Lectures 16, 17, 18, and 19 Flashcards

1
Q

Which clotting factors do oral anticoagulants target?

A

Xa, IIa, VIIa, and IXa

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2
Q

What are some anticoagulants?

A
  • Vitamin K antagonists (warfarin)
  • Direct thrombin inhibitors (bivalirubin, dabigatran)
  • Direct Xa inhibitors (rivaroxaban, apixaban)
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3
Q

What is the function of warfarin?

A
  • Inhibits vitamin K1 2,3-epoxide reductase (prevents conversion of vitamin K epoxide to vitamin K, and conversion of vitamin K to vitamin K hydroquinone)
  • Inactivates factors VII, IX, X, and II (thrombin)
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4
Q

What are consequences of warfarin action?

A
  • Inhibits reduction of vitamin K
  • Reduces gamma-carboxylation of clotting factors (reduces activity of clotting factors)
  • Decreases production of new and active clotting factors II, VII, IX, and X
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5
Q

What is the function fo gamma-carboxyl glutamate?

A

Calcium chelator

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6
Q

Does warfarin have any effect on existing carboxylated clotting factors?

A

NOOO, they still remain active

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7
Q

How long does it take for warfarin to reach its full anticoagulant effect?

A

5 days b/c need to clear existing clotting factors

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8
Q

What are the uses of warfarin?

A
  • Prevent venous thromboembolism
  • Treat atrial fibrillation
  • Prevent clotting w/ prosthetic heart valves
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9
Q

What are side effects of warfarin?

A
  • Bleeding (major) – intracranial bleeding; incidence increases as tx duration and INR increase
  • Skin necrosis (rare)
  • Allergy
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10
Q

What is warfarin INR?

A
  • International normalized ratio

- Ratio of px prothrombin time to a control (prothrombin time measures the activity of factors I, II, VII, and X)

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11
Q

What does the INR value mean?

A
  • Normal untreated INR = 1
  • Typical tx target INR = 2-3
  • INR > 5 means overdose
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12
Q

What is needed to reach the target INR?

A

5 doses over 5 days

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13
Q

What is the antidote to warfarin?

A

Vitamin K or plasma (has clotting factors)

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14
Q

Which isomer of warfarin is more potent?

A

S

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15
Q

What is the S isomer of warfarin metabolized by?

A

CYP 2C9

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16
Q

What is the R isomer of warfarin metabolized by?

A

CYP 3A4, 1A2, and 2C19

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17
Q

Which drugs interact w/ warfarin?

A
  • ASA (decrease platelet function)
  • NSAIDs (GI ulceration)
  • Antibiotics (decreased gut vitamin K synthesis)
  • Cotrimoxazole (altered warfarin metabolism)
  • Acetaminophen, doses over 2g/day (interference w/ vitamin K cycle)
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18
Q

Which drugs will interact w/ warfarin and increase bleeding?

A
  • Metronidazole, macrolides, fluoroquinolones
  • Azole antifungals, fluconazole, miconazole
  • SSTI
  • Clopidogrel, ASA
  • NSAIDs, acetaminophen
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19
Q

What are some contraindications w/ warfarin?

A
  • Foods rich in vitamin K

- Crosses placenta and causes birth defects; doesn’t cross into breast milk

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20
Q

What are the types of thrombin inhibitors?

A
  • Direct or univalent (bind to active site of IIa; dabigatran, argatroban)
  • Bivalent (bind to active site and exosite; lepiruidin, bivalirudin)
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21
Q

Bivalirudin is a ____ inhibitor of IIa

A

Non-competitive

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22
Q

What does bivalirudin bind to?

A
  • IIa active site of fibrin-bound and free IIa to reduce platelet activation
  • Exosite 1
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23
Q

What is bivalirudin used for?

A

As an anticoagulent in px undergoing percutaneous coronary intervention, w/ heparin induced thrombocytopenia

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24
Q

Bivalirudin is usually used w/ ___

A

ASA

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25
Q

What is dabigatran etexilate?

