Ellen - Pharmacology 2: Histamine And Serotonin

Front 1

What are Autacoids?

Back 1

are a diverse group of endogenous bioactive compounds, with various, largely undesirable physiological effects

Front 2

What are the aa metabolite Autacoids?

Back 2

histamine
serotonin

Front 3

What are the peptide Autacoids?

Back 3

kinins, angiotensin, endothelins, cytokines and chemokines.

Front 4

What are the lipid metabolites Autacoids?

Back 4

prostaglandins
leukotrienes

Front 5

When was histamine first synthesized and how was it used?

Back 5

First synthesized in 1907. Administration to animals produced anaphylactic shock-like symptoms.

Front 6

What converts L-Histidine to histamine?

Back 6

L-histadine decarboxylase

Front 7

What cells provide vesicular storage of histamine?

Back 7

Mast cells
Basophils
Neurons
Parietal cells

Front 8

Where are mast cells and basophils found?

Back 8

Mast cells : skin, nose, mouth, airways
Basophils: blood

Front 9

How is histamine involved in brain neurons?

Back 9

involved in neurotransmission and neuromodulation

Front 10

What does histamine mediate when released from mast cells and basophils?

Back 10

immediate (acute, type I) local allergic reactions

Front 11

What does histamine degranulation induce?

Back 11

induces asthma, hay fever and hives, and can cause severe systemic anaphylaxis

Front 12

Which chemicals stimulate histamine release?

Back 12

Morphine, tubocurarine and vancomycin (red man syndrome) displace histamine from its intracellular protein complexes.
Bradykinin releases histamine in the lung.

Front 13

What mechanical forces stimulate histamine release?

Back 13

Volume expanders cause histamine release.
Trauma

Front 14

What type of receptors are the histamine receptors?

Back 14

Seven transmembrane-spanning, G-protein coupled receptors

Front 15

Where are the H1 histamine receptors located and what happens when they're stimulated?

Back 15

Smooth muscle, endothelium, brain
Increased IP3, DAG (Gq)

Front 16

Where are the H2 histamine receptors located and what happens when they're stimulated?

Back 16

Gastric mucosa, endothelium, brain
Increased cAMP (Gs)

Front 17

Where are the H3 histamine receptors located and what happens when they're stimulated?

Back 17

Presynaptic: brain, myenteric plexus
Decreased cAMP, [Ca2+]i (Gi)

Front 18

Where are the H4 histamine receptors located and what happens when they're stimulated?

Back 18

Eosinophils, neutrophils, CD4T cells
Decreased cAMP, [Ca2+]i (Gi)

Front 19

What are the H1 histamine receptors homologous to?

Back 19

Muscarinic receptor

Front 20

What are the H2 histamine receptors homologous to?

Back 20

5HT1

Front 21

What are the H3 and H4 histamine receptors homologous to?

Back 21

40% are homologous to eachother

Front 22

What are the effects of histamine on H1 and H2 receptors in the nervous system? (where are these located?)

Back 22

pain, itching and urticarial response to insect and nettle stings
(Sensory nerve endings)

Front 23

What are the effects of histamine on H3 receptors in the nervous system? (where are these located?)

Back 23

neuromodulation, reduces the release of histamine, serotonin, dopamine and norepinephrine
(presynaptic CNS)

Front 24

What are the effects histamine on blood vessels? (which receptors are involved)

Back 24

Decrease of systolic and diastolic blood pressure (due to release of NO from endothelial cells of arterioles H1; vasodilation of resistance vessels H2)

Front 25

What are the effects histamine on the heart? (mechanism?)

Back 25

Increases heart rate: via reflex tachycardia and via direct stimulatory action on the heart (contractility and pacemaker rate)

Front 26

What are the effects histamine on bronchial smooth muscle? (How can this be blocked?)

Back 26

bronchoconstriction
H1 receptor antagonists
Muscarinic receptor blockers (atropine, ipratropium bromide); cholinergic reflex

Front 27

What are the effects histamine on asthmatics?

Back 27

They are 100-1000 fold more sensitive to low doses of histamine than healthy individuals.

Front 28

What are the effects histamine on the GI tract? (mechanism?)

Back 28

Contraction of GI smooth muscle (H1) = increase GI motility and cause diarrhea in high doses

Front 29

What are the effects histamine on secretory tissue? (mechanism?)

Back 29

Gastric acid secretion from parietal cells in the stomach fundus (H2)

Front 30

What are the effects histamine on edema? (mechanism?)

Back 30

contracts endothelial cells and induces release of NO = SM relax = gaps formed between endothelial cells = increased permeability and accumulation of liquid in adjacent tissues → EDEMA.

Front 31

What's the effect of an intradermal injection of histamine?

