Download 2- H1 and H2 Receptors

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Autacoids
are biologically active amines that function as neurotransmitters and found in non-neural
tissues, have complex physiologic and pathologic effects through multiple receptor subtypes,
and are often released locally. Sometimes called autacoids (Greek, "self-remedy") or local
hormones in recognition of these properties. These amines involve Histamine, serotonin (5hydroxytryptamine), prostaglandins , leukotrienes and cytokines,…e.t.c.
Histamine
1. Location: Histamine present in practically all tissues, with significant amounts in the lungs,
skin, blood vessels, and GI tract. It found at high concentration in mast cells and basophils.
Histamine functions as a neurotransmitter in the brain. It also occurs as a component of
venoms and in secretions from insect stings.
2. Synthesis: Histamine is an amine formed by the decarboxylation of the amino acid histidine
by the enzyme histidine decarboxylase
3. Release of histamine: Most often, histamine is just one of several chemical mediators
released in response to stimuli. The stimuli for release of histamine from tissues may include
destruction of cells as a result of cold, toxins from organisms, venoms from insects and
spiders, and trauma. Allergies and anaphylaxis can also trigger significant release of
histamine.
Mechanism of action
Histamine released in response to certain stimuli exerts its effects by binding to various types
of histamine receptors (H1, H2, H3, and H4). H1 and H2 receptors are widely expressed and
are the targets of clinically useful drugs.
Pharmacological actions of histamine
1-H1 receptor:
EXOCRINE EXCRETION
Increased production of nasal and bronchial mucus, resulting in respiratory symptoms.
BRONCHIAL SMOOTH MUSCLE
Constriction of bronchioles results in symptoms of asthma and decreased lung capacity.
INTESTINAL SMOOTH MUSCLE
Constriction results in intestinal cramps and diarrhea.
SENSORY NERVE ENDING
Causes itching and pain.
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2- H1 and H2 Receptors
CARDIOVASCULAR SYSTEM
Lowers systemic blood pressure by reducing peripheral resistance ( vasodilation ). Causes
positive chronotropism (mediated by H2 receptors) and a positive inotropism (mediated by both
H1 and H2 receptors).
Skin
Dilation and increased permeability of the capillaries results in leakage of proteins and fluid
into the tissues. In the skin, this results in the classic “triple response”: wheal formation,
reddening due to local vasodilation, and flare (“halo”).
3-H2receptor
Stomach
Stimulation of gastric hydrochloric acid secretion.
Histamine antagonism
The effects of histamine released in the body can be reduced in several ways.
1-Physiologic antagonists, especially epinephrine, have smooth muscle actions opposite to
those of histamine, but they act at different receptors. This is important clinically because
injection of epinephrine can be lifesaving in systemic anaphylaxis
2-Release inhibitors reduce the degranulation of mast cells that results from immunologic
triggering by antigen-IgE interaction. Cromolyn and nedocromil appear to have this effect
and are used in the treatment of asthma.
3-Histamine receptor antagonists, receptor blockers.
H1 receptor antagonists
The term antihistamine refers primarily to the classic H1-receptor blockers. The H1-receptor
blockers can be divided into first- and second generation drugs. The older first-generation
drugs are still widely used because they are effective and inexpensive. However, most of these
drugs penetrate the CNS and cause sedation. Furthermore, they tend to interact with other
receptors, producing a variety of unwanted adverse effects.
In contrast, the second-generation agents are specific for peripheral H1 receptors. Because they
are made polar mainly by adding carboxyl groups (for example, cetirizine is the carboxylated
derivative of hydroxyzine), the second-generation agents do not penetrate the blood–brain
barrier, causing less CNS depression than the first- generation drugs. Among the secondgeneration agents, Desloratadine, and loratadine.
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Mechanism of action
The action of all the H1-receptor blockers is qualitatively similar. Most of these compounds
do not influence the formation or release of histamine. Rather, they block the receptormediated response of a target tissue. However, most of these agents have additional effects
unrelated to their ability to block H1 receptors. These effects reflect binding of the H1receptor antagonists to cholinergic, adrenergic, or serotonin receptors.
The antimuscarinic activity of several first-generation H1-blockers may account for their
effectiveness in combating motion sickness and their limited ability to suppress parkinsonian
symptoms.
The phenothiazines have some capacity to block α-adrenergic receptors, whereas
cyproheptadine (Periactin) is an antagonist at serotonin receptors.
Diphenhydramine (Benadryl), pyrilamine (Ryna), and promethazine (Phenergan) are
effective local anesthetics.
