Pharmacology Lecture 17 Antihistamines

Front 1

How many types of histamine receptors are there?

Back 1

4

Front 2

What enzymes metabolize histamine?

Back 2

Histamine methyl transferase
Diamine oxidase

Front 3

Explain H1 receptors

Back 3

H1 receptors are coupled to phospholipase C. Their activation causes formation of inositol 1,4,5 triphosphate (IP3) and diacyl glycerols from phospholipids in cell membrane. IP3 causes release of calcium from endoplasmic reticulum, diacyl glycerols activate protein kinase C in target cell. Human H1-receptors have approximately 45 percent homology with muscarinic receptors.

Front 4

Explain H2 receptors

Back 4

H2 receptors are linked to stimulation of adenyl cyclases and activation of cyclic AMP dependent-protein kinase.

Front 5

Explain H3 receptors

Back 5

H3 receptors are presynaptic autoreceptors on histaminergic and non-histaminergic CNS and peripheral neurons

Front 6

Explain H4 receptors

Back 6

Unknown

Front 7

Explain the immediate hypersensitivity reaction

Back 7

a. Antibodies (IgE) are generated as part of the allergic response to an antigen.
b. Bind to surface of mast cells and basophils at high affinity (FceRI) receptors; IgE molecules then function as receptors.
c. Antigen bridges the IgE molecules and causes activation of tyrosine kinases which cause protein phosphorylation.
d. Release of calcium from intracellular stores occurs, causing an increase in cytosolic calcium.
e. Exocytosis of histamine secretory granules (fusion of secretory granule with plasma membrane).
f. Histamine exerts a wide range of physiological effects.

Front 8

Explain the allergic reaction to certain drugs

Back 8

A
llergic urticaria to drugs which have antigenic activity.
Anaphylactoid reactions which are caused by release of histamine independent of IgE stimulation of mast cells without prior sensitization (many drugs used in anesthesia, tubocurarine, succinylcholine, morphine radiocontrast media, drugs which are organic bases; may account for unexpected anaphylactoid reactions).

Front 9

Besides allergic reactions, what else can cause histamine release?

Back 9

Cold urticaria and urticaria associated with physical trauma.
Cold and scratching can cause histamine release.

Front 10

What is the effect of histamine on vasculation?

Back 10

Dilation of finer blood vessels
Increased capillary permeability

Front 11

How does histamine cause dilation of finer blood vessels?

Back 11

lower total peripheral resistance and a fall in systemic blood pressure. This action results from relaxation of arteriolar vascular smooth muscle and involves H1 and H2 receptors distributed through out the resistance vessels in most vascular beds. The H1 receptors which reside on the endothelial cells have higher affinity for histamine and cause a rapid and short
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vasodilation which involves the release of EDRF (endothelial derived relaxing factor). The H2 receptors on vascular smooth muscle have less affinity and cause dilation that develops more lowly and is more sustained.

Front 12

How does histamine cause increased capillary permeability?

Back 12

Histamine causes an increased capillary permeability which is mediated by H1 receptors. This results in passage of plasma proteins and fluid into the extracellular space and edema formation. Its action is on post-capillary venules where histamine causes endothelial cells to contract and separate at their boundaries to expose their basement membranes which is permeable to plasma roteins and fluid.

Front 13

What is histamine shock?

Back 13

p
Histamine release in large amounts (systemic anaphylaxis) causes a profound fall in the blood pressure, called “histamine shock”. Large amounts of blood trapped in the small vessels, and increased permeability results in plasma escape from the circulation. This results in decreased blood volume and venous return, and a ecreased cardiac output

Front 14

What are the cardiac effects of histamine?

Back 14

Histamine acts on the heart only in high concentrations. Its effects on the heart in low concentrations are a result of the baroreceptor response to the fall in blood pressure. In large amounts histamine increases force of contraction by promoting calcium influx (H2 receptor effect). It also speeds sinus rate and increases ventricular automaticity (H2 receptor effect). Histamine slows AV nodal conduction (H1 receptor effect). Histamine may be involved in causing cardiac arrhythmias that occur in anaphylaxis by causing AV block and increasing ventricular automaticity.

Front 15

What are the pulmonary effects of histamine?

Back 15

Histamine causes bronchconstriction (H1 receptor effect). This action is more pronounced in patients with asthma or certain pulmonary diseases than in normal people. Histamine acts on H1 receptors to increase secretion of airway fluid and electrolytes. Actions of histamine can result in bronchial obstruction in the setting of extrinsic asthma.

Front 16

What are the GI effects of histamine?

Back 16

Histamine release from gastric mucosa stimulates secretion of acid from parietal cells through an action on the H2 receptors.

Front 17

What are the nervous system effects of histamine?

Back 17

Histamine functions as a neurotransmitter in some regions of the CNS. H1 receptors are densely concentrated in the hypothalamus. Histamine increases wakefulness, explaining sedation by some antihistaminics (see below). It also may participate in regulation of drinking, body temperature and ADH secretion, and the control of blood pressure and erception of pain.
p
Histamine stimulates peripheral nerve endings (H1 receptors) to cause pain and itching

Front 18

Which first generation H1-receptor antagonists are important?

Back 18

promethazine (Phenergan)
chlorpheniramine (Chlortrimeton)
cyclizine (Marezine)
dimenhydrinate (Dramamine)
diphenhydramine (Benadryl)
meclizine (Antivert, Bonine)

Front 19

How are H1-receptor antagonists characterized?

Back 19

Drugs which antagonize the H1 receptor may be classified into first generation drugs which have sedating properties and second generation drugs which are non-sedating (terfenadine, astemizole, loratidine, fexofenadine).

