to? By?

A

to Ang II by ACE

311
Q

ACE

Contains?

Cleaves peptides with? But not?

Hydrolyzes Ang I and also?

A
  • Zn2+
  • Tripeptide sequence but not cleave peptides with penultimate prolyl residue
  • Bradykinin and Substance P
312
Q

Ang III does not have any vasoconstriction properties but it does?

A

Stimulate Aldosterone secretion which increases plasma volume and blood pressure

313
Q

Site of Mechanism of Action of Diuretics Summary

314
Q

Overview of Site of Mechanism of Action Picture

315
Q

The action of ACE results in?

A
  • Generation of a potent hypertensive agent Angiotensin II
  • Release of a hypertensive agent Aldosterone
  • Degradation of a potent antihypertensive agent Bradykinin (a vasodilator)
  • The outcome of all the above actions of ACE is hypertension, an increase in blood pressure.
316
Q

ACEs can be classified into three groups based on their structure

A
  • Sulfhydryl (SH) group containing inhibitors (e.g. Captopril)
  • Dicarboxylate-containing inhibitors (e.g. Enalapril)
  • Phosphonate-containing inhibitors (e.g. Fosinopril)
317
Q

The difference in ACE classes? 3 ways

A
  • In their potency
  • Whether the activity is due to the drug itself, or the conversion of a prodrug to an active metabolite
  • Pharmacokinetics (extent of absorption; effect of food; plasma half-life; tissue distribution; mechanism of elimination etc)
319
Q

Thiazide Diuretics?

A
  • Further modified sulfonamides, characterized by the presence of a benzothiadiazine 1,1-dioxide core
  • Weakly acidic compounds (pKa ~ 7). Actively secreted into the proximal tubule and are carried to the site of action.
  • Site of Action: Thick ascending loop of Henle and distal convoluted tubule
  • Mechanism of Diuretic Action: Binds to the Na+/Cl– symporter and inhibits the reabsorption of sodium and chloride ions (saluretic agents)
  • Used alone, or as add-on therapy. Rapid oral absorption. Excreted mainly unchanged (urine)
323
Q

Loop Diuretics?

A
  • Diverse structural classes
  • The most efficacious among the various diuretic classes
  • Peak diuresis produced > other commonly used diuretics (High-Ceiling Diuretics)
  • Site of Action: Loop of Henle (thick ascending limb)
  • Inhibits the luminal Na+/ K+/ 2Cl- co-transporter
  • Characterized by quick onset (~ 30 min) and relatively short duration of action (~ 6 hrs)
326
Q

AEs of ACE-Is

A
  • Generally well-tolerated drugs. Serious untoward reactions are rare.
  • Side effects may include, hypotension, hyperkalemia, dry cough (in 5-20% of patients), dizziness, renal insufficiency, skin rash, neutropenia (rare), and angioedema etc.
  • The use of ACE inhibitors during pregnancy (especially during 2nd / 3rd trimester) is contraindicated
  • Renal elimination is the primary route of elimination for majority of the ACE inhibitors (except Fosinopril). Therefore, dosage should be reduced in patients with renal impairment.
327
Q

DIs of ACE-Is

A
  • Antacids may reduce bioavailability. NSAIDS (including aspirin) may reduce the anti-hypertensive response to ACE inhibitors.
329
Q

Ang II receptor blockers MOA?

AT1 receptor

AT2 receptor

A
  • Also called receptor antagonists, displace/prevents binding of angiotensin II at the binding site
  • Located in brain, neuro, vascular, renal, hepatic, adrenal, myocardial mediate effects at these sites
  • 2 is growth, development
330
Q

RAS a Bp Elevation picture

331
Q

RAS drug target?

334
Q

Ang II receptor blockers application

AEs

DIs

A
  • All the ARBs are approved for the treatment of hypertension. Can be used as stand-alone drugs, or in combination with other anti-hypertensive agents (e.g. Diuretics; Calcium channel blockers).
  • Additionally, some of the ARBs also find use in the treatment of nephropathy in type 2 diabetes (Losartan / Irbesartan), heart failure (Candesartan / Valsartan), and cardiovascular risk-reduction of MI and stroke (Telmisartan) etc.

AEs

  • ARBs are generally well tolerated. Unlike ACE inhibitors, does not effect the levels of bradykinin or prostaglandins. The most common side-effects include:
  • Headache; Dizziness; Fatigue; Hypotension; Upper respiratory tract infection etc. q ARBs are contraindicated during pregnancy.

