Smooth Muscle (pt 2/4) Histamine Flashcards
What are Autocoids?
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.
What does Paracrine mean?
Effects are mostly localized but large amounts can be produced and moved into circulation.
What does Endocrine mean?
May have systemic effect by being transported via circulation.
What are the different examples of Autocoids?
-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
What are the similarities between Histamine and Serotonin?
-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
What is Histamine?
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
Where is Mast Cell Histamine located?
-Found throughout most tissues
-High concentrations at sites of potential injury: Nose, Mouth, Feet, Internal body surfaces, Blood Vessels (pressure points and bifurcations)
Where is Non-Mast Cell histamine located?
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)
Explain the Sensitization and Effector Phases of Immunologic Histamine Release.
-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).
What occurs with Immunologic Histamine release on re-exposure to the antigen?
-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)
How does Histamine release contribute to inflammation? 3 ways
-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
How can Histamine be released by non-injury related causes?
Anaphylaxis to an amine or a drug (ex: Morphine)
-Doesn’t have degranulation or Mast Cell activation
T/F: Humans are more sensitive than rats/mice to histamine, but less sensitive than guinea pigs.
True
What type of receptor are the Histamine receptors?
All are GPCRs.
Explain the similarities with Histamine receptors and other receptors.
-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.
Which Histamine Receptors are found in the brain?
H1, H2, and H3
Where are H1 receptors found?
-Smooth Muscle
-Endothelium
-Brain
post-synaptic
What are the actions of the H1 receptors in the brain?
-⬆Phosphoinositol Hydrolysis →
-⬆ IP3 & ICF Ca++
Need inc Ca for release of NTs in the brain via exocytosis.
Where are H2 receptors found?
-Gastric Mucosa
-Cardiac Muscle
-Mast Cell
-Brain
post-synaptic
What are the actions of the H2 receptors in the brain?
-⬆ ICF cAMP
-Activates the IP3-DAG cascade
-(↑ICF Ca++ & Protein Kinase C)
Where are H3 receptors found?
-Pre-synaptic Autoreceptors (negative feedback)
-Heteroreceptors
-Brain
-Myenteric Plexus
-Other Neurons
What are the actions of the H3 receptors in the brain?
⬇Histamine release
Where are the H4 receptors located?
-Eosinophils
-Neutrophils
-CD4 T Cells
Immune system. More cellular than tissues.
What are the actions of the H4 receptors?
Chemotaxic effects on Eosinophils & Mast cells
-Moves them to the site
-Cascade of immune response
What are the Nervous System effects associated with stimulation of solely the H1 receptor?
-Urticarial response
-Reactions to insects & stings
-Signal INSP & EXP in respiratory neurons
What are the Nervous System effects associated with stimulation of the H1 AND H3 receptor?
-Appetite & Satiety
-(Weight gain is an Adverse Effect of Anti-psychotics that block these receptors)
What are the Nervous System effects associated with stimulation of solely the H3 receptor?
-Regulates neurotransmitter release in the brain and peripheral tissues
-Ach, Amine/Peptide Release
Negative feedback loop. Pre-synaptic receptor
What are the CV effects associated with Histamine release?
-⬇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
Low dose Histamine causes what?
H1 mediated vasodilation effects.
-Can be blocked with a H1 antagonist
Higher doses of Histamine cause what?
H2 mediated cAMP vasodilation
Edema is the result of the ___ effects on the microcirculation.
H1
What Histamine receptor causes direct stimulation of the heart to increase contractility and rate?
H2 (!)
What are the Bronchiolar Effects of H1 receptor stimulation?
-Bronchoconstriction
-Not an issue with small doses
Asthma/Cystic Fibrosis patients are very sensitive to Histamine effects.
What are the GI Effects of H1 receptor stimulation?
-Contraction of intestinal smooth muscle
-Large doses of Histamine cause diarrhea
What are the effects of H2 stimulation on the Parietal Cells?
-Powerful stimulation of gastric acid secretion, gastric pepsin, and intrinsic factor production.
-Associated with an increased Adenylyl cyclase, cAMP, and ICF Ca++
What is the red spot, wheal/edema, and flare associated with Histamine called?
The Triple Response of Histamine
Describe the Triple Response of Histamine.