A
  • Pro-drug for oral absorption (metabolized by esterases), but only absorbs in pH less than 3
  • Direct thrombin (IIa) inhibitor (binds to thrombin active site and prevents conversion of fibrinogen to fibrin)
  • Binds to free and fibrin bound thrombin => decreased platelet activation
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26
Q

Is the binding of dabigatran to thrombin reversible?

A

Yes

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27
Q

What are some drug interactions w/ dabigatran?

A
  • Other drugs effecting clotting (warfarin, heparin, rivaroxaban)
  • Anti-platelet aggregation (aspirin, NSAID, clopidogrel)
  • Contraindicated in pregnancy and breast feeding
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28
Q

What are uses of dabigatran?

A
  • Prevent venous thromboembolism following hip or knee replacement
  • Prevent atrial thrombus and subsequent stroke in atrial fibrillation
  • Alternative to warfarin (esp. if risk of stroke is high)
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29
Q

What are side effects of dabigatran?

A
  • Dyspepsia

- Bleeding/hemorrhage

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30
Q

What is argatroban?

A
  • Direct thrombin competitive inhibitor
  • Given as continuous IV infusion
  • Used in px w/ heparin-induced thrombocytopenia
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31
Q

What is AZD 0837?

A
  • Direct thrombin competitive inhibitor

- Has to be in a pro-drug form for absorption

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32
Q

What does benzamidine do?

A

Broad spectrum inhibitor of most serine proteases; acts as a mimic for guanidine group of arginine

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33
Q

What is important about benzamidine when used in inhibitors?

A
  • Fits in S1 site of IIa and Xa, producing potent inhibitors
  • Charged at physiological pH, drastically reducing absorption and necessitating formation of a pro-drug
  • Removal from IIa and Xa inhibitors reduces potency
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34
Q

What is rivaroxaban and apixaban?

A
  • Direct competitive Xa inhibitor
  • Used for prevention of venous thromboembolism in total knee or hip replacement surgery
  • Tx of venous thromboembolism or deep vein thrombosis, pulmonary embolism, and prevention of recurrent DVT and PE
  • Prevention of stroke and embolism in px w/ atrial fibrillation
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35
Q

What is the mechanism of clopidogrel, prasugrel, and ticagrelor?

A
  • Glycoprotein GPIb binds collagen via von Willebrand factor
  • Platelets “degranulate” releasing ADP
  • ADP binds type 2 purinergic receptors (P2Y12) => intracellular release of Ca+2 via IP3 by activation of Gaq
  • Ca2+ activates GP IIb/IIIa receptor complex, which binds fibrinogen => platelet aggregation
  • Clopidogrel and prasugrel alkylate P2Y12 receptor irreversibly, which inhibits P2Y12 preventing platelet aggregation
  • Ticagrelor is competitive antagonist of P2Y12 receptor
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36
Q

What is ticagrelor usually given w/?

A

ASA

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37
Q

What are the functions of H1 receptors around the body?

A
  • Lungs/GI – smooth muscle contraction
  • CNS – sleep wake regulation, vomiting
  • Vasculature – increase vascular permeability
  • Systemic – allergic response
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38
Q

What are the cellular effects of H1 receptors?

A
  • Increase phospholipase C, IP3, DAG, and intracellular [Ca2+]
  • Decrease K+ outflow
  • Result = excitation
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39
Q

H1 receptors are G alpha ___

A

q

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40
Q

H2 receptors are G alpha __

A

s

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41
Q

H3 receptor are G alpha __

A

i

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42
Q

What are the functions of H2 receptors around the body?

A
  • GI parietal cells – increase acid secretion
  • CNS – memory
  • Heart – increase force and heart rate (very minor)
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43
Q

What are the cellular effects of H2 receptors?

A
  • Increase adenylate cyclase and cAMP

- Result = excitation

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44
Q

What are the functions of H3 receptors?

