Core Ii Pharmacology

Front 1

What is an autacoid?

What are the major ones with which we are concerned?

Back 1

An autacoid is a locally acting hormone.

We are concerned with eicosanoids (thromboxanes, prostaglandins, leukotrienes) and platelet activating factor (PAF).

Front 2

How are eicosanoids stored?

Back 2

They are not stored- they are produced and released as needed.

Front 3

Where is prostacyclin synthesized?

Where is thromboxane synthesized?

Back 3

Prostacyclin is produced in endothelial cells.

Thromboxane is produced by platelets.

Front 4

What drug might be used to suppress COX-2 expression?

What enzyme must it inhibit to do this?

Back 4

Glucocorticoids (ie: dexamethasone) suppress COX-2 expression by inhibiting phospholipase A2.

Front 5

What drugs inhibit all three COXes?

Back 5

Aspirin irreversibly inhibits COXes, and other NSAIDS reversibly inhibit.

Front 6

What response is COX-2 involved in?

What selective antagonists inhibit COX-2 action?

Back 6

COX-2 is involved in the local inflammatory response, but not in the GI tract or kidney.

It is selectively antagonized by Celecoxib and Rofecoxib.

Front 7

Name a COX-3 selective antagonist.

What effects does this have or not have?

Back 7

Acetaminophen is a COX-3 inhibitor. It blocks pain and fever, but has no effect on platelets or inflammation.

Front 8

What drug blocks 5-LOX? What three conditions did this successfully treat in trials?

Back 8

Zileuton blocks 5-LOX. It treats ulcerative colitis, asthma, and allergic rhinitis.

Front 9

What is the signaling function of PGD2 and PGI2?

Back 9

PGD2 and PGI2 activate adenylate cyclase.

Front 10

What is the signaling function of PGE?

Back 10

PGE either activates or inhibits adenylate cyclase.

Front 11

What is the signaling function of PGF2, TXA2, and LTD4?

Back 11

PGF2, TXA2, and LTD4 all activate PLC and increase cytosolic calcium.

Front 12

List how each of the following acts on the cardiovascular system: PGE1/2, PGI2, PGF2α, TXA2, LT.

Back 12

PGE1/2: vasodilation

PGI2: vasodilation

PGF2α: vasoconstriction of pulmonary arteries and veins

TXA2: vasoconstriction of pulmonary arteries and veins

LT: endothelial contraction leading to lower blood volume by exudation (1000X histamine potency)

Front 13

List how each of the following acts on the blood: PGE1, PGI2, TXA2, LTB4.

Back 13

PGE1: inhibits platelet aggregation

PGI2: inhibits platelet aggregation

TXA2: induces platelet aggregation (action can be blocked by aspirin inhibition of COX)

LTB4: chemotactic agent for PMNS, eosinophils and monocytes

Front 14

List how each of the following acts on the renal system: PGE1, PGI2, PGEs

Back 14

PGE1 stimulates diuresis.

PGI2 stimulates secretion of renin.

All PGEs inhibit water reabsorption by antidiuretic hormone.

Front 15

List how each of the following acts on the GI tract: PGE1/2, PGF2α, PGI2, PGFs, LT.

Back 15

PGE1/2 contract longitudinal muscles and inhibit gastric acid secretion but promote mucus secretion, as well as stimulating water movement into the intestinal lumen. PGE2 relaxes circular muscle.

PGF2α contracts circular muscles and stimulates water movement into the intestinal lumen.

LT contract gastrointestinal smooth muscle.

PGI2 inhibits gastric acid secretion.

Front 16

List how each of the following acts on bronchial smooth muscle: PGE1/2, PGI2, PGF2α, TXA2, LTC4, LTD4.

Back 16

PGE1/2 relax bronchial smooth muscle.

PGI2 relaxes bronchial smooth muscle.

PGF2α contracts bronchial smooth muscle.

TXA2 contracts bronchial smooth muscle.

LTC4 and LTD4 are extremely potent bronchoconstrictors and also induce bronchial edema.

