Bez nadpisu

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HISTAMINE Histamine is formed from the amino
acid histidine and is stored in high
concentrations in mast cells. Localisation ?
lungs, skin, GIT Excess production of histamine
in the body it is released from mast cells in
response to ? IgE-mediated (immediate) allergic
reactions, this autacoid plays an important
pathophysiologic role in seasonal rhinitis (hay
fever), urticaria, and angioneurotic edema. ?
Drugs (tubocurarine, morfine etc.)
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H1 receptor This receptor is important in
smooth muscle effects, especially those caused by
IgE-mediated responses. IP3 and DAG are released.
Bronchoconstriction and vasodilation, the
latter by release of endothelium-derived relaxing
factor (EDRF), are typical retracts, opening gaps
in the permeability barrier and resulting in the
formation of local edema. These effect are
manifest in allergic reactions and in
mastocytosis, a rare neoplasm of mast cells.
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H2 receptor This receptor mediates gastric
acid secretion by parietal cells in the stomach.
It also has a cardiac stimulant effect. A third
action is to reduce histamine release from mast
cells - a negative feedback effect. These
actions are mediated by activation of adenylyl
cyclase, which increases intracellular cAMP.
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H3 receptor This receptor appears to be
involved mainly in presynaptic modulation of
histaminergic neurotransmission in the central
nervous system. In the periphery, it appears to
be a presynaptic heteroreceptor with modulatory
effects on the release of other transmitters.
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Antihistaminika - H1

• sedative
• difenhydramin
• embramin
• prometazin
• cyproheptadin
• bisulepin
• dimetinden
• azatadin
• klemastin