DIs

  • ARBs are relatively free of clinically important drug interactions. Telmisartan is the only agent among this class reported to increase the plasma concentration of Digoxin.
  • However, non-steroidal antiinflammatory drugs (NSAIDs) may alter the response to ARBs and other anhtihypertensive agents (including ACE inhibitors and Ca2+-channel blockers) due to the inhibition (COX) of vasodilatory prostaglandins.
    *
336
Q

Captopril

A
  • First ACE inhibitor drug (1981); Contains a sulfhydryl (SH) group
  • Oral drug; Rapid absorption; Bioavailability ~ 75%; T1/2 = 2 hrs
  • Partially eliminated unchanged in urine (~50%), remainder as disulfide dimer and captopril-cysteine disulfide
  • Used for the therapy of hypertension and heart failure
  • Food reduces oral bioavailability by 25-30%
  • Sulfhydryl group implicated in skin rashes and taste disturbance
337
Q

Captopril Binding site interaction?

338
Q

Captopril Metabolic Pathway

339
Q

Enalapril

A
  • An ester prodrug. Hydrolyzed by hepatic esterase to the active carboxylic acid form. Dicarboxylate class of ACE inhibitor.
  • More potent than Captopril.
  • Oral drug; Readily absorbed; Oral bioavailability ~ 60%, not reduced by food. Eliminated unchanged in urine
  • Enalaprilat not absorbed orally. Available in IV formulation.
  • Used for the therapy of hypertension and heart failure; Only ACE inhibitor approved for pediatric use.
340
Q

Benzapril

A
  • A prodrug; Ester hydrolysis produces the active drug.
  • Belongs to the dicarboxylate class of ACE inhibitors
  • More potent than captopril or enalaprilat
  • Oral drug. Indicated for hypertension.
  • Readily but incompletely absorbed. Glucuronide conjugate excreted via urine and bile.
  • Also available in combination with Hydrochlorothoazide (Lotensin HCT®) or Amlodipine (Lotrel®)
341
Q

Fosinopril

A
  • Phosphinate group containing ACE inhibitor.
  • A prodrug. Cleavage of the ester moiety by hepatic esterases generates the active drug Fosinoprilat
  • Slowly and incompletely (36%) absorbed after oral administration.
  • Fosinoprilat and glucuronide conjugate excreted in urine and bile; Clearance not significantly altered by renal impairment.
  • Indicated for the treatment of hypertension and heart failure.
342
Q

Other examples of ACEs in Dicarboxylate group

343
Q

SAR of ACE Is

A
  • The N-ring carboxylic acid is essential (mimics the C-terminal carboxylate of ACE substrates)
  • Large hydrophobic functionalities in the N-ring increases potency
  • Zn-ion binding groups (sulfhydryl, carboxylate, phosphinic acid etc) required for potency
  • ‘X’ is usually methyl (mimics the side-chain of alanine), the exception being Lisinopril
  • For optimum activity, stereochemistry should be consistent with natural L-amino acid
346
Q

Pharmacokinetic Properties of ACEs table

348
Q

Losartan

A
  • The first clinically approved ARB drug (1995)
  • Highly protein bound (~98%); Adequate oral bioavailability (33%)
  • Approximately 14% of an oral dose is oxidized by the isozymes CYP2C9 and CYP3A4 to a more potent (10-40 times) carboxylic acid metabolite
    • (-CH2OH —-> -CO2H)
  • Primarily excreted by the fecal route.
349
Q

Candesartan cilexitil

A
  • Inactive ester prodrug. Completely hydrolyzed during absorption from the GI tract to form the active drug Candestran; High plasma protein binding (99%); Oral bioavailability = 15%; T1/2 = 9 hrs.
350
Q

Other ARBs in use

Features of all ARBs

A
  • All the ARBs are acidic drugs. The tetrazole ring has a pKa ≃ 6, and the carboxylic acid pKa = 3-4.
  • Azilsartan medomoxil and Olmesartan medomoxil are prodrugs that are completely hydrolyzed during absorption from the GI tract to generate the active carboxylic acid metabolites.
351
Q

Pharmacokinetics of ARBs

353
Q

Renin

Only drug in class

A
  • Development of Aliskiren: The First (and only) Renin Inhibitor in Clinical Use
358
Q

HTN is a risk factor for?

A

Stroke, MI, Renal Failure, CHF, Progressive Atherosclerosis and Dementia

359
Q

What is the RAS?