Front 17

List how each of the following acts on the uterus: PGE1/2, PGF2α, TXA2, PGI2.

Back 17

PGE1/2 contract uterine muscle. PGE2 may cause abortion.

PGF2α contracts uterine muscle and may cause abortion.

TXA2 contracts uterine muscle.

PGI2 relaxes the uterus.

Front 18

List how each of the following acts on the CNS: PGE1/2, PGD2, PGI2, LTB4.

Back 18

PGE1/2 increase body temperature (prevented by aspirin) and sensitize afferent nerves to noxious stimuli.

PGD2 induces natural sleep.

PGI2 sensitizes afferent nerves to noxious stimuli.

LTB4 produces hyperalgesia.

Front 19

Name four non-selective COX1-2 inhibitors.

Describe their four major physiological actions.

Back 19

Aspirin/acetylsalicylic acid
Indomethacin
Ibuprofen
Naproxen

Anti-inflammatory, anti-pyretic, analgesic, anti-platelet aggregation.

Front 20

What is a common adverse effect of NSAIDS?

Back 20

Gastric irritation and bleeding

Front 21

What are two important drug interactions of NSAIDS?

Back 21

1. NSAIDS potentiate the effects of anticoagulants with their non-platelet aggregation effects.
2. They may reduce the effects of diuretics and anti-hypertensive agents.

They also may affect other drugs because they bind to plasma proteins.

Front 22

In what condition are COX-2 selective inhibitors indicated?

What is a significant adverse effect?

Back 22

Selective COX-2 inhibitors are indicated for arthritis.

They may elevate MI risk by 2-5X, because COX-1 production of thromboxane may proceed, uninhibited.

Front 23

Name a LOX inhibitor.

In what conditions is it useful?

Back 23

Zileuton is a LOX inhibitor.

It is useful in allergic reaction and asthma because it is a bronchodilator.

Front 24

Name a LT receptor antagonist.

In what condition is it useful?

Back 24

Zafirlucast is a LT receptor antagonist.

It is useful in treating asthma because it is a bronchodilator.

Front 25

Name two PGE1 analogs, their uses, and their side effects.

Back 25

1. Alprostadil: vasodilator, inhibits platelet aggregation, used to maintain patency of ductus arteriosus in certain congenital heart conditions, treats erectile dysfunction. Side effects include bradycardia, hypotension, fever, ductal fragility, pain, and priapism.
2. Misoprostol: prevents gastric ulcers. Side effects include abdominal pain and diarrhea. Contraindicated in pregnancy.

Front 26

Name a PGE2 analog, its uses, and its side effects.

Back 26

Dinoprostone: facilitates labor/ induces abortion by promoting uterine contractions. Side effects include vomiting, diarrhea, fever, and bronchoconstriction (paradoxical).

Front 27

Name a PGF2α analog and its uses.

Back 27

Latanoprost: reduces intraocular pressure, used to treat glaucoma.

Front 28

Name a PGI2 analog, its uses, and its side effects.

Back 28

Epoprostenol/treprostinil (longer half-life): lowers vascular pressure, used to treat pulmonary hypertension. Side effects include nausea, headache, hypotension, flushing.

Front 29

Name four cell types that produce PAF.

Back 29

1. Mast cells
2. Blood cells (eosinophils, neutrophils, platelets, monocytes)
3. Renal medullary cells
4. Endothelial cells

Front 30

Does PAF act intra- or extracellularly?

Back 30

Both

Front 31

What is the cellular signaling mechanism of PAF?

Back 31

PAF stimulates GPCRs to activate PLC/D/A2.

Front 32

Describe the effects of PAF on the cardiovascular system.

Back 32

PAF causes vasodilation, increased vascular permeability (venular endothelial cell contraction), platelet aggregation and is a chemotactic factor for WBCs. It also causes PMNs to aggregate, release LTs, and generate superoxide.

Front 33

Describe the effects of PAF on smooth muscle.

Back 33

PAF stimulates almost all smooth muscle to contract. It is also a potent ulcerogenic substance.

