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Flashcards in Drugs With Important Actions On Smooth Muscle Deck (187):
0

What is an autacoid?

Endogenous molecules with powerful pharmacologic effects that do not fall in the traditional autonomic groups.

1

What are the two most important amine autacoids?

Histamine and serotonin (5-hydroxytryptamine)

2

What are the ergot alkaloids (not autacoids)?

An heterogeneous group of drugs that interact with serotonin receptors, dopamine receptors, and α receptors.

3

Where is histamine stored?

In vesicles :
1. Mast cells
2. Enterochromaffin cells in the gut
3. Some neurons

4

How is histamine metabolized?

By the enzymes :
1. Monoamine oxidase
2. Diamine oxidase

5

How can excess of histamine in the body be detected?

By measurement of its major metabolite :
Imidazole acetic acid, in the urine.

6

What is the pathophysiologic role of histamine?

IgE mediated responses :
1. Seasonal rhinitis (hay fever)
2. Urticaria
3. Angioneurotic edema

7

What are the receptors for histamine?

4 receptors :
1. H1 and H2 mediate most of the peripheral actions.
2. H3 and H4 have also been identified.

8

What is the triple response?

Mediated mainly by H1 and H2 :
1. Small red spot at the center of an intradermal injection of histamine.
2. Surrounded by a red edematous wheal.

9

What G protein does the H1 receptor utilize?

Gq coupled - important in smooth muscle effects - IgE mediated responses.

10

What G protein does H2 receptor utilize?

Gs coupled - mediates gastric acid secretion by parietal cells in the stomach.

11

What G protein does the H3 receptor utilize?

Gi coupled - presynaptic modulation of histaminergic neurotransmission in the CNS.

12

What G protein does the H4 receptor utilize?

Gi coupled - it is located on the leukocytes (especially eosinophils) and mast cells : chemotactic responses by these cells.

13

Is there any clinical application of histamine ?

No - only for the H1 and H2 blockers.

14

What are the first generation H1 blockers?

1. Diphenhydramine (prototype)
2. Chlorpheniramine
3. Cyclizine

15

What are the major second generation H1 blockers?

1. Cetirizine
2. Fexofenadine
3. Loratadine

16

How are the H1 administered ?

Orally

17

What is the half life of the older H1 blockers ?

4-12h

18

What is the half life of second generation H1 blockers?

12-24h

19

What is the mechanism of action of H1 blockers?

Competitive antagonists at the H1 receptor - no effect on histamine release from storage sites. (More effective if given before histamine release occurs)

20

What resembles the structure of many of the first generation H1 blockers?

The structure of M blockers and α blockers - so the first generation H1 blockers are potent antagonists at these ANS sites.

21

What is the major application of H1 blockers?

In allergies (type I) (hay fever, urticaria etc.)

22

What H1 blockers are used as anti motion sickness drugs?

1. Diphenhydramine
2. Dimenhydrinate
3. Cyclizine
4. Meclizine
5. Promethazine

23

What H1 blocker is also used for the management of chemotherapy-induced vomiting?

Diphenhydramine

24

With what H1 blockers is sedation common?

1. Diphenhydramine
2. Promethazine

25

What antimuscarinic effects may the old H1 blockers have?

1. Dry mouth
2. Blurred vision

26

Which H1 blocker can cause orthostatic hypotension?

Promethazine - through α-adrenoceptor blockade.

27

What are the 4 major H2 blockers that are available?

1. Cimetidine (prototype)
2. Ranitidine
3. Famotidine
4. Nizatidine

28

How are the H2 blockers administered?

Orally

29

What is the half life of H2 blockers?

1-3h

30

Why can H2 blockers be given in large doses?

Because they all are relatively nontoxic.

31

What is the mechanism of action of H2 blockers?

Surmountable pharmacologic blockade of H2 receptors. Relative selective.

32

What is the main therapeutic effect of H2 blockers ?

The reduction of gastric acid secretion.

33

What is the clinical use of H2 blockers?

