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Pharm Exam 5 -- Smooth Muscle, GI and OTC > Smooth Muscle (pt 2/4) Histamine > Flashcards

Smooth Muscle (pt 2/4) Histamine Flashcards

1
Q

What are Autocoids?

A

Biological factors which act like local hormones, have a brief duration, and act near the site of synthesis.
-Generally produced locally, act locally and are metabolised locally.
-Biological actions include modulation of the activity of smooth muscles, glands, nerves, platelets and other tissues.

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2
Q

What does Paracrine mean?

A

Effects are mostly localized but large amounts can be produced and moved into circulation.

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3
Q

What does Endocrine mean?

A

May have systemic effect by being transported via circulation.

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4
Q

What are the different examples of Autocoids?

A
  • Endogenous Peptides: Vasoconstrictors: Angiotensin, Vasopressin, Endothelins, Neuropeptide Y, Urotensin and
  • Vasodilators: Bradykinin/kinins; Natriuretic Peptides, Vasoactive Intestinal Peptide, Substance P, Neurotensin, Calcitonin Gene-Related Peptide, Adrenomedullin
  • Prostaglandins
  • Leukotrienes
  • Cytokines
  • Histamine
  • Serotonin
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5
Q

What are the similarities between Histamine and Serotonin?

A

-Biologically active amines that function as neurotransmitters
-Found in both neural and non-neural tissues
-Broad and undesirable peripheral effects
-No clinical application for the treatment of disease BUT selective agonism/antagonism of receptors has proven clinically useful

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6
Q

What is Histamine?

A

A Neurotransmitter, Neuromodulator
-Mediates allergic & inflammatory reactions
-Modest role in anaphylaxis
-Important role in gastric acid secretion
-Possible role in immune function and chemotaxis of WBC (mobilization of a WBC towards bacteria)
-Sequestered/bound in granules on mast cells and basophils

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7
Q

Where is Mast Cell Histamine located?

A

-Found throughout most tissues
-High concentrations at sites of potential injury: Nose, Mouth, Feet, Internal body surfaces, Blood Vessels (pressure points and bifurcations)

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8
Q

Where is Non-Mast Cell histamine located?

A

Brain and Gut.
-Neurotransmitter in the brain. Functions in Neuroendocrine control, CV regulation. Thermal & body weight regulation, and Sleep & arousal.
-Enterochromaffin-Like (ECL) cells of the fundus of the stomach. ECL cells release histamine, which activates the acid producing parietal cells of the mucosa (digestion)

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9
Q

Explain the Sensitization and Effector Phases of Immunologic Histamine Release.

A

-Sensitization phase: Promotes the development of antibodies.
-Effector Phase: IgE receptors attach to the surface of a sensitized mast cell. Allergen connects to them (Cross-linking).

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10
Q

What occurs with Immunologic Histamine release on re-exposure to the antigen?

A

-Degranulation and release of pharmacologic mediators (Histamine, ATP, etc)
-Type 1 Allergic Rxn (Hay fever, urticaria)
-Release is mediated by the H2 via Negative feedback displayed by skin mast cells and basophils (lung mast cells do not display negative feedback)

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11
Q

How does Histamine release contribute to inflammation? 3 ways

A

-causes local vasodilation and release of inflammatory mediators (Ex: C-reactive protein) and antibodies
-chemotactic attraction for the inflammatory cells (neutrophils, eosinophils, basophils, monocytes, lymphocytes)
-Inhibits the release of lysosome contents and several T&B lymphocytes

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12
Q

How can Histamine be released by non-injury related causes?

A

Anaphylaxis to an amine or a drug (ex: Morphine)
-Doesn’t have degranulation or Mast Cell activation

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13
Q

T/F: Humans are more sensitive than rats/mice to histamine, but less sensitive than guinea pigs.

A

True

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14
Q

What type of receptor are the Histamine receptors?

A

All are GPCRs.

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15
Q

Explain the similarities with Histamine receptors and other receptors.

A

-H1: similar structure to a Muscarinic receptor
-H2: Similar to a 5HT receptor
-H3 and H4 are 40% similar to each other
-All have constitutive activity
-Drugs can be an AGONIST at 1 receptor, AND an ANTAGONIST or INVERSE AGONIST at another.

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16
Q

Which Histamine Receptors are found in the brain?

A

H1, H2, and H3

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17
Q

Where are H1 receptors found?

A

-Smooth Muscle
-Endothelium
-Brain

post-synaptic

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18
Q

What are the actions of the H1 receptors in the brain?

A

-⬆Phosphoinositol Hydrolysis →
-⬆ IP3 & ICF Ca++

Need inc Ca for release of NTs in the brain via exocytosis.

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19
Q

Where are H2 receptors found?

A

-Gastric Mucosa
-Cardiac Muscle
-Mast Cell
-Brain

post-synaptic

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20
Q

What are the actions of the H2 receptors in the brain?