Many second generation antihistamines also have been found to inhibit the non–histaminemediated release of various inflammatory substances; this may account for some of their
effectiveness in allergic conditions.
Therapeutic uses
1. Allergic and inflammatory conditions: H1-receptor blockers are useful in treating and
preventing allergic reactions caused by antigens acting on immunoglobulin E antibody. For
example, oral antihistamines are the drugs of choice in controlling the symptoms of allergic
rhinitis and urticaria. However, the H1-receptor blockers are not indicated in treating
bronchial asthma, because histamine is only one of several mediators that are responsible
for causing bronchial reactions.
2. Motion sickness and nausea: Along with the antimuscarinic agent scopolamine, certain H1receptor blockers, such as diphenhydramine, cyclizine, and promethazine.
3. Somnifacients: Although they are not the medications of choice, many first-generation
antihistamines, such as diphenhydramine and doxylamine have strong sedative properties and
are used in the treatment of insomnia.
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Adverse effects
First-generation H1-receptor blockers have a low specificity, interacting not only with
histamine receptors but also with muscarinic cholinergic receptors, α-adrenergic receptors, and
serotonin receptors .The extent of interaction with these receptors and, as a result, the nature of
the side effects varies with the structure of the drug. Some side effects may be undesirable, and
others may be of therapeutic value. Furthermore, the incidence and severity of adverse reactions
for a given drug varies between individual subjects.
1. Sedation: First-generation H1 antihistamines, such as chlorpheniramine, diphenhydramine,
hydroxyzine and promethazine, bind to H1 receptors and block the neurotransmitter effect of
histamine in the CNS.
2. Other effects: First-generation antihistamines exert anticholinergic effects, leading not
only to dryness in the nasal passage but also to a tendency to dry out the oral cavity. They
also may cause blurred vision and retention of urine. The most common adverse reaction
associated with second-generation antihistamines is headache. Topical formulations of
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diphenhydramine can cause hypersensitivity reactions such as contact dermatitis when
applied to the skin.
3. Drug interactions: Interaction of H1-receptor blockers with other drugs can cause serious
consequences, such as potentiation of effects of other CNS depressants, including alcohol.
Histamine H2-receptor blockers
(H2 antagonists or H2-receptor blockers) block the actions of histamine at all H2 receptors,
their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and
heartburn.
The four H2-receptor blockers are cimetidine, ranitidine, famotidine, and nizatidine
Side effects (Mostly Associated with Cimetidine (Tagamet))
1. Most common (seen in only 1-2% of patients):diarrhea, dizziness, somnolence, headache,
and rash. Also constipation, vomiting and arthralgia.
2. CNS effects: slurred speech, delirium, confusion. Most commonly seen in older patients
or those with liver or kidney impairment
3. Endocrine function (minor and reversible):anti androgen effects, e.g., loss of libido,
impotence, reduced sperm count
4. Blood dyscrasias.
5. Liver: reversible cholestasis.
H2 Antagonist Drug Interaction
Cimetidine: increased activity of drugs that are metabolized through cytochrome P450 pathway
(enzyme inhibitor ) and also reduces blood flow through the liver including. e.g., warfarin,
phenytoin, propanolol, metoprolol, quinidine, caffeine, lidocaine, theophylline,
benzodiazepines, ethanol, tricyclic antidepressants, and calcium channel blockers.
Serotonin
Serotonin was the name given to an unknown vasoconstrictor substance found in the serum
after blood had clotted. It was subsequently found in the gastrointestinal tract and central
nervous system (CNS), and shown to function both as a neurotransmitter and as a local
hormone in the peripheral vascular system.
Based on biochemical and pharmacological criteria, serotonin receptors are classified into
seven main receptor subtypes, 5-HT1–7. Of major pharmacotherapeutic importance are those
designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the
5-HT3 subtype represents a ligand-gated ion channel.
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Important actions are:
1-increased gastrointestinal motility (direct excitation of smooth muscle and indirect action via
enteric neurons).
2-contraction of other smooth muscle (bronchi, uterus).
3-mixture of vascular constriction (direct and via sympathetic innervation) and dilatation
(endothelium-dependent) .
4-platelet aggregation.
5-stimulation of peripheral nociceptive nerve endings.
6-excitation/inhibition of central nervous system neurons.
Clinical conditions associated with disturbed 5-hydroxytryptamine(serotonin) function
include migraine, carcinoid syndrome, mood disorders and anxiety
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