1. In acid-peptic disease.
2. In gastric peptic ulcers.
3. IV H2 blockers are useful in preventing gastric erosions and hemorrhage that occur in stressed patients in IC units.
4. In Zollinger-Ellison syndrome/GERD : but proton pump inhibitors are preferred.

34

What is the toxicity of cimetidine?

1. Potent inhibitor of hepatic drug metabolizing enzymes.
2. May also reduce hepatic blood flow.
3. Significant antiandrogen effects in high doses.

35

What is the "root" of serotonin?

Tryptophan

36

Where is serotonin stored?

In vesicles :
1. Enterochromaffin cells of gut.
2. Neurons of the CNS (neurotransmitter).
3. Neurons of enteric nervous system (as a local hormone).
4. Platelets

37

How is serotonin metabolized?

By MAO

38

How can excess of serotonin be detected?

By measuring its major metabolite : 5-HIAA in the urine.

39

How many serotonin receptors have been identified?

14

40

In clinical use, where do most of the serotonin agonists act?

At 5-HT(1D) receptor.

41

What G protein does the 5-HT1 receptor utilize?

Gi coupled :
In the brain : mediate synaptic inhibiton via increased K conductance.
Peripheral : excitatory/inhibitory effects in various smooth muscle tissues.

42

What is the main action mediated by 5-HT2 receptors?

Synaptic excitation in the CNS and smooth muscle contraction (gut, bronchi, uterus, some vessels) or relaxation (other vessels).

43

Where are 5-HT3 mainly found?

1. In the CNS : chemoreceptive area and vomiting center.
2. In the peripheral sensory and enteric nerves.

44

What category of drugs act at 5-HT3 receptors ?

Antiemetic drugs.

45

Where are the 5-HT4 receptors found?

In the GI tract - role in intestinal motility.

46

Has serotonin a clinical application?

NO!

47

What is the prototype 5-HT(1D) agonist?

Sumatriptan

48

For what conditions are 5-HT(1D) the first line of treatment?

1. Acute migraine
2. Cluster headache attacks

49

How are 5-HT(1D) agonists administered?

Orally - yet sumatriptan is also available for nasal and parenteral administration.

50

What is the major 5-HT4 partial agonist?

Tegaserod

51

What is the main clinical use of Tegaserod?

It was approved for use in chronic constipation (restricted because of CVS toxicity).

52

With what syndromes are sometimes serotonin agonists associated ?

Hyperpyrexic syndromes :
1. High fever
2. Skeletal muscle effects
3. CVS abnormalities

53

Mention 3 effective 5-HT2 blockers?

1. Ketaserin
2. Phenoxybenzamine
3. Cyproheptadine

54

Mention 4 effective 5-HT3 blockers.

1. Ondasetron
2. Granisetron
3. Dolasetron
4. Alosetron

55

What is the mechanism of action of ketanserin and cyproheptadine?

Competitive 5-HT2 blockers

56

What is the mechanism of action of phenoxybenzamine?

Irreversible 5-HT2 blocker

57

Are ketanserin, cyproheptadine, and phenoxybenzamine selective agents?

No, they are poorly selective.
Other actions include α-blockade (ketanserin, phenoxybenzamine) or H1-blockade (cyproheptadine).

58

What is the mechanism of action of ondasetron, granisetron, and dolasetron?

Selective 5-HT3 blockers.
Important antiemetic effects.
(Alosetron appears to lack these antiemetic effects.)

59

What is the clinical use of ketanserin outside the USA?

As a hypertensive drug.

60

What can ketanserin, cyproheptadine, and phenoxybenzamine help to treat?

Carcinoid tumor :
Neoplasm that secretes large amounts of serotonin - diarrhea, bronchoconstriction and flushing.

61

What is the clinical use of ondasetron and its congeners?

Useful in the control of vomiting with cancer chemotherapy and post operative vomiting.

62

What is the clinical use of alosetron?

Used in the treatment of women with irritable bowel syndrome associated with diarrhea.

63

What are the main adverse effects of ketanserin?

1. α blockade
2. H1 blockade

64

What are the main toxicities of ondasetron, granisetron, and dolasetron?

1. Diarrhea
2. Headache

65

What other toxicity has dolasetron been associated with?