Back 31

Triple response:
1.Endothelial cell:
Release relaxing factors (NO) H1 = Increased permeability and fluid accumulation of perivascular tissues == edematous wheal.
2. SM cells: peripheral vasodilation = reddening; constriction of veins = induration.
3. Nerve endings: itching and pain.

Front 32

What is a cluster headache?

Back 32

Histamine headache - pain in and around one eye

Front 33

What is the mechanism behind a formation of a cluster headache?

Back 33

Inflammation of nearby nerves (trigeminal) releases histamine = dilates blood vessels in the preorbital area = distinctive stabbing and throbbing pain usually felt in one eye.

Front 34

Name 2 histaminic drugs.

Back 34

betazole (H2 agonist)
HISTAMINE

Front 35

Name 7 H1-Antihistamines.

Back 35

brompheniramine
CHLORPHENIRAMINE
DIPHENHYDRAMINE
FEXOFENADINE
hydroxyzine
loratadine
promethazine

Front 36

Name 4 H2-Antihistamines.

Back 36

CIMETIDINE
FAMOTIDINE
nizatidine
RANITIDINE

Front 37

Name 2 Antidegranulating drugs.

Back 37

CROMOLYN SODIUM
nedocromil sodium

Front 38

Name 3 Drugs for Motion Sickness.

Back 38

DIMENHYDRINATE
promethazine
scopolamine

Front 39

Clinical uses of histamine and histamine agonists?

Back 39

no major clinical use - aerosol is used (rarely) as a provocative test for pulmonary hyperreactivity.
Betazole (H2) is used for testing gastric acid secretion.

Front 40

Clinical uses of histamine antagonists?

Back 40

For treatment of allergic reactions: hay fever, stings, urticaria
Tx sleep disorders
Antiemetics
Local anesthetics

Front 41

What are the therapeutic goals in the treatment of allergy and anaphylaxis?

Back 41

Inhibition of mast cell degranulation (histamine release inhibitors).
Physiological antagonists: inhibit allergic responses by activation of non-histamine receptors.
Histamine receptor antagonists.

Front 42

What's an example of a physiologic antagonist of histamine? What is it used for?

Back 42

Epinephrine: lifesaver in systemic anaphylaxis or other conditions associated with massive release of histamine, serotonin and/or kinins.

Front 43

What do cromolyn and nedocromil do?

Back 43

prevent the release of mediators from mast cells and basophils

Front 44

How do beta2 receptor agonists effect histamine?

Back 44

Inhibit IgE-stimulated degranulation of mast cells via increased cAMP

Front 45

What are H1 antagonists clinical uses?

Back 45

rhinitis, urticaria, conjunctivitis, airway constriction, motion sickness

Front 46

What are H2 antagonists clinical uses? (name of drug?)

Back 46

the first selective antagonist (burimamide) was used as antagonist of gastric acid secretion

Front 47

What are H3 antagonists clinical uses? (name 2 drugs?)

Back 47

No clinical use (thioperamide and clobenpropit).

Front 48

What are H4 antagonists clinical uses? (name of drug?)

Back 48

No clinical use (JNJ7777120).

Front 49

Characteristics of first generation H1 antagonists? (BBB? sedation? specificity?)

Back 49

1. Lipophilic:readily cross BBB
2. Strong sedatives (sleep aids)
3. Relatively low specificity: block autonomic alpha-adrenergic, muscarinic and serotonin receptors (antiemetics).

Front 50

Characteristics of second generation H1 antagonists? (BBB? sedation? specificity?)

Back 50

1. Hydrophilic:don't cross BBB
2. Poor sedatives
3. Higher specificity: rare adrenergic, muscarinergic or serotoninergic side effects.

Front 51

Absorption and peak concentration time of H1 antagonists?

Back 51

Rapid absorption following oral administration.
Peak blood concentration in 1-2 hours (oral).

Front 52

Metabolism of H1 antagonists? Duration of action?

Back 52

Liver CYP (for some)
Duration = 4-6 hours, some second generation = 12-24

Front 53

What CYP is inhibited by 2nd generation antihistamines? Name the 2 drugs.

Back 53

terfenadine, astemizole
CYP3A → interactions at the level of metabolism led to withdrawal

Front 54

What type of antagonists are H1 antagonists?

Back 54

Reversible competitive

Front 55

What is scombroid poisoning?

Back 55

Poisoning from fish (scombroidae family (tuna and mackerel) plus bluefish, dolphin, mahi-mahi and amberjack) due to muscle breakdown by bacteria, which produces histamine

Front 56

What are the signs of scombroid poisoning?

Back 56

dizziness, sweating, nausea, may advance to facial rash, hives and blurred vision.

Front 57

Name the active ingredient in sleep aids. How do they work?