A

Highly regulated pathway, integral in regulating arterial blood pressure, body fluid volume, and electrolyte balance

360
Q

What two major enzymes are involved in the RAS?

A

Renin and Angiotensin Converting Enzyme

361
Q

Angiotensin II is a?

What is its precursor?

Angiotensin II is also responsible for?

A
  • Potent vasodilator
  • Angiotensinogen
  • Production of Aldosterone which in turn contributes towards an increase in plasma volume and Bp.
362
Q

Angiotensinogen

Hydrolyzed by? to release?

A

Renin to release angiotensin I

363
Q

Renin?

Type of enzyme?

A

Protease

Angiotensinogen to form Angiotensin I

364
Q

Angiotensin I is converted to? By?

A

to Ang II by ACE

365
Q

ACE

Contains?

Cleaves peptides with? But not?

Hydrolyzes Ang I and also?

A
  • Zn2+
  • Tripeptide sequence but not cleave peptides with penultimate prolyl residue
  • Bradykinin and Substance P
366
Q

Ang III does not have any vasoconstriction properties but it does?

A

Stimulate Aldosterone secretion which increases plasma volume and blood pressure

369
Q

The action of ACE results in?

A
  • Generation of a potent hypertensive agent Angiotensin II
  • Release of a hypertensive agent Aldosterone
  • Degradation of a potent antihypertensive agent Bradykinin (a vasodilator)
  • The outcome of all the above actions of ACE is hypertension, an increase in blood pressure.
370
Q

ACEs can be classified into three groups based on their structure

A
  • Sulfhydryl (SH) group containing inhibitors (e.g. Captopril)
  • Dicarboxylate-containing inhibitors (e.g. Enalapril)
  • Phosphonate-containing inhibitors (e.g. Fosinopril)
371
Q

The difference in ACE classes? 3 ways

A
  • In their potency
  • Whether the activity is due to the drug itself, or the conversion of a prodrug to an active metabolite
  • Pharmacokinetics (extent of absorption; effect of food; plasma half-life; tissue distribution; mechanism of elimination etc)
380
Q

AEs of ACE-Is

A
  • Generally well-tolerated drugs. Serious untoward reactions are rare.
  • Side effects may include, hypotension, hyperkalemia, dry cough (in 5-20% of patients), dizziness, renal insufficiency, skin rash, neutropenia (rare), and angioedema etc.
  • The use of ACE inhibitors during pregnancy (especially during 2nd / 3rd trimester) is contraindicated
  • Renal elimination is the primary route of elimination for majority of the ACE inhibitors (except Fosinopril). Therefore, dosage should be reduced in patients with renal impairment.
381
Q

DIs of ACE-Is

A
  • Antacids may reduce bioavailability. NSAIDS (including aspirin) may reduce the anti-hypertensive response to ACE inhibitors.
383
Q

Ang II receptor blockers MOA?

AT1 receptor

AT2 receptor

A
  • Also called receptor antagonists, displace/prevents binding of angiotensin II at the binding site
  • Located in brain, neuro, vascular, renal, hepatic, adrenal, myocardial mediate effects at these sites
  • 2 is growth, development
388
Q

Ang II receptor blockers application

AEs

DIs

A
  • All the ARBs are approved for the treatment of hypertension. Can be used as stand-alone drugs, or in combination with other anti-hypertensive agents (e.g. Diuretics; Calcium channel blockers).
  • Additionally, some of the ARBs also find use in the treatment of nephropathy in type 2 diabetes (Losartan / Irbesartan), heart failure (Candesartan / Valsartan), and cardiovascular risk-reduction of MI and stroke (Telmisartan) etc.

AEs

  • ARBs are generally well tolerated. Unlike ACE inhibitors, does not effect the levels of bradykinin or prostaglandins. The most common side-effects include:
  • Headache; Dizziness; Fatigue; Hypotension; Upper respiratory tract infection etc. q ARBs are contraindicated during pregnancy.

DIs

  • ARBs are relatively free of clinically important drug interactions. Telmisartan is the only agent among this class reported to increase the plasma concentration of Digoxin.
  • However, non-steroidal antiinflammatory drugs (NSAIDs) may alter the response to ARBs and other anhtihypertensive agents (including ACE inhibitors and Ca2+-channel blockers) due to the inhibition (COX) of vasodilatory prostaglandins.
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Medicinal Chem (15 decks)

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