Transcript Bez nadpisu - Univerzita Karlova

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.)
Histamine and serotonin receptor subtypes.1
Receptor Distribution
Postreceptor
Prototype
Subtype
Mechanism
Antagonist
H1
Smooth muscle
Diphenhydramine
 IP3, DAG
H2
Stomach, heart,
Cimetidine
 cAMP
mast cells
H3
Nerve endings, G protein-coupled Impromidine
CNS
5-HTfd
Brain
 cAMP
5-HT2
Smooth muscle,
Ketanserin
 IP3, DAG
platelets
5-HT3
Area postrema
Gated caution Ondansetron
(CNS), sensory
channel
and enteric nerves
1
Many other serotonin receptors are recognized in the CNS. They are
discussed in Chapter 20.
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.
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.
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.
Antihistaminika - H1
• sedative
difenhydramin
embramin
prometazin
cyproheptadin
bisulepin
dimetinden
azatadin
klemastin
• nonsedative
terfenadine
astemizol
cetirizin
loratidin
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.
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.
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.
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.
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.
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.
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)
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.
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.
Histamine and serotonin receptor subtypes.1
Receptor Distribution
Postreceptor
Prototype
Subtype
Mechanism
Antagonist
H1
Smooth muscle
Diphenhydramine
 IP3, DAG
H2
Stomach, heart,
Cimetidine
 cAMP
mast cells
H3
Nerve endings, G protein-coupled Impromidine
CNS
5-HTfd
Brain
 cAMP
5-HT2
Smooth muscle,
Ketanserin
 IP3, DAG
platelets
5-HT3
Area postrema
Gated caution Ondansetron
(CNS), sensory
channel
and enteric nerves
1
Many other serotonin receptors are recognized in the CNS. They are
discussed in Chapter 20.
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
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.
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.
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-HTgated 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.
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.
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.
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.
Toxicity
Adverse effects of ketanserin are those of alpha
blockade and H1 blockade.
The toxicities of ondasetron include diarrhea and
headache.