Back 57

Diphenhydramine
Mechanism: the effect resembles that of some antimuscarinic drugs (stop histamine exitement of septohippocampal GABA-type neurons)

Front 58

What Neurotransmitter receptor antagonists have anti-emetic effects?

Back 58

anti-....histamine, acetylcholine, dopamine, norepinephrine, serotonin, substance P.

Front 59

Name 3 antihistamine drugs used to tx post operative nausea.

Back 59

cinnarizine, cyclizine, promethazine

Front 60

Name 4 antihistamine drugs used to tx motion sickness.

Back 60

cyclizine, meclizine, diphenhydramine, prometazine

Front 61

Name 1 antihistamine drug used to tx morning sickness.

Back 61

doxylamine

Front 62

Are antihistamines used to tx nausea due to chemotherapy?

Back 62

No, they're not very effective for that.

Front 63

Name 2 antihistamines used for local anesthesia. What's the mechanism?

Back 63

diphenhydramine and promethazine
Block sodium channel in excitable membranes

Front 64

Name 4 selective H2 antagonists.

Back 64

Cimetidine, ranitidine, famotidine and nizatidine

Front 65

What's the effect of H2 antagonists on the stomach?

Back 65

Inhibit acid and pepsin secretion.

Front 66

What conditions are treated (in part) by H2 antagonists?

Back 66

Gastric/peptic duodenal ulcer.
Erosive esophagitis.
Zollinger-Ellison syndrome: hypersecretion of gastric acid due to gastrin-secreting tumors

Front 67

Drug interactions with H2 antagonists? (what drug's involved)

Back 67

Cimetidine (and ranitidine less so) inhibits CYP1A2, 2C9 and 2D6, leading to delayed metabolism of some drugs

Front 68

Cimetidine's effects on the liver, kidneys, and androgens?

Back 68

Reduces liver blood flow.
Inhibits renal tubular secretion of basic drugs
Inhibits androgen receptors = antiandrogenic effects (gynecomastia, galactorrhea)

Front 69

How are H3 and H4 antagonists used?

Back 69

Biomedical research

Front 70

Trace the formation of 5-HT, serotonin from L-tryptophan.

Back 70

L-tryptophan converted to 5-hydroxytryptophan by tryptophan hydroxylase which is then converted to serotonin (5-hydroxytryptamine) by decarboxylase.

Front 71

What's the degredation of serotonin?

Back 71

Metabolized by MAO to melatonin (in the pineal gland) or 5-hydroxyindolacetic acid (5-HIAA)
(in the liver)

Front 72

Where's 5-HT found naturally?

Back 72

plant and animal tissues, and in venoms and stings.

Front 73

Where's 5-HT found in human tissue?

Back 73

Approximately 90% of serotonin is stored in granules (vesicles) in enterochromaffin cells in the GI tract. (Function = motility)

Front 74

What's carcinoid syndrome?

Back 74

carcinoid tumor (neoplasm) of stomach, small intestines, colon, appendix and bronchial tubes. Tumor cells synthesize excessive amounts of serotonin – prokinetic effect

Front 75

Where are the blood stores of 5-HT? What does it do?

Back 75

Blood stores: in vesicles of platelets. Released 5-HT stimulates platelet aggregation

Front 76

What's the effect of serotonin in the brain and where's it found?

Back 76

Brain stores: raphe nuclei of the brain stem.
Neurotransmitter - regulates mood, sleep, appetite, body temperature, perception of pain, blood pressure and vomiting reflex

Front 77

How is 5-HT release stimulated in the GI tract?

Back 77

Through vagal stimulation or through mechanical stretch following food intake

Front 78

What does activation of the 5-HT3 receptor cause?

Back 78

rapid neuronal excitation

Front 79

What type of 5-HT receptor is most prevalent in the CNS? What's the effects of stimulation?

Back 79

5-HT1A
inhibitory action due to activation of K channels and hyperpolarization

Front 80

What does serotonin regulate in the CNS?

Back 80

sleep, temperature regulation, appetite, sexual behavior and vomiting reflex

Front 81

What is the effect of serotonin in the peripheral nerves?

Back 81

Pain and itch
Bradycardia and hypotension (5-HT3)

Front 82

What is the effect of serotonin in the airways? Mechanism?

Back 82

Modest bronchoconstrictor in healthy individuals, by direct effect on the smooth muscle, and by release of ACh from bronchial vagal nerve endings.
Potent bronchoconstriction in patients with carcinoid syndrome.

Front 83

What is the effect of serotonin on vascular smooth muscle?

Back 83

Contraction of denuded vascular smooth muscle (5-HT2) = constricting in splanchnic, renal, pulmonary and cerebral vascular beds.
Relaxation of vessels supplying skeletal and cardiac muscle: release of relaxing factors by endothelial cells.