Front 34

Describe the role of PAF in reproduction.

Name an antagonist of its action.

Back 34

PAF may play a role in ovulation, implantation, and parturition.

Ginkgolide B is an antagonist.

Front 35

Describe the role of PAF in inflammation and allergic response.

Back 35

PAF increases vascular permeability, infiltration of PMNs, edema, and causes hyperalgesia.

Front 36

Where is histamine stored?

Back 36

Histamine is stored in mast cells of skin, bronchial mucosa, intestinal mucosa. It is also stored in CSF and basophils of blood.

Front 37

Name the components of the histamine synthesis and metabolism pathways.

Back 37

Histamine is synthesized from histidine by L-histidine decarboxylase.

It is metabolized by histamine-N-methyl transferase and MAO-B. Small amounts of histamine may also be deaminated by diamine oxidase (DAO). Inactive metabolites are excreted in the urine.

Front 38

Name three physiologic functions of histamine.

Back 38

1. Allergic and inflammatory mediator
2. Gastric acid secretion
3. Neurotransmitter/neuromodulator

Front 39

What happens in cells as a result of PLC activation?

Back 39

PLC activation leads to histamine release, ATP release, and activation of PLA which leads to production of PAF, PGD2, LTD4, and kinins. Release of these substances results in bronchoconstriction, hypotension, increased capillary permeability, and edema.

Front 40

What inhibits the degranulation of mast cells in the lung?

Back 40

Cromolyn sodium inhibits degranulation of mast cells in the lung.

Front 41

Name five therapeutic agents that induce histamine release.

Back 41

1. Organic bases
2. Tubocurarine
3. Succinylcholine
4. Morphine (not fentanyl)
5. Vancomycin

Front 42

What protein receptor family do all histamine receptors belong to?

Back 42

GPCR

Front 43

Describe the major functions of each histamine receptor.

Name any known antagonists.

Back 43

H1: increased phosphoinositol hydrolysis. Antagonists: pyrilamine (first generation antihistamines) and second-generation antihistamines

H2: increased cAMP. Antagonists inhibit gastric acid secretion.

H3: Presynaptic feedback inhibition of histamine, norepinephrine, serotonin, acetylcholine release, decreased intracellular Ca. Antagonist: thioperamide (not clinically approved)

Front 44

What happens to the cardiovascular system with injection of histamine?

Back 44

Decreased BP, flushed face (vasodilaton), EDRF/NO release (H1-mediated)

Smooth muscle relaxation, increased heart rate (H2-mediated)

Front 45

What happens to the GI tract with histamine release?

Through which histamine receptor is this mediated?

Back 45

Histamine causes contraction of smooth muscle, increasing GI motility and potentially causing diarrhea. This is mediated by the H1 receptor.

H2 receptor stimulation results in increased gastric acid secretion via increased cAMP and intracellular Ca.

Front 46

What is the effect of histamine on the bronchial smooth muscle?

Which receptor?

Back 46

H1 receptor stimulation causes bronchoconstriction.

Front 47

What is the effect of histamine on the uterus?

Which receptor?

Back 47

Histamine causes contraction of the uterus via the H1 receptor, and a pregnant woman in anaphylaxis may abort.

Front 48

What is the effect of histamine on nerve endings?

Which receptor?

Back 48

Histamine causes pain and itching via the H1 receptor.

Front 49

What histamine receptor works with H1 to cause the triple response?

Back 49

H1 is involved in mediation of all parts of the triple response, and is aided by H2 in producing the red flare.

Front 50

What is the major physiological antagonist of histamine receptors?

Back 50

Epinephrine

Front 51

What drug is used to prevent mast cell degranulation in asthma patients?

Back 51

Nedocromil

Front 52

Name the six groups of H1 receptor antagonists and the prototypical drug for each group.

Back 52

1. Ethanolamines: Diphenhydramine
2. Ethylenediamines: Pyrilamine
3. Piperazine: Cetirizine
4. Alkylamines: Chlorpheniramine
5. Phenothiazines: Promethazine
6. Piperidines: Cyproheptadine, loratadine, fexofenadine

Front 53

Name the seven major off-target effects of H1 receptor antagonists.