A

In CNS, auto-receptor, presynaptic inhibition, and blocks histamine release

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45
Q

What are the cellular effects of H3 receptors?

A
  • Decrease cAMP and intracellular [Ca2+]
  • Increase K+ outflow
  • Result = inhibition
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46
Q

What is the function of histamine release?

A

To fight off parasitic infections

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47
Q

Which receptors primarily mediate the allergic histamine response?

A

H1 receptors

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48
Q

Which cells release histamine and in response to what?

A

Mast cells, in response to binding of allergens to IgE antibodies on mast cell surface

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49
Q

What effects are caused by histamine after it is released?

A
  • Increased nasal secretion and vascular permeability
  • Nasal congestion
  • Clear rhinorrhea (won’t be clear in a sinus infection)
  • Sneezing, itching, conjunctivitis
  • Postnasal drip => coughing
  • Wheals and flares (bumps w/ surrounding redness)
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50
Q

What is delayed-type hypersensitivity?

A
  • Mediated by CD8 cells
  • Manifests as a rash
  • Takes 48h post-contact to develop
  • Ex: exposure to poison ivy
  • Treated w/ glucocorticoids; cannot be treated w/ antihistamines
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51
Q

What is anaphylactic shock?

A
  • Causes life threatening bronchoconstriction w/ inability to breathe = medical emergency
  • Treated w/ adrenaline
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52
Q

What is the predominant form of histamine?

A

Nt-tautomer (mono-cation form at physiological pH 7.4; charged N is needed for interaction w/ negatively charged aa in H1 and H2 receptors)

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53
Q

What are antihistamines?

A

H1 receptor antagonists

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54
Q

What are the 2 classes of H1 antagonists?

A

1) First gen or classical antihistamines - have affinity for many other receptor groups producing additional pharmacological effects and side effects
2) Second gen or “non-sedating” antihistamines - more specific for H1 receptors and have less side effects

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55
Q

Why do second gen antihistamines cause less sedation?

A

Less hydrophobic and can’t cross BBB

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56
Q

What are uses of first gen antihistamines?

A
  • Tx of allergic response caused by release of histamine from mast cells
  • Common cold (usually used for drowsiness)
  • Hypnotics (ie for sleeping)
  • Motion sickness
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57
Q

What are side effects of first gen antihistamines?

A
  • Antimuscarinic and alpha adrenergic antagonist activity

- Sedation, dizziness

58
Q

What are the 5 types of first gen antihistamines?

A
  • Ethanolamines
  • Ethylenediamines
  • Piperazines
  • Alkylamines
  • Phenothiazines
59
Q

What are the different dosings of diphenhydramine used for?

A
  • 25 mg for antihistamine

- 50 mg for sleep aid

60
Q

What are side effects of diphenhydramine and dimenhydrinate?

A
  • Antiemetic activity
  • Antimuscarinic
  • Sedation
  • Alpha adrenergic antagonist activity
61
Q

Does dimenhydrinate or diphenhydramine have greater activity?

A

Same

62
Q

What is significant about the 8-chlorotheophylline on dimenhydrinate?

A

CNS stimulant like caffeine, so thought to counteract sedation of diphenhydramine (potent sedation results in an overall net mild sedation)

63
Q

What can increase affinity for H1 receptors?

A

N (sp2 hybridized) as part of an aromatic ring

64
Q

For histamine antagonists, do 2 pyridine groups increase potency over 1 pyridine and 1 benzyl?

A

No b/c one pyridine ring is already in the histamine imidazole binding site

65
Q

What is an advantage to ethylenediamines over other first gen antihistamines?

A

Exhibit similar sedation, but generally have less antimuscarinic side effects

66
Q

What can decrease the pKa of a nitrogen?

A

Attach it directly to an aromatic ring

67
Q

What are piperazines used for?

A
  • Prevention and tx of motion sickness

- Nausea and vomiting in general

68
Q

Which first gen antihistamines produce less sedation?