A

-⬆ ICF cAMP
-Activates the IP3-DAG cascade
-(↑ICF Ca++ & Protein Kinase C)

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21
Q

Where are H3 receptors found?

A

-Pre-synaptic Autoreceptors (negative feedback)
-Heteroreceptors
-Brain
-Myenteric Plexus
-Other Neurons

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22
Q

What are the actions of the H3 receptors in the brain?

A

⬇Histamine release

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23
Q

Where are the H4 receptors located?

A

-Eosinophils
-Neutrophils
-CD4 T Cells

Immune system. More cellular than tissues.

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24
Q

What are the actions of the H4 receptors?

A

Chemotaxic effects on Eosinophils & Mast cells
-Moves them to the site
-Cascade of immune response

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25
Q

What are the Nervous System effects associated with stimulation of solely the H1 receptor?

A

-Urticarial response
-Reactions to insects & stings
-Signal INSP & EXP in respiratory neurons

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26
Q

What are the Nervous System effects associated with stimulation of the H1 AND H3 receptor?

A

-Appetite & Satiety
-(Weight gain is an Adverse Effect of Anti-psychotics that block these receptors)

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27
Q

What are the Nervous System effects associated with stimulation of solely the H3 receptor?

A

-Regulates neurotransmitter release in the brain and peripheral tissues
-Ach, Amine/Peptide Release

Negative feedback loop. Pre-synaptic receptor

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28
Q

What are the CV effects associated with Histamine release?

A

-⬇SBP - ⬇DBP: Arterial vasodilation ⇒ flushing, sense of warmth & HA
-⬆HR: Direct stimulation of the heart to increase contractility and rate via H2 + reflex tachycardia from ⬇BP
-Separation of endothelial cells (edema) as a result of the H1 effects on microcirculation
-Urticaria: signals additional histamine release in the skin

29
Q

Low dose Histamine causes what?

A

H1 mediated vasodilation effects.
-Can be blocked with a H1 antagonist

30
Q

Higher doses of Histamine cause what?

A

H2 mediated cAMP vasodilation

31
Q

Edema is the result of the ___ effects on the microcirculation.

A

H1

32
Q

What Histamine receptor causes direct stimulation of the heart to increase contractility and rate?

A

H2 (!)

33
Q

What are the Bronchiolar Effects of H1 receptor stimulation?

A

-Bronchoconstriction
-Not an issue with small doses

Asthma/Cystic Fibrosis patients are very sensitive to Histamine effects.

34
Q

What are the GI Effects of H1 receptor stimulation?

A

-Contraction of intestinal smooth muscle
-Large doses of Histamine cause diarrhea

35
Q

What are the effects of H2 stimulation on the Parietal Cells?

A

-Powerful stimulation of gastric acid secretion, gastric pepsin, and intrinsic factor production.
-Associated with an increased Adenylyl cyclase, cAMP, and ICF Ca++

36
Q

What is the red spot, wheal/edema, and flare associated with Histamine called?

A

The Triple Response of Histamine

37
Q

Describe the Triple Response of Histamine.

A

1) Smooth muscle of the microcirculation dilations to enhance the access of immune cells to initiate repair processes, causing erythema (red spot)
2) Capillary/Venular Endothelium contracts and separates, resulting in the release of plasma proteins and fluids from the venules, causing edema (wheal).
3) Sensory Nerve Endings are depolarized, resulting in itch/pain sensation (flare)

38
Q

Explain how Histamine release leads to Erythema (Red Spot).

A

During infection or injury or intradermal injection, histamine-induced post-capillary venule dilation engorges the local microvasculature with blood, enhances the access of immune cells that initiate repair processes in the damaged area, and causes erythema (red spot)

39
Q

How does Histamine release lead to Edema (Wheal)?

A

Histamine also induces endothelial cell contraction and separation, resulting in the release of plasma proteins and fluids from post-capillary venules, causing edema (Wheal).

40
Q

How does Histamine release cause itch/pain (Flare)?

A

Histamine directly depolarizes afferent nerve terminals, resulting in itch and pain sensations (flare).

41
Q

What are the adverse effects of Histamine Release?

A

Effects are Dose-Related.
-Flushing
-Hypotension
-Tachycardia (reflexive)
-Headache
-Wheals
-Bronchoconstriction
-GI Upset (parietal cells)

42
Q

Explain Physiologic Anti-Histamines

A

Have the opposite effect of Histamine on smooth muscle but act on different receptors
-Ex: Epinephrine – lifesaving in systemic anaphylaxis

43
Q

Explain the MOA of Histamine Release Inhibitors.

A

-Reduce mast cell degranulation resulting from IgE-antigen complex
-Historic meds mentioned in research and discussion: Cromolyn & Nedocromil
-Useful in prevention
-Β2 agonists

44
Q

Explain the MOA of Histamine Receptor Antagonists.