Front 84

What is the effect of serotonin on veins?

Back 84

Contraction of veins: causes increased capillary filling and flush.

Front 85

What is the effect of serotonin on the heart?

Back 85

Direct inotropic and chronotropic effects are blunted by reflexes.
Valvular and electrical malfunction of the heart (relevant to carcinoid syndrome).

Front 86

What is the effect of serotonin on clotting?

Back 86

taken up by platelets and contributes to regulation of thrombosis and hemostasis.

Front 87

What is the effect of serotonin on the GI tract? Mechanism?

Back 87

Contracts GI smooth muscle and increases tone and peristalsis: prokinetic effect. Via: Activation of 5-HT2/4 and release of ACh.

Front 88

Clinical use of serotonin agonists?

Back 88

Cluster (histamine) headache
Migraine headache
Depression
Others

Front 89

What's the mechanism behind txing cluster headaches with serotonin agonists?

Back 89

Headache caused by histamine-mediated dilation of cranial blood vessels. Activation of 5-HT1D and 5-HT1B receptors are present in serotoninergic nerve endings in cerebral and meningeal blood vessels = vasoconstriction

Front 90

What type of serotonin agonists are used to tx cluster and migraine headaches?

Back 90

Sumatriptan (IMITREX), naratriptan, rizatriptan and zolmitriptan: potent but short-lasting effect
Ergot alkaloids (ergotamine)

Front 91

What's the mechanism behind migrane headaches?

Back 91

overexcited nerves = vasodilation = severe unilateral pain with nausea, dizziness, and visual disturbances

Front 92

Mechanism of serotonin agonists used to tx migraine headaches?

Back 92

Reduce the release of relaxing factors from trigeminal nerve endings, and induce vasoconstriction of cranial blood vessels (5-HT1B and 1D receptors)

Front 93

What's the serotonin hypothesis in depression?

Back 93

serotonin insufficiency determines the severity of depression

Front 94

Therapeutic goals when txing depression with serotonin agonists?

Back 94

Increase content of endogenous serotonin

Front 95

What's the rate limiting process in the formation of serotonin?

Back 95

The step L- to 5-hydroxy-tryptophan catalyzed by tryptophan hydroxylase

Front 96

What drugs are used to tx depression?

Back 96

MAO inhibitors: Tranylcypromine and Phenelzine
Reuptake inhibs: Fluoxetine (PROZAC) or Paroxetine (PAXIL)

Front 97

What's serotonin syndrome?

Back 97

Overly-increased concentration of serotonin in synapses = Hyperthermia, muscle rigidity, myoclonia, rapid changes in mental status and vital signs

Front 98

What's Buspirone? Use?

Back 98

5-HT1A agonist - effective non-benzodiazepine anxiolytic (no sedation, hypnotic, anticonvulsant or muscle relaxant properties)

Front 99

What's Dexfenfluramine? Use?

Back 99

serotonin release agonist - appetite suppressant and anorexigenic drug: no longer in use due to occurrence of pulmonary hypertension and valvular lesions in young women

Front 100

What's Cisapride? Use?

Back 100

a 5-HT4 agonist: prokinetic drug, used (in the past) for treatment of gastroesophageal reflux and motility disorders

Front 101

What are the clinical uses of serotonin antagonists?

Back 101

Carcinoid syndrome
Hypertension
Nausea and vomiting

Front 102

What are the inhibitors of serotonin synthesis at tryptophan hydroxylase?

Back 102

p-chlorophenylalanine
p-chloroamphetamine

Front 103

What's a serotonin storage inhibitor? Why isn't it used often?

Back 103

Reserpine
Limited due to sympatholytic effects and high levels of circulating serotonin.

Front 104

What's Cyproheptadine? Uses?

Back 104

H1 and 5-HT2A receptor antagonist.
Used to tx of the smooth muscle form of carcinoid syndrome

Front 105

What's Ketanserin? Uses?

Back 105

A 5-HT1C and 5-HT2 antagonist, also blocks vascular alpha1-receptors.
Use in Europe to tx htn and vasospastic conditions.

Front 106

What are Ondansetron and granisetron? Uses?

Back 106

5-HT3 antagonists.
Used for prevention of nausea and vomiting during cancer chemotherapy and radiation

Front 107

What are the beneficial effects of serotonin? (serotonin agonist uses)

Back 107

Maintains normal sleep, emotions, temperature and appetite.
Effective against cluster (histamine) headache and migraine
Antidepressant.
Prokinetic effects in the GIT

Front 108

What are the detrimental effects of serotonin?

Back 108

Mediates allergic reactions, pain and itching
Mediates n/v reflex
Platelet aggregation