A

Alkylamines

69
Q

What effect do phenothiazines have on other analgesic and sedative drugs?

A

Increase their sedating effects

70
Q

Why do second gen antihistamines have long duration of action?

A

Form active metabolites w/ similar receptor binding profiles

71
Q

Why do second gen antihistamines have lower affinity for muscarinic and adrenergic receptors?

A

Affinity is reduced by the large polar or charged alkyl groups linked to the piperidine/piperazine rings

72
Q

What is the most sedating second gen antihistamine?

A

Cetirizine

73
Q

How are antihistamines metabolized?

A

Aromatic hydroxylation, N-oxydation, or N-dealkylation by CYP P450, except once by MAO

74
Q

What do PPIs act as?

A

Pro-drugs; only activated by acid secreted by parietal cells

75
Q

What are PPIs used for?

A

H. pylori eradication w/ antibiotics

76
Q

Are PPIs or H2 antagonists more effective for GERD?

A

PPIs

77
Q

What do PPIs do?

A

Inhibit transmembrane H+/K+ ATPase

78
Q

What is the rate of onset PPIs determined by?

A
  • pKa1 (nitrogen of pyridine ring)

- pKa2 (nitrogen of benzimidaole ring)

79
Q

Do all PPIs have the same mechanism?

A

Yes

80
Q

Where can uncharged omeprazole travel?

A

Into parietal cell from blood and then into gastric lumen where pH = 1-2

81
Q

Why can’t the predominant form of omeprazole cross the membrane into parietal cells?

A

Has a positive charge

82
Q

What is the first step to make active omeprazole?

A
  • Undergoes a series of rearrangement steps leading to the active form (uncharged)
  • *Can only happen in gastric lumen next to parietal cell and in close proximity to the H+/K+ ATPase; cannot happen in blood!
83
Q

Where does the active sulfenamide form of PPI occur?

A

In the low pH area immediately next to H+/K+ ATPase, so is the only protein that is alkylated

84
Q

What is the active sulfenamide form of PPIs?

A

Unstable form that is very reactive and can react w/ any exposed Cys SH on a protein (but doesn’t b/c is only produced in low pH)

85
Q

Ionized form of omeprazole displaces the equilibrium to the ___ side

A

Luminal

86
Q

PPI’s w/ a higher pKa1 will have a ____ onset of action

A

Faster

87
Q

What do ED pyridine ring substituents do to PPIs?

A

Increase alkalinity of the nitrogen and make it a better nucleophile

88
Q

Which substituents will increase rate of reaction most for PPIs?

A

Para substituents that are ED by resonance

89
Q

What does pKa1 determine?

A

The extent of ionization on the pyridine nitrogen (pKa1) dictates how much of the drug is sequestered at the site of action, which determines speed of onset

90
Q

What does pKa2 determine?

A

The rate of conversion of PPIs to the active sulfenamide

91
Q

A higher pKa2 means ____ protonation of the benzimidazole group and ___ onset

A

Faster; faster

92
Q

Which PPI converts to the protonated sulfenamide that slowest?

A

Pantoprazole

93
Q

What is significant about disulfide bonds in alkylated H+/K+ ATPase formed w/ PPIs?

A

Can exchange w/ endogenous sulfhydryl containing compounds such as GSH, Cys, and homocysteine (GSH most common)

94
Q

When is the alkylated H+/K+ ATPase inactive?

A

When disulfide forms w/ particular cysteines

95
Q

When is the H+/K+ ATPase active?

A

If GSH or another -SH compound removes the PPI

96
Q

What is significant about GSH w/ respect to PPIs?

A

Can remove PPI from H+/K+ ATPase, forming GS-S-PPI, restoring activity of H+/K+ ATPase

97
Q

What determines the duration of action from the point of recovery of acid secretion?

A

Cysteines in PPI’s and H+/K+ ATPase

98
Q

Which cysteines are in the proton transport domain of the H+/K+ ATPase?