QRS and QTc prolongation - contraindicated in patients with heart disease.

66

What is the toxic effects of alosetron?

1. Significant constipation
2. Fatal bowel movement complications

67

What is the mechanism of action of most ergot alkaloids?

Partial agonists at :
1. α receptors
2. 5-HT receptors
Some are also potent dopamine agonists.

68

What is the main classification of ergot alkaloids?

Into 3 subgroups based on the organ or tissue in which they have their primary effects. (Vessels, uterus, brain)

69

What is the action of ergot alkaloids on vessels?

They can produce marked and prolonged α-receptor mediated vasoconstriction.

70

What is the prototype ergot alkaloid that acts on vessels?

Ergotamine

71

In what else can ergotamine be used?

In epinephrine reversal, because it acts as a partial agonist (α-receptor).

72

What do the ergot alkaloids cause on uterus?

Powerful contraction

73

What is the prototype ergot alkaloid that causes uterine contraction?

Ergonovine

74

What can LSD (lysergic acid diethylamide) cause on the brain?

Prominent hallucinations

75

What is the mechanism of action of LSD?

1. It is a potent 5-HT2 blocker in peripheral tissues.
2. Actions in the CNS thought to be due to agonists at dopamine receptors.

76

What can some ergot alkaloids cause in the pituitary?

Inhibition of prolactin (dopaminergic effect) - bromocriptine and pergolide.

77

What is the clinical use of ergotamine?

In migraines : acute attacks with caffeine.

78

What ergot alkaloids have been used for migraine prophylaxis?

1. Methysergide
2. Dihydroergonovine
3. Ergonovine

79

What other clinical use do ergotamine/ ergonovine have (besides migraine prophylaxis)?

Reduction of postpartum bleeding.

80

What other clinical uses do bromocriptine and pergolide have?

1. Used to reduce prolactin secretion (pituitary tumors)
2. Parkinson.

81

What are the toxic effects of ergot alkaloids in the vasculature?

Severe prolonged vasoconstriction :
1. Ischemia
2. Gangrene

82

When used for long periods, what ergot alkaloid toxicity can occur in the vessels?

Unusual hyperplasia of connective tissue (fibroplasia).
Retroperitoneal - retropleural - subendocardial.

83

What other toxic effects do the ergot alkaloids have, other than vascular effects?

1. GI upset
2. Marked uterine contractions
3. CNS effects : hallucinations resembling psychosis (LSD and methysergide)

84

What are the major effects of ANGII?

1. "Classic" effects
2. Facilitates the release of NE from the adrenergic nerve endings via presynaptic heteroreceptor action.
3. Also AT2 receptor : vasodilation via NO during fetal development.
4. Also mitogenic - role in cardiac remodeling.

85

What is the major vasopeptidase inhibitor?

Omapatrilat : block both neutral endopeptidase 24.11 and ACE.

86

How is bradykinin produced?

From kininogen by a family of enzymes, the kallikreins.
Rapidly degraded by various peptidases, including ACE.

87

How is the action of bradykinin mediated?

Through its 2 receptors : B1 and B2 - IP3 + DAG, cAMP, NO, PGs.

88

What are the main actions of bradykinin?

1. Vasodilation
2. Inflammation : edema and pain.
3. Saliva : major role in stimulating secretion.

89

Where may bradykinin play an important role?

1. In the antihypertensive action of ACE inhibitors.
2. In hereditary angioedema

90

What anti-bradykinin drugs have been approved?

1. Ecallantide (kallikrein inhibitor)
2. Icatinant (B2 blocker)
Used in angioedema.

91

What are the two main natriuretic peptides?

1. ANP
2. BNP
3. C-type natriuretic peptide.

92

Where are the two natriuretic peptides synthesized and stored?

In the cardiac atria (BNP also from brain tissue).

93

What are the major effects of natriuretic peptides?

1. Vasodilators as well as natriuretic agents.
2. Increased GFR
3. Decreased Na reabsorption
4. Inhibitory effects on renin
5. Inhibition on ANGII and aldosterone

94

What is the serious condition in which BNP can be used as a diagnostic marker?