A

H1: OTCs, cold pills, sleep aids
-Ex: Diphenhydramine

H2: GI therapies
-Ex: Cimetidine, Ranitidine, Famotidine, Nizatidine

H3 & H4: Not available for clinical use

45
Q

Describe the effects associated with 1st generation H1 Antagonists.

A

-CNS Effects
-Very strong sedatives

46
Q

What are the example drugs in the 1st generation of H1 Antagonists?

A

-Diphenhydramine
-Hydroxyzine (Atarax)
-Meclizine
-Chlorpheniramine (Chlor-Trimeton)
-Promethazine

47
Q

What are the effects associated with the 2nd generation of H1 Antagonists?

A

2nd gen is less sedating than 1st gen!!
-Less CNS distribution
-Non-sedating

48
Q

What are the example drugs in the 2nd generation of H1 Antagonists?

A

-Foxofenadine (Allegra)
-Loratidine (Claritan)
-Cetirizine (Zyrtec)

49
Q

What are the pharmacokinetics associated with H1 Antagonists?

A

-Absorption – rapid, peak 1-2hrs
-Distribution – DOA 4-6 hours. 2nd Gen: 12-24 hours due to ⬇lipid solubility
-Metabolism – extensively by liver enzymes. 2nd Gen have drug-to-drug interactions
-CYP3A4 group of drugs

Active metabolites available as meds:
-Hydroxyzine → Cetirizine (Zertec)
-Terfenadine → Fexofenadine (Allegra)
-Loratidine → Desloratadine

50
Q

What is the MOA for H1 Antagonists?

A

-Reversible competitive binding to H1
-Negligible effects on H2
-Little to no effect on H3

51
Q

1st generation H1 Antagonists have a similar structure to what other drugs?

A

1st Gen have a similiar structure to drugs that effect MR, α, 5-HTR, & Local Anesthetics

52
Q

What are the effects associated with ONLY the 1st generation of H1 Antagonists?

A

-Sedation
-Anticholinergic Effects
-Local Anesthesia

53
Q

Explain the sedative effects of 1st generation H1 Antagonists?

A

-Useful sleep aids
-Not the same degree/type of sedation that is achieved with sedative-hypnotic medications
-High doses can produce marked stimulation, agitation, convulsions, and coma
-Caution when taking with other meds that cause sedation/CNS depression

54
Q

Explain the anti-nausea/anti-emetic effects associated with H1 Antagonists.

A

Effective in the prevention of motion sickness, not as effective in the treatment of motion sickness

55
Q

How do H1 Antagonists have Anti-Parkinsonism Effects?

A

Suppresses EPS of anti-psychotic drugs

56
Q

What are the anti-cholinergic effects associated with 1st generation H1 Antagonists?

A

“Atropine Like” effect on peripheral MR
-Blurred vision
-Urinary retention

57
Q

What are the adrenoreceptor blocking actions associated with H1 Antagonists?

A

Especially from the Phenothiazines (Promethazine)
α blockade = orthostatic hypotension

58
Q

Which H1 Antagonist can be used if the patient is allergic to traditional local anesthetics (Lido/Procaine)?

A

Diphenhydramine (1st gen)

59
Q

What are the toxicity symptoms of H1 Antagonists (!!)

A

-Excitation & convulsions in children
-Postural hypotension
-Allergic response

60
Q

What are the clinical uses of H1 Antagonists?

A

An extensively promoted/used OTC
-Prevalence of allergic reactions to other drugs
-Relatively safe

-Allergic Reactions (effective for hay fever and allergic rxns if done preventatively)
-Motion Sickness: Diphenhydramine, Promethazine, Meclizine
-Not for morning Sickness (Teratogenic)

61
Q

___ Antagonist is the 1st line in prevention/treatment of Allergic Rxns.

A

H1 Antagonist.

62
Q

How are H1 Antagonists used for allergic rhinitis (hay fever)?

A

-H1 Antagonists 2nd line after corticosteroids

63
Q

How are H1 Antagonists used for Atopic Dermatitis?

A

-Used more for sedation than anti-itch effect
-Decrease awareness of itching

64
Q

Do H1 Antagonists have an effect on Asthma or angioedema?

A

No

65
Q

T/F: Clinical effectiveness of one group of H1 Antagonists may decrease over time, but changing drug groups may restore effectiveness.

A

True

66
Q

Why don’t we use 2nd generation H1 Antagonists to treat allergic rhinitis and chronic urticaria?

A

VERY expensive - even the OTC versions

67
Q

What is an example of some endogenous peptides that are autocoids?

A

Vasoconstrictors and Vasodilators

68
Q

What are some examples of vasoconstrictors that are autocoids?

A

Vasopressin
Uropressin
Angiotensin
Endothelian
Neuropeptide Y

69
Q

What are some examples of vasodilators that are autocoids?

A

Bradykinin
Patriotic Peptide
Vasoactive intestinal peptide
Substance P
Neurotensin
Calcitonin
Adrenomedullin

Pharm Exam 5 -- Smooth Muscle, GI and OTC (10 decks)

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