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)
Explain how Histamine release leads to Erythema (Red Spot).
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)
How does Histamine release lead to Edema (Wheal)?
Histamine also induces endothelial cell contraction and separation, resulting in the release of plasma proteins and fluids from post-capillary venules, causing edema (Wheal).
How does Histamine release cause itch/pain (Flare)?
Histamine directly depolarizes afferent nerve terminals, resulting in itch and pain sensations (flare).
What are the adverse effects of Histamine Release?
Effects are Dose-Related.
-Flushing
-Hypotension
-Tachycardia (reflexive)
-Headache
-Wheals
-Bronchoconstriction
-GI Upset (parietal cells)
Explain Physiologic Anti-Histamines
Have the opposite effect of Histamine on smooth muscle but act on different receptors
-Ex: Epinephrine – lifesaving in systemic anaphylaxis
Explain the MOA of Histamine Release Inhibitors.
-Reduce mast cell degranulation resulting from IgE-antigen complex
-Historic meds mentioned in research and discussion: Cromolyn & Nedocromil
-Useful in prevention
-Β2 agonists
Explain the MOA of Histamine Receptor Antagonists.
H1: OTCs, cold pills, sleep aids
-Ex: Diphenhydramine
H2: GI therapies
-Ex: Cimetidine, Ranitidine, Famotidine, Nizatidine
H3 & H4: Not available for clinical use
Describe the effects associated with 1st generation H1 Antagonists.
-CNS Effects
-Very strong sedatives
What are the example drugs in the 1st generation of H1 Antagonists?
-Diphenhydramine
-Hydroxyzine (Atarax)
-Meclizine
-Chlorpheniramine (Chlor-Trimeton)
-Promethazine
What are the effects associated with the 2nd generation of H1 Antagonists?
2nd gen is less sedating than 1st gen!!
-Less CNS distribution
-Non-sedating
What are the example drugs in the 2nd generation of H1 Antagonists?
-Foxofenadine (Allegra)
-Loratidine (Claritan)
-Cetirizine (Zyrtec)
What are the pharmacokinetics associated with H1 Antagonists?
-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
What is the MOA for H1 Antagonists?
-Reversible competitive binding to H1
-Negligible effects on H2
-Little to no effect on H3
1st generation H1 Antagonists have a similar structure to what other drugs?
1st Gen have a similiar structure to drugs that effect MR, α, 5-HTR, & Local Anesthetics
What are the effects associated with ONLY the 1st generation of H1 Antagonists?
-Sedation
-Anticholinergic Effects
-Local Anesthesia
Explain the sedative effects of 1st generation H1 Antagonists?
-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
Explain the anti-nausea/anti-emetic effects associated with H1 Antagonists.
Effective in the prevention of motion sickness, not as effective in the treatment of motion sickness
How do H1 Antagonists have Anti-Parkinsonism Effects?
Suppresses EPS of anti-psychotic drugs
What are the anti-cholinergic effects associated with 1st generation H1 Antagonists?
“Atropine Like” effect on peripheral MR
-Blurred vision
-Urinary retention
What are the adrenoreceptor blocking actions associated with H1 Antagonists?
Especially from the Phenothiazines (Promethazine)
α blockade = orthostatic hypotension
Which H1 Antagonist can be used if the patient is allergic to traditional local anesthetics (Lido/Procaine)?
Diphenhydramine (1st gen)
What are the toxicity symptoms of H1 Antagonists (!!)
-Excitation & convulsions in children
-Postural hypotension
-Allergic response
What are the clinical uses of H1 Antagonists?
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)
___ Antagonist is the 1st line in prevention/treatment of Allergic Rxns.
H1 Antagonist.
How are H1 Antagonists used for allergic rhinitis (hay fever)?
-H1 Antagonists 2nd line after corticosteroids
How are H1 Antagonists used for Atopic Dermatitis?
-Used more for sedation than anti-itch effect
-Decrease awareness of itching
Do H1 Antagonists have an effect on Asthma or angioedema?
No
T/F: Clinical effectiveness of one group of H1 Antagonists may decrease over time, but changing drug groups may restore effectiveness.
True
Why don’t we use 2nd generation H1 Antagonists to treat allergic rhinitis and chronic urticaria?
VERY expensive - even the OTC versions