Front 20

Which second generation H1-receptor antagonists are important?

Back 20

i.
loratidine (Claritin)*
ii.
desloratidine (Clarinex)*
iii.
fexofenadine (Allegra)*

Front 21

What is the mechanism of action for H1 antihistamines?

Back 21

H1 antihistamines act as inverse agonists that combine with and stabilize the inactive form of the H1 receptor, shifting the equilibrium toward the inactive state. This mechanism is different than the traditional competitive or non-competitive blocking drug.

Front 22

How are antihistamines metabolized?

Back 22

All first-generation H1-antihistamines and some second-generation H1-antihistamines, such as loratadine, are metabolized by the hepatic cytochrome P450 (CYP450) system. Loratidine is metabolized to the active metabolism, desloratidine which is marketed as Clarinex. It is unclear how deloratidine is metabolized. Hepatic impairment requires reducing the dose of orally administered drug that are metabolized by the liver

Front 23

How are antihistamines excreted?

Back 23

Cetirizine, is excreted largely unchanged in the urine and requires reduction in dose in patients with renal impairment. Fexofenadine is excreted largely unchanged in the feces, although some is excreted by the kidney..
Some H1 antihistamines are available only in topical formulations (levocabastine, olopatadine,azelastine).

Front 24

What is the effect of H1 antihistamines on smooth muscle?

Back 24

These drugs inhibit rapid vasodilator effects of histamine (H1 receptors), hile the residual slow vasodilator effect remains (H2 receptors).
w
While they antagonize the constrictor effect on bronchial smooth muscle, allergic bronchoconstriction may not be entirely prevented because it is caused, to a large extent, by other mediators such as leukotrienes. Therefore, antihistaminics are not effective alone in the treatment of bronchial asthma, although they might prevent some of the bronchoconstriction and increased secretion associated with seasonal allergies.

Front 25

What is the effect of H1 antihistamines on vascular permeability?

Back 25

Antihistaminics prevent increased capillary permeability caused by istamine.
h
As a result of their effects on vascular smooth muscle and capillary permeability, immediate hypersensitivity reactions and allergic responses can be controlled with these drugs (see Therapeutic Uses). The drugs cannot be used alone in treatment of anaphylaxis because of the important role played by other mediators.

Front 26

What is the effect of H1 antihistamines on the CNS?

Back 26

CNS depression, manifested as sedation, usually accompanies therapeutic doses of first generation H1 antagonists. This effect may be desirable in infants or in over the counter sleeping medications where these drugs can be used as sedatives, but undesirable when only an antihistaminic effect for an allergic reaction is required. The second generation H1 antagonists are non-sedating (loratidine, fexofenadine) because they do not cross the lood brain barrier.
b
CNS excitation sometimes occurs with first generation H1 antagonist drugs since they enter the CNS (restlessness, nervous, unable to sleep). CNS excitation is a central feature of poisoning; convulsions can occur in nfants.
i
The first generation drugs have the ability to prevent motion sickness. These drugs have muscarinic blocking effects both peripherally and centrally, which may be the central mechanism of action (remember the antimotion sickness effects of scopolamine which is also a muscarinic locker) (cyclizine, meclizine).
b
Some of the drugs (promethazine) have an antiemetic effect by blocking entral muscarinic and dopamine receptors.
c
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Second generation drugs (loratidine, fexofenadine) have no effects on muscarinic receptors and do not enter the CNS. Therefore, they do not have anti-motion sickness effects or CNS toxic effects.

Front 27

What is the effect of H1 antihistamines on the PNS?

Back 27

H1 blockers prevent pain and itch caused by histamine action on peripheral nerve endings.

Front 28

What are the therapeutic uses of H1 antihistamines?

Back 28

1. Allergy
Seasonal rhinitis and conjunctivitis (hay fever, pollynosis); antihistaminic drugs relieve sneezing, rhinorrhea, and itching of the eyes, nose and hroat.
t
(In bronchial asthma histamine antagonists have limited beneficial effects ecause of other mediators involved.)
b
In the treatment of systemic anaphylaxis, other autocoids are involved so antihistaminics are not very effective.
2. Allergic drug reactions
3. Common cold
Of little use except perhaps drying effect of antimuscarinic action of first generation drugs.
4. Motion sickness, vertigo and sedation (first generation drugs).

Front 29

What are the side effects of H1 antihistamines?

Back 29

1. Sedation is an undesirable side effect of the first generation drugs. This effect is additive with other CNS depressants such as alcohol.
2. Antimuscarinic actions of first generation drugs exerted on the peripheral autonomic nervous system (dryness of mouth and respiratory passages, urinary retention). Second generation drugs do not have these effects.
3.
Prolongation of the QT interval on the electrocardiogram and polymorphic ventricular tachycardia. This potentially lethal side effect occurred unexpectedly in some patients who were taking the second generation drug terfenadine. It occurred when hepatic metabolism of terfenadine was impaired, resulting in accumulation of a large amount of terfenadine in the circulation (terfenadine is normally rapidly metabolized to fexofenadine). This most commonly occurred with co-administration of another drug that inhibited the cytochrome P450 enzyme CYP3A4 (erythromycin, ketoconazole). The parent drug (terfenadine) blocks delayed rectifier potassium channels in the heart, prolonging the duration of ventricular muscle action potentials, which causes the serious ventricular arrhythmias. Because of this toxicity, fexofenadine is now marketed rather than terfenadine. Loratidine is also metabolized by CYP3A4, but is not associated with toxicity even when this enzyme system is inhibited because it does not block potassium channels in the heart.