Back 53

1. Sedation
2. Antiemetic
3. Anti-Parkinson's
4. Peripheral antimuscarinic
5. alpha-adrenoreceptor blocking
6. Serotonin blocking
7. Local anesthetic

Front 54

Name the five major clinical uses of H1 receptor antagonists.

Back 54

1. Anti-allergy
2. Sedation
3. Anti-Parkinson's
4. Motion sickness/vestibular disturbances
5. Nausea and vomiting of pregnancy

Front 55

Name the four H2 receptor antagonists.

Back 55

1. Cimetidine (Tagamet)
2. Ranitidine (Zantac)
3. Famotidine (Pepcid)
4. Nizantidine (Axid)

Front 56

Which H2 receptor antagonist has a bioavailability of 90% rather than 50%?

Which two are renally excreted?

Back 56

Nizantidine has 90% bioavailability.

Cimetidine and ranitidine are renally excreted.

Front 57

What is the physiological effect of H2 antagonists?

Back 57

All four block acid secretion by histamine, gastrin, ACh, and vagal stimulation. In addition, nizantidine increases GI motility/decreases gastric empying time.

Front 58

What three conditions are H2 antagonists used to treat?

Back 58

1. Peptic duodenal/gastric ulcers
2. Gastroesophageal reflux
3. Zollinger-Ellison syndrome (gastrin-secreting mast cell tumors)

Front 59

Which H2 antagonist inhibits CYT?

Back 59

Cimetidine inhibits CYT.

Front 60

5-HT is another name for what?

Back 60

5-HT is another name for serotonin.

Front 61

From what amino acid is serotonin/5-HT synthesized?

What two enzymes are required to get from this amino acid to serotonin?

Back 61

Tryptophan.

Tryptophan hydroxylase and L-amino acid decarboxylase.

Front 62

What enzyme metabolizes serotonin?

Which isoform prefers serotonin? What does the other isoform prefer?

Name an inhibitor of each isoform.

Back 62

Serotonin is metabolized by monoamine oxidase.

MAO-A prefers serotonin, while MAO-B prefers histamine.

Clorgyline inhibits MAO-A.
Selegiline inhibits MAO-B.

Front 63

Describe the G coupling of 5-HT1 receptors and their physiological effects.

Back 63

5-HT1 receptors are coupled to Gi/Go, which means they are negatively coupled to adenylate cyclase.
Subtypes 1B and 1D produce cranial vessel constriction.
Subtype 1F prevents dural extravasation of inflammatory peptides, preventing migraine headaches.

Front 64

Describe the G coupling of 5-HT2 receptors and their physiological effects.

Back 64

5-HT2 receptors are coupled to Gq and activate PLC and inositol triphosphate.
Subtype 2A functions in platelet aggregation, contraction of smooth muscle, and neuronal excitation.

Front 65

Describe the physiological effects of 5-HT7 receptors.

Back 65

5-HT7 receptors cause endothelium-independent relaxation of cranial vasculature and migraine headaches.

Front 66

Where is serotonin/5-HT stored?

Back 66

Serotoinin/5-HT is stored in enterochromaffin cells in the GI tract.

Front 67

Describe the effects of different 5-HT receptors on the cardiovascular system.

Back 67

5-HT1B and 2A receptors cause direct vasoconstriction of arteries and veins.

5-HT2B stimulation causes indirect vasodilation, EDRF release, and stimulation of 5-HT7 receptors.
Subendocardial fibroplasia (damage to valves and electrical conduction) can result from chronic high serotonin levels.

Front 68

Describe the effects of different 5-HT receptors on smooth muscle.

Back 68

5-HT2A,C cause smooth muscle contraction and bronchoconstriction (in carcinoid syndrome patients).
5-HT7 causes vascular muscle relaxation.

Front 69

Describe the effects of different 5-HT receptors on the GI tract.