A

Cys 321, 813, and 822

99
Q

What effect does disulfide formation w/ cys 892 have?

A

No effect on H+/K+ ATPase b/c not in the proton transport domain

100
Q

Alkylation of cys ___ cannot be reversed by GSH

A

822

101
Q

Which PPI has the longest half life for recovery of acid secretion and why?

A
  • Pantoprazole

- Binds to Cys 822, which is is difficult for GSH to cleave the PPI-enzyme disulfide bond to free the enzyme

102
Q

Which Cys is most easily reversed by GSH?

A

Cys 321

103
Q

All PPIs bind to Cys ___

A

813

104
Q

Which enantiomer of PPIs is less susceptible to metabolism by CYP 3A4?

A

(S)-enantiomer

105
Q

Which PPI is only the (S)-enantiomer and what does this mean for kinetics?

A
  • Omeprazole = racemic mixture
  • Esomeprazole = (S)-enantiomer (has decreased metabolism, which means increased bioavailability and increased circulating drug)
106
Q

What types of salts of PPIs are easier to form and why?

A

Na and Mg salts b/c PPIs are more stable in high pH environment (pH 7-10)

107
Q

Why are PPIs unstable in low pH?

A
  • If taken orally, PPIs will form active sulfenamide form in acid environment of stomach, and would alkylate any protein w/ exposed Cys or decompose rapidly
  • B/c there are many other proteins to alkylate and b/c the H+/K+ ATPase is not necessarily in close proximity, PPIs cannot act “topically” in the stomach but must be absorbed
108
Q

How do PPIs reach parietal cells if they are sensitive to low pH?

A
  • Formulated w/ enteric coating that protects drug from gastric acid and drug is only released when it reaches the intestine
  • Drug remains mostly unionized after release and is only protonated/activated at proton pump acid secretory site
109
Q

What should PPIs not be taken w/ and why?

A
  • Antacids

- May allow release of PPIs in the stomach

110
Q

How are liquid formulations of PPIs made?

A

1) Suspension of delayed release granules

2) Can mix omeprazole powder (or crushed tablets) in a 8.4% sodium bicarbonate solution

111
Q

What is a good predictor of the duration of activity for PPIs?

A

Half life for acid recovery better than half life of PPI

112
Q

How is omeprazole metabolized?

A
  • Hydroxylation by CYP 2C19
  • O-demethylation by CYP 2C19
  • Sulfone metabolite by CYP 3A4 (all PPIs do this)
113
Q

Which drugs do PPIs interact w/?

A
  • Azole antifungals (inhibit metabolism of PPIs and PPIs decrease absorption of ketoconazole)
  • Macrolide antibiotics (inhibit PPI metabolism)
  • Warfarin (PPIs increase warfarin effects)
  • Digoxin
  • BZDs (PPIs increase plasma levels of BZDs)
114
Q

What are PPIs used for?

A
  • GERD tx
  • Combined w/ NSAIDs to prevent NSAID-associated ulceration of GI
  • Part of “triple therapy” for treatment of ulcers caused by H. pylori
115
Q

What effect does ACh have w/ respect to gastric acid?

A

Increase mucosal defences and increase HCl

116
Q

What does gastrin do?

A

Increases HCl

117
Q

Is histamine the only signal that increases production of gastric acid?

A

No

118
Q

What is the effect of prostaglandins w/ respect to gastric acid and which prostaglandins have this effect?

A
  • Increase mucosal defences and decrease HCl

- PGE2 and PGI2

119
Q

What are the important cells of the stomach and what does each do?

A
  • Superficial epithelial cells – produce mucus
  • Chief cells – produce digestive enzymes
  • Parietal cells – produce HCl
  • G cells – produce gastrin
  • Enterochromaffin-like cells – release histamine (this only happens in the GI)
120
Q

What occurs when histamine enters the H2 ligand binding site?

A
  • H-bond interactions btwn NH and Asp as well as btwn N and Thr
  • Ionic bond interactions btwn Asp and NH3+
121
Q

What change can be made when histamine enters the H2 ligand binding site if you want an antagonist?