CHF

95

What is the "BNP drug" that is approved for acute HF?

Nesiritide (significant toxicity)

96

What are the endothelins?

Peptide vasoconstrictors formed in and released by endothelial cells in blood vessels.

97

How many endothelins have been identified?

ET1, ET2, and ET3.

98

How many endothelin RECEPTORS have been identified?

ETa and ETb (G-protein coupled).

99

What is the endothelin receptor responsible for the vasoconstriction produced by endothelin?

The ETa receptor.

100

What are the major effects of endothelins?

1. More vasoconstriction than NE.
2. Relatively long lasting effect.
3. Stimulate the heart + increase NP release.
4. Activate smooth muscle proliferation.

101

In what disorders may endothelins be involved?

1. Forms of hypertension
2. Other CVS disorders

102

Mention 2 major ETa blockers used in pulmonary hypertension?

1. Bosentan
2. Ambrisentan

103

What is the VIP?

Vasoactive instestinal peptide - extremely potent vasodilator : more important as a neurotransmitter. Found in CNS and GI tract.

104

What are the major neurokinins?

1. Substance P
2. Neurokinin A
3. Neurokinin B

105

What are the main neurokinin receptors?

NK1 and NK2 receptors in the CNS and periphery.

106

What are the vascular effects of substance P?

Mixed vascular effects :
1. Potent arteriolar dilator
2. Stimulant of veins/intestinal/airway smooth muscle.

107

Is substance P found in the GI tract?

Yes - local hormone.

108

Is substance P found in the CNS?

Yes - higher concentrations are found in neurons subserving pain.

109

What does Capsaicin? (Hot component of chili peppers)

Releases substance P from its stores in nerve endings and depletes the peptide.
Has been APPROVED for topical use on arthritic joints and post herpetic neuralgia.

110

What the action of aprepitant?

Oral NK1 blocker : approved for chemo induced vomiting and nausea.

111

Where is CGRP mainly found?

1. Thyroid
2. Most smooth muscle tissues

112

What is the major action of CGRP ?

Most potent hypotensive agent found to date. Causes reflex tachycardia.

113

What is the neuropeptide Y?

A potent vasoconstrictor peptide that also stimulates the heart.

114

What are the eicosanoids?

An important group of endogenous fatty acid autacoids that are produced from arachidonic acid.

115

What are the two major subgroups of eicosanoids?

1. Leukotrienes (straight-chain derivatives).
2. Prostacyclin, prostaglandins, and thromboxane (cyclic derivatives).

116

Where do we find COX1?

In many tissues - PGs produced from COX1 appear to be important for a variety of physiologic processes.

117

Where do we find COX2?

In inflammatory cells (primarily).

118

Besides inflammatory functions, what other functions is COX2 responsible for?

1. Synthesis of prostacyclin.
2. Synthesis of PGs important in renal function.

119

Where is preferentially Tx and prostacyclin synthesized?

1. Tx : platelets.
2. Prostacyclin : endothelial cells.

120

What is the half life of eicosanoids?

Seconds to minutes - inactive when given orally.

121

What are the eicosanoids most directly involved in pathologic processes?

1. PGF2a
2. TXA2
3. LTC4 and LTD4 (slow-reacting substance of anaphylaxis SRS-A).

122

What is the role of PGs on the renal function?

Important modulators of GFR :
Act on the afferent and efferent arterioles, and mesangial cells.
NSAIDs with diuretics = reduced efficacy of diuretics...

123

What is the clinical use of PGE2 (dinoprostone) and PGF2a?

In obstetrics :
Cause contraction of the uterus.
PGE2 : approved for use to soften the cervix before induction of labor by oxytocin.
Both have been used as abortifacients.

124

What are the possible adverse effects of PGE2 and PGF2a?

1. Nausea
2. Vomiting
3. Diarrhea

125

Describe an extremely effective and safe abortifacient combination.

PGE2 analog (misoprostol) + progesterone blocker (mifepristone)

126

What is the clinical use of PGs in pediatrics?

PGE1 : given to maintain patency of the ductus arteriosus in infants with transposition of the great arteries, till surgery.