Back 69

Six of the 5-HT receptors are involved directly or indirectly in motility.
5-HT3 plays a role in emesis.

Front 70

What is fenfluramine?

Name a similar drug.

Back 70

Fenfluramine is an appetite suppressant, but was recently banned because of cardiotoxicity.

Methylenedioxymethamphetamine (MDMA)- ecstasy

Front 71

What are selective serotonin reuptake inhibitors (SSRI) used for? Name one.

Back 71

SSRIs are used to treat depression and OCD. Fluoxetine/Prozac is a common SSRI.

Front 72

Name two 5-HT receptor agonists and the receptors that they agonize. What is their function?

Back 72

1. Sumatriptan: Agonizes 5-HT1B,D,F. Treats acute migraine by causing vasoconstriction of intracranial blood vessels and preventing dural extravasation.

2. Tegaserod: 5-HT4 partial agonist. Stimulates peristalsis and gastric emptying. Until 2007 used to treat IBS. Withdrawn 4/07 because of increased MI, angina, and stroke in CV patients.

Front 73

Name three 5-HT receptor antagonists and the receptors that they antagonize. What is their function?

Back 73

1. Ondansetron: Antagonizes 5-HT3. Treats chemotherapy-induced nausea and emesis.

2. Methysergide: 5-HT2A,B,C antagonist. Prophylactic migraine treatment. Chronic treatment may result in inflammatory fibrosis.

3. Cyproheptadine: 5-HT2A antagonist and H1 blocker. Antimuscarinic and antidepressant. Used to treat post-gastrectomy dumping syndrome.

Front 74

What is a kinin? Include factors that stimulate synthesis and physiologic actions.

Back 74

A kinin is a locally acting peptide autacoid. Kinins are synthesized in response to tissue damage, allergic reactions, and acute and chronic inflammation. They case pain, vasodilation, increased vascular permeability, and synthesis of prostaglandins.

Front 75

What are the three major kinins?

Back 75

1. Bradykinin
2. Kallidin (Lysyl-bradykinin)
3. Methionyl-lysylbradykinin

Front 76

Describe the basic synthesis and metabolism of kinins.

Back 76

Kinins are synthesized as low or high molecular weight precursors called kininogens. Kininogens are cleaved to kinins by kallikreins (serine proteases), which exist as prekallikreins until they are activated. Bradykinin is made from high MW kininogen and lysyl-bradykinin is made from low MW kininogen.

Kinins are metabolized by kininase I and II (angiotensin converting enzyme and dipeptidyl carboxypeptidase).

Front 77

Name the two kinin receptors and describe their functions.

Back 77

B1: Upregulated during inflammation. Responsible for most kinin effects during inflammation.

B2: Constitutively expressed in most tissues. High affinity for bradykinin. Coupled to G-protein and activates PLA2 and PLC.

Front 78

Describe the effects of kinins on the cardiovascular system.

Back 78

Kinins cause vasodiation in arterial vascular beds both directly and indirectly through NO and PGE2 and PGI2 synthesis. Kinins also vasoconstrict veins via synthesis of PGF2α. These two actions result in edema.

Front 79

Describe the effects of kinins on inflammation.

Back 79

Kinins cause edema and bronchospasm in asthmatics.

Front 80

Describe how the two kinin receptors mediate pain.

Back 80

B2 receptors mediate acute pain, while B1 receptors mediate pain of chronic inflammation.

Front 81

Describe the action of kinins in neonates.

Back 81

In neonates, kinins promote dilation of the pulmonary artery, closure of the ductus arteriosus, and constriction of the umbilical arteries.

Front 82

Describe the clinical uses of kinins.

Back 82

At this point, there are no directly approved uses of kinins themselves, but ACE inhibitors block kininase II, kinin levels become elevated and the kinins have hypotensive action.

Front 83

What is the physiologic function of angiotensin II?

Back 83

Angiotensin II is a vasoconstrictor.

Front 84

Where are the components of the angiotensin synthesis pathway produced?