A

Don’t want an ionic bond interaction

122
Q

____ within the H2 receptor is critical for formation of the ligand receptor complex

A

Tautomerism

123
Q

Which tautomer of histamine is required for initial binding to the H2 receptor?

A

Nt tautomer

124
Q

What effect does increased Nt tautomer have?

A

Increased affinity for H2 receptor over H1

125
Q

Which characteristics of histamine produce affinity for the H2 receptor?

A
  • 4-methyl group retains H2 affinity while nearly eliminating H1 affinity
  • 2 nitrogen’s in the 1 and 3 positions adjacent to the point of attachment of the amino ethyl group (side chain) produces some affinity for H2
126
Q

Which characteristics of histamine produce affinity for the H1 receptor?

A
  • 2-methyl group retains some H1 affinity while nearly eliminating H2 affinity b/c produces 50:50 ratio of Nt:N-pi tautomers
  • N in the aromatic ring immediately adjacent to side chain needed for affinity for H1
  • 2 methyl groups on the R2 N retain the most affinity for H1 receptors (3 methyl groups, making a quaternary amine, eliminate affinity for H1 and H2 receptors)
127
Q

What makes guanylhistamine a partial H2 agonist?

A

Can bind to 2 sites w/in the H2 receptor, an agonist and antagonist site

128
Q

What is the difference btwn a positive charged guanidine group on histamine vs. a neutral uncharged guanidine group on histamine w/ respect to agonists and antagonists?

A
  • Positive charged guanidine would always be a partial agonist b/c it would bind to the agonist binding site
  • Neutral uncharged guanidine would be capable of forming H-bond w/ antagonist binding site but would be incapable of forming an ion pair w/ agonist binding site, making it a pure antagonist
129
Q

What effect does side chain length have on H2 antagonism?

A

Increasing side chain length increases binding w/ antagonist bind site, producing a pure antagonist

130
Q

How can you improve potency of an H2 antagonist?

A

Add CH3 group to position 4, which increase proportion of Nt tautomer and increases H2 affinity

131
Q

What can be added to a molecule to decrease the pKa of a guanidine group?

A

CN (triple bond) b/c it is strongly EW

132
Q

What is cimetidine used for? Why isn’t it available OTC in Canada?

A
  • Tx of GERD b/c inexpensive

- Has many drug interactions b/c of imidazole ring and subsequent CYP inhibition

133
Q

What is the effect of cimetidine’s CYP inhibition?

A

Inhibits CYP enzymes, so drugs that are metabolized by CYP have delayed elimination and increased serum concentration

134
Q

What are the major drug interactions w/ cimetidine?

A
  • Carbamazepine
  • Pentoxifylline
  • Phenytoin
  • Propafenone
  • Theophylline
  • Warfarin
135
Q

What are some side effects of cimetidine?

A
  • Anti-androgenic activity leading to gyneomastia

- Diarrhea, dizziness, rash (also w/ other H2 antagonists)

136
Q

How is cimetidine metabolized?

A
  • Aliphatic hydroxylation by CYP P450

- S-oxidation by CYP P450

137
Q

What are the uses and side effects of ranitidine, famotidine, and nizatidine?

A
  • Used as a cheap alternative to PPI’s for tx of GERD, though not as effective as PPI’s
  • Diarrhea and dizziness are chief side effects
138
Q

How is ranitidine metabolized?

A
  • S-oxidation by CYP
  • N-oxidation by CYP
  • N-dealkylation by CYP
139
Q

Which is the most potent and polar H2 antagonist?

A

Famotidine

140
Q

What effects do NO2 and sulfonamide have on the planar, polar, neutral H-bonding group of H2 antagonists?

A

Both reduce pKa of planar, polar, neutral H-bonding group

141
Q

Are H2 antagonists ever used over PPI’s?

A

Nope, PPI’s are first line and H2 antagonists are second line