127

What is the clinical use of PGs in pulmonary hypertension and dialysis?

Prostacyclin (PGI2) is approved for use (epoprostenol) in SEVERE pulmonary hypertension + to prevent platelet aggregation in dialysis machines.

128

What is the clinical use of PGs in peptic ulcer associated with NSAID use?

PGE1 analog (misoprostol) : prevention of peptic ulcers in patients taking high doses of NSAIDs for arthritis and have history of peptic ulcers.

129

What is the clinical use of PGs in ophthalmology ?

1. Latanoprost (PGF2a derivative) - used for glaucoma.
2. Bimatoprost
3. Travoprost
4. Unoprostone
Increase the outflow of aqueous humor - reducing intraocular pressure.

130

What is the action of zileuton?

A selective inhibitor of lipoxygenase.

131

Mention two blockers of the LTD4 receptor used in the treatment of asthma.

1. Zafirlukast
2. Montelukast

132

What is the main inhibitory action of corticosteroids?

Inhibit the production of arachidonic acid by phospholipases in the membrane. Also inhibit the synthesis of COX2.

133

What is the main effect of NSAIDs?

Inhibition of cycloxygenase and the production of the thromboxane, prostaglandins, and prostacyclin. (Most inhibit inselectively both COX1 and COX2)

134

Mention some selective COX2 inhibitors.

1. Celecoxib
2. Meloxicam (slightly selective)
3. Rofecoxib
4. Valdecoxib
Last 2 withdrawn due to CVS toxicity.

135

Where is aspirin allergy more common?

For unknown reasons, in people with nasal polyps.

136

Where does the antiplatelet action of aspirin stem from?

Permanent drug inhibition of TX synthesis. Platelets cannot produce new enzymes (in contrast to inhibition of PGI2 synthesis in the endothelium).

137

Where are zileuton, zafirlukast, and montelukast primarily used?

In asthma.

138

What is NO?

An autacoid produced by arginine in the body + the active metabolite of the drugs that release it (NO donors).

139

How is endogenous NO synthesized?

By a family of enzymes collectively called nitric oxide synthase (NOS).

140

How can NOS be inhibited?

By arginine analogs such as N(g)-monomethyl-L-arginine (L-NMMA)

141

Is NO stored ?

NO! Because it is a gas at body temperature, it very rapidly diffuses from its site of synthesis to the surrounding tissues.

142

What drugs stimulate the production of NO?

1. M agonists
2. Histamine
3. Certain vasodilators (bradykinin, hydralazine).

143

Mention some important drugs that release NO.

1. Nitroprusside
2. Nitrates
3. Nitrites

144

How is NO released from nitroprusside?

Spontaneously in the blood in the presence of oxygen.

145

How is NO released from nitrites and nitrates?

Intrecellularly : requires the mitochondrial enzyme ALD2 and thiol compounds such as cysteine.

146

What is the second messenger induced by NO?

cGMP (Not cAMP)

147

What is the effect of NO in cell adhesion?

1. Reduced platelet aggregation
2. Reduced platelet adhesion

148

What is the effect of NO in inflammation?

Tissue injury causes NO synthesis and NO appears to facilitate inflammation both directly and through stimulation of PG synthesis by COX2.

149

What other effects is NO suspected to have?

1. Action as a neurotransmitter.
2. Involved in some types of apoptosis.

150

How is acute bronchospasm treated in asthma?

With :
1. β2 agonists
2. M blockers
3. Theophylline and derivatives.

151

What requires the long term preventing treatment in asthma?

Anti-inflammatory drugs :
1. Corticosteroids
2. Long acting β2 agonists
3. Anti-IgE antibodies

152

What drugs have effects on both bronchoconstriction and inflammation but are used only for prophylaxis?

The leukotrienes blockers.

153

Mention some important short acting β2 agonists used in asthma.

1. Albuterol
2. Terbutaline
3. Metaproterenol

154

Mention some important long acting β2 agonists used in asthma.

1. Salmeterol
2. Formoterol
3. Indicaterol (only for COPD)

155

How are the β2 agonists administered in asthma?