Back 84

Angiotensinogen, the angiotensin precursor, is synthesized in the liver. Renin, which converts angiotensinogen to angiotensin I, is produced in the kidney. ACE, which converts angiotensin I to angiotensin II, is produced in endothelial cells.

Front 85

Name three factors that increase angiotensinogen concentration.

Back 85

1. Corticosteroids
2. Thyroid hormones
3. Estrogen

Front 86

What are the two rate-limiting factors in angiotensin II production?

Back 86

1. Renin secretion
2. Levels of circulating angiotensinogen

Front 87

How is angiotensin II metabolized?

Back 87

Angiotensin II is rapidly removed from the blood by several proteases like angiotensinase.

Front 88

Through which receptor is the majority of angiotensin II action mediated? What kind of recepotr is it and what does it activate?

Back 88

The majority of angiotensin II activity is mediated through the AT1 receptor. AT1 is a GPCR that generates IP2 and diacylglycerol, resulting ultimately in smooth muscle contraction.

Front 89

Describe the effect of angiotensin II on the cardiovascular system.

Back 89

Angiotensin II is a potent vasoconstrictor, with the vasoconstriction mostly mediated by vascular smooth muscle contraction. It also resets the baroreceptor reflex to a higher threshold, preventing bradycardia. It potentiates sympathetic signal transmission by increasing norepinephrine release and reducing reuptake.

Front 90

Describe the effects of angiotensin II on the adrenal cortex, kidneys, and CNS.

Back 90

Angiotensin II stimulates biosynthesis of aldosterone and glucocorticoids. It causes renal vasoconstriction, sodium reabsorption, and vasopressin release. It also stimulates thirst.

Front 91

Name some clinically useful drugs that are involved in the renin-angiotensin system.

Back 91

Renin inhibitors suppress angiotensin production and lower blood pressure, but they are still in clinical trials. ACE inhibitors (captopril, enalapril) prevent the conversion of angiotensin I to angiotensin II and inhibit the catabolism of bradykinin, lowering blood pressure. However, pulmonary edema and cough are frequent side effects. Third, non-peptide angiotensin II antagonists (losartan, valsartan) have the same effect as ACE inhibitors, but without the side effects.

Front 92

What is NO?

Back 92

NO is a ubiquitous, short-lived vasodilator. It is also known as endothelium-derived relaxing factor (EDRF).

Front 93

Describe the synthesis and metabolism of NO.

Back 93

NO is synthesized by one of three nitric oxide synthase (NOS) isoforms. NOS converts 1-arginine to 1-citrulline and NO, using NADPH, FAD, and tetrahydrobiopterin as cofactors.

NO can also be spontaneously synthesized by donor molecules like nitroprusside and nitroglycerine.

NO is inactivated by heme and superoxide, therefore antioxidants increase its potency.

Front 94

What is the cellular effect that NO has?

Back 94

NO activates guanylyl cyclase, which promotes formation of cGMP, which activates PKG.

Front 95

What are the effects of NO on the cardiovascular system?

Back 95

NO is important for the maintenance of vascular tone. Inhibitors of NO increase vascular tone and arterial pressure, as well as potentiate the action of vasopressor drugs. NO induction of cGMP relaxes vascular smooth muscle.
In addition, NO blocks oxidation of LDL (prevent foam cell formation) and inhibits platelet aggregation.

Front 96

What three conditions decrease levels of NO?

Back 96

1. Diabetes
2. Atherosclerosis
3. Cardiac ischemia

Front 97

What are the effects of NO on the CNS?

Back 97

NO acts as a diffusible second messenger that facilitates the release of neurotransmitters like glutamate. It assists in developmental, learning, and memory functions. It also assists in erection and subsequent activation of cGMP causes relaxation.

Front 98

Describe the effect of sildenafil (Viagra) on the action of NO.

Back 98

Sildenafil inhibits the phosphodiesterase that normally breaks down cGMP, which for many restores erectile function.

Front 99

Describe the effect of NOS inhibitors on inflammation.

Back 99

NOS inhibitors reduce edema and vascular permeability in acute inflammation and may have a protective effect in chronic arthritis.