• nonsedative
• terfenadine
• astemizol
• cetirizin
• loratidin

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HISTAMINE H1 ANTAGONISTS Diphenhydramine and
chlorpheniramine may be considered prototypes.
H1 blockers are all active by the oral route.
Most are metabolized extensively in the liver.
Half-lives of the older H1 blockers vary from 4
to 12 hours. Several newer agents (eg,
terfenadine, astemizole) have half-lives of 12 to
24 hours and decreased CNS penetration.
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Mechanism Effects ? H1 blockers are
competitive antagonists at the H1 receptor. ?
Because their structure closely resembles that of
muscarinic blockers and alpha adrenoceptor
blockers, many of these agents are pharmacologic
antagonists at these autonomic receptors. A few
also block serotonin receptors. However, they
have negligible effects at H2 receptors. ? Many
H1 blockers are potent local anesthetics.
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Clinical Use In the periphery, they
competitively inhibit the effects of histamine
(especially if given before histamine release
occurs). ? major applications in allergies of the
immediate type (ie, those caused by antigens
acting of IgE antibody-sensitized mast cells).
These conditions include hay fever and
urticardia. The drugs have a broad spectrum of
adverse effects that limit their usefulness but
can sometimes be used to good effect (eg, the
sedative effect is used in over-the-counter-sleep
aids). H1-blocking drugs have sedative and
antimotion sickness effects in the CNS.
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Toxicity ? Sedation is common, especially with
diphenhydramine and promethazine. It is much less
common with newer agents that do not enter the
CNS readily. ? Antimuscarinic effects (dry
mouth, blurred vision etc.) ? a-blocking actions
may cause orthostatic hypotension. Interaction
? Drugs with sedative effects, eg,
benzodiazpeines and alcohol. ? Drug that inhibit
hepatic metabolism (ketaconazole) may result in
dangerously high levels of nonsedating
antihistaminic drugs (e.g. terfenadine) ? the
plasma concentration of either antihistamine may
increase and precipitate lethal arrhythmias.
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HISTAMINE H2 ANTAGONISTS cimetidine is the
prototype. (ranitidine, famotidine) These drugs
do not resemble H1 blockers structurally. They
are orally active, with half-lives of 1-3 hours.
Because they are relatively nontoxic, they can
be given in large doses, so that the duration of
action of a single dose may be 13-24 hours.
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Mechanism Effects ? selective and have no
significant blocking action at H1 or autonomic
receptors. ? The only therapeutic effect of
clinical importance is the reduction of gastric
acid secretion ? Blockade of cardiovascular H2
receptor-mediated effects can be demonstrated,
but has no clinical significance.
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Clinical Use Acid-peptic disease, especially
duodenal ulcer ? Acute ulcer is usually treated
with two more doses per day, ? recurrence of the
ulcer can often be prevented with a single
bedtime dose. H2 blockers are also effective in
accelerating healing and prevneting recurrences
of gastric peptic ulcers. Zollinger-Ellison
syndrom Gastroesophageal reflux disease (GERD)
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Toxicity Cimetidine is a potent inhibitor of ?
hepatic drug-metabolizing enzymes and may reduce
hepatic blood flow. ? has significant
antiandrogen effects in many patients.
Ranitidine has a weaker inhibitory effect on
hepatic drug metabolism, neither it nor the newer
H2 blockers appear to have endocrine effects.
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SEROTONIN (5-HYDROXYTRYPTAMINE, 5-HT) RELATED
AGONISTS Serotonin is produced from tryptophan
and stored in the enterochromaffin cells of the
gut and in the CNS. Excess production in the
body can be detected by measuring its major
metabolite, 5-hydroxy-indoleacetic acid, in the
urine.
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Serotonin appeas to play a physiologic role as a
neurotransmitter in both the CNS and the enteric
nervous system, and possibly as a local hormone
that modulates gastrointestinal activity.
Serotonin is also stored (but synthesized to only
a minimal extent) in platelets. Only one drug
is in use for its serotonin agonist effects
several are in use or under investigation as
serotonin antagonist
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5-HT1 receptors 5-HT1 receptors are most
important in the brain and mediate synaptic
inhibition via increased potassium conductance
(Table 16-2). Peripheral 5-HT1 receptors
mediate both excitatory and inhibitory effects in
various smooth muscle tissues.
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5-HT2 receptors 5-HT2 receptors are important
in both brain and peripheral tissues. These
receptors mediate synaptic excitation in the CNS
and smooth muscle contration (gut, bronchi,
uterus, vessels) or dilation (vessels). The
mechanism involves (in different tissues)
decreased potassium conductance, decreased cAMP,
and increased IP3. In carcinoid tumor, this
receptor probably mediates some of the
vasodilation, diarrhea, and bronchoconstriction
characteristic of the disease.
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5-HT3 receptors 5-HT3 receptors are found in the
CNS, especially in the chemoreceptive area and
vomiting center, and in peripheral sensory and
enteric nerves. These receptors mediate
excitation via a 5-HT-gated cation channel (ie,
the mechanism of serotonin at the 5-HT3 receptor
resembles that of Ach at nicotinic cholinergic
cation channels). Antagonists acting at this
receptor have proved to be useful antiemetic
drugs.
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Clinical Use Serotonin has no clinical
applications. Other agonists Sumatriptan ?
5-HTld agonist. It is effective in the treatment
of acute migraine and cluster headache attacks,
an observation that strengthens the association
of serotonin abnormalities with these headache
syndromes. At present it is available only for
parenteral injection, unlike the ergot
antimigraine medications, which are available for
oral and rectal (suppository) use. A number of
important antidepressant drugs act at
serotonergic synapses by inhibiting the reuptake
carrier for 5-HT.
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Serotonin antagonists Ketanserin is 5-HT2 and
alpha adrenoceptor blocker. Phenoxybenzamine
(an alpha adrenoceptor blocker) and
cyproheptadine (an H1 blocker and antimuscarinic
compound) are also good 5-HT2 blockers.
Ondansetron, dolasetron are a 5-HT3 blockers.
The ergot alkaloids are partial agonists at
5-HT (and other) receptors.
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Clinical Uses Ketanserin is under
investigation as an AHT drug. Ketanserin,
cyproheptadine, and phenoxybenzamine may be of
value (separately or in combination) in the
treatment of carcinoid tumor, a neoplasm that
secretes large amounts of serotonin (and
peptides) and causes diarrhea, bronchoconstriction
, and flushing. Ondasetron is used to control
postoperative vomiting and vomiting associated
with cancer chemotherapy.
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Toxicity Adverse effects of ketanserin are
those of alpha blockade and H1 blockade. The
toxicities of ondasetron include diarrhea and
headache.