By inhalation

156

What is the half life of the older and the new β2 agonists used in asthma?

Old : 6h or less.
New : 12-24h.

157

What is the mechanism of action of β2 agonists used in asthma?

Increase in cAMP in smooth muscle cells - powerful bronchodilator response.

158

What is the first line of treatment in acute asthma ?

Sympathomimetics (β2 agonists)

159

What happens when long lasting β2 agonists are used alone?

They increase asthma mortality - should be used in combination with corticosteroids.

160

What are the adverse effects of β2 agonists given in asthma?

1. Skeletal muscle tremor.
2. Even by inhalation, some cardiac effect if common (tachycardia - when given in high doses, there is also some β1 selectivity.)

161

What can increase the risk of arrhythmias in patients with asthma, when they being given β2 agonists?

COPD with concurrent cardiac disease.

162

What are the three most common methylxanthines that are found in plants?

1. Caffeine (in coffee)
2. Theophylline (in tea)
3. Theobromine (cocoa)

163

What is the only methylxanthine that is important in the treatment of asthma?

Theophylline

164

How is theophylline metabolized?

In the liver, by P450 drug metabolizing enzymes.

165

When is theophylline clearance higher?

1. In young adolescents
2. In smokers
3. Other drugs that induce hepatic enzymes.

166

What is the main mechanism of theophylline action?

1. Inhibition of phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP. (High doses required)
2. Also block adenosine receptors in the CNS and elsewhere.

167

In asthma, what is the most important therapeutic action of theophylline?

Bronchodilation

168

Besides bronchodilaton, what other effects does theophylline have?

1. CNS stimulation
2. Cardiac stimulation
3. Vasodilation
4. Slight increase in BP
5. Diuresis
6. Increased GI motility

169

What the main clinical use of methylxanthines?

In asthma and COPD.

170

What is the most commonly used methylxanthine in asthma?

Slow-release theophylline (for control of nocturnal asthma).

171

What salt of theophylline is usually prescribed for asthma?

Aminophylline

172

Mention some important adverse effects of methylxanthines.

1. GI distress
2. Tremor
3. Insomnia
4. Severe nausea
5. Vomiting
6. Hypotension
7. Arrhythmias

173

What is used to reverse the severe cardiovascular toxicity from theophylline OD?

β blockers.

174

What are the main muscarinic blockers that are used in asthma?

1. Ipratropium
2. Tiotropium

175

How is ipratropium administered?

Orally, in aerosol form - little systemic action.

176

What is the difference between ipratropium and tiotropium?

Tiotropium is a longer-lasting analog.

177

When given orally, what is the mechanism of action of ipratropium and tiotropium?

Competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge.

178

When given systemically (NOT APPROVED), what is the mechanism of action of ipratropium and tiotropium?

They are indistinguishable from other short acting M blockers.

179

What are the main effects of ipratropium and tiotropium?

1. Reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD.
2. No effect on the chronic inflammatory aspects of asthma.

180

What percentage of the asthmatics responds to ipratropium and tiotropium? (For acute bronchospasm)

1/3-2/3. β2 agonists are effective in almost all.

181

What is the main difference between β2 agonists and antimuscarinic agents used in asthma regarding their toxicity?

In contrast to β2 agonists, M blockers do not cause tremor or arrhythmias.

182

What is the main characteristic of cromolyn and nedocromil?

They are unusually insoluble chemicals, so that even massive doses given orally or by aerosol result in minimal systemic levels.
Now rarely used for asthma in the USA.

183

When do we use corticosteroids in the treatment of asthma?

Because of their toxicity, only chronic use, when other therapies are unsuccessful (prednisone).

184

What is the first line therapy for patients with moderate to severe asthma?

Surface active corticosteroids via inhalation.

185

Mention some relatively safe surface active corticosteroids that are used as first line treatment in moderate to severe asthma?

1. Beclomethasone
2. Budesonide
3. Dexamethasone
4. Flunisolide
5. Fluticasone
6. Mometasone

186

What are the corticosteroids used for status asthmaticus?

1. Prednisolone (active metabolite of prednisone)
2. Hydrocortisone

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