AUTOCOID

PHARMACOLOGY

AUTOCOIDS
biological factors that are primarily
characterized by the effect they have
upon smooth muscle
VASODILATOR AUTOCOIDS can be
released during periods of exercise
comes from the GREEK "autos"(self)
and "acos"(drug)

SOME NOTABLE AUTOCOIDS:

eicosanoids
angiotensin
neurotensin
nitric oxide
kinins
histamine
serotonin
endothelins

DISTRIBUTION, TURNOVER and

STORAGE OF HISTAMINES

tissues- 1 to over 100mg/g

plasma- normally very low
CSF- high
brain, stomach, healing tissues
and some cells in the skin histamine
is not stored in granules
identical to mast cells therefore
wherever mast cells are, there will
most likely be histamine present

 MAST CELLS ARE DISTRIBUTED IN:

skin
bronchial mucosa
gut mucosa
other mucosal surfaces
high turnover
low steady state levels

What triggers the release of

histamine?

anaphylactic triggers
antigen specific, IgE mediated
anaphylactoid triggers
organic bases
morphine
tubocuravine
succinylchloride
dextran
contrast media used in radiography
vancomycin
some neuropeptides
venom from insects

Diseases associated with

increased histamine
urticaria pigmentosa
systemic mastocytosis
myelogenous leukemia
gastrinoma
gut ulcers and diarrhea, urticaria,
pruritus

EFFECTS OF HISTAMINE IN
HUMANS
burning due to sensory nerve
stimulation
itching
warmth
skin flush vasodilation
hypotension vasodilation
headache vasodilation
skin edema
GI irritation
acid hypersecretion
bronchospasm

HISTAMINE RECEPTORS

H1
H2
H3
all are 7 transmembrane spanning
G coupled receptors

HISTAMINE IN THE BRAIN

H1 receptors in the brain

found in hypothalamus
affect wakefulness
appetite suppression
H1 and H2 receptors are involveed in:

drinking
BP regulation
thermoregulation
secretion of ADH

HISTAMINE IN THE HEART

in atrial and ventricular force via
H2 receptors
in HR
in AV conduction time (H1
receptors)
arrhythmias

HISTAMINE IN SMOOTH MUSCLES

bronchial smooth muscle
Gut smooth muscle
HISTAMINE IN THE VESSELS
H1- activates endothelial relaxation
via NO
H2- activates a slower onset of
direct relaxation

AGONIST
- no therapeutic use
- only used in specialties such as in
bronchial hyperactivity testing for
asthmatics
- used by dermatologists as a
+control to test for allergen activity
ANTAGONIST
- H1 antagonists are used to treat
mild allergies
- H2 antagonists are often used to
treat peptic ulcers, dyspepsia, gastric
reflux

- classic H1 antagonists are

sedative, short acting, significant
anti-cholinergic action
NON SEDATING H1 ANTAGONIST
- low or zero CNS penetration
- long acting
- little anticholinergic effects

IMPORTANT POINTS ABOUT SOME

OF NEW GENERATION DRUGS:
Polymorphic Ventricular
Tacycardia (PVT) may occur when
ASTEMIZOLE and TERFENADINE are
taken in high doses in conjunction
with erythromycin and
clarithromycin or ketoconazole and
itraconazole

H1 ANTAGONISTS: GENERAL
PROPERTIES
both 1st and 2nd generation cmpds
orally active and more metabolized
by the liver using cytochrome P450
duration of action is 4-6 hrs
MECLIZINE and other 2nd gen drugs
effects for about 12-24 hrs
1st gen are relatively more
sedating
2nd gen are less sedating

HISTAMINE PHARMACODYNAMICS
H1 receptor blockers cannot affect in
gastric acid secretion
H1 receptor blockers do not completely
prevent cardiovascular effects

NON HISTAMINE RECEPTOR-MEDIATED

EFFECTS
1st gen H1 receptor blockers causes
effects mediated by many other receptor
systems, these other effects in the
mediated
by
muscarinic
cholinergic
receptors,

adrenergic
receptors,
serotonergic
receptors
and
local
anesthetics receptor sites

SEDATION
- common side effect of 1st gen H1
antagonist
- used as sleep aids (hypnotics)
- produce a paradoxical excitement
in children
- toxic rxns: stimulation, agitation,
coma

ANTI-EMETIC/NAUSEA
- some 1st gen H1 antagonist
prevent motion sickness
- should be taken well in advance
- DIPHENHYDRAMINE
- PROMETHAZINE
- MECLIZINE
less sedating
- CYCLIZINE

ANTI-PARKINSONISM
- bcoz of their antimuscarinic
properties, turn out to be effective in
suppressing Parkinsonian symptom
ANTI-CHOLINERGIC EFFECTS
- some 1st gen H1 antagonists have
strong antimuscarinic actions
- includes blurred vision and urinary
retention
pxs
w/
benign
prostatic
hypertrophy are contraindicated for
the usage of these drugs

ALPHA ADRENERGIC BLOCKING

EFFECTS
- blockade of adrenergic receptor
can cause orthostatic hypotension
SEROTONERGIC BLOCKADE
LOCAL ANESTHETIC EFFECTS
DIPHENHYDRAMINE
and
PROMETHAZINE are more potent
than procaine as a local anesthetic

H1 BLOCKERS TOXICITY
excessive excitation and convulsions
in children
orthostatis hypotension
drug allergy
1st gen overdose is similar to
atropine overdose
2nd gen overdose induce cardiac
arrythmias

H2 ANTAGONISTS
inhibit histamine-induced stomach
acid secretion

CIMETIDINE
FAMOTIDINE
RANITIDINE
NIZATIDINE

EFFECTS ON ORGAN SYSTEMS

acid secretion and gastric motility

rdxn in gastric acid secretion
reduced gastric acid volume
reduced pepsin concentration
CIMETIDINE
- inhibits cytochrome P450
CIMETIDINE and RANITIDINE
- inhibit renal clearance of basic drugs
that use renal secretory transport
sytems

OTHER USES: H2 RECEPTOR

ANTAGONISTS
PEPTIC ULCER DUODENAL DISEASE
- reducing gastric acidity has
advanced tx of peptic ulcer disease
OTHER AGENTS THAT REDUCE
GASTRIC ACID:
OMEPRAZOLE
and
LANZOPRAZOLE- inhibits enzymepump w/c produces hydrogen ionsin
the stomach

 SUCRALFATE - promotes healing

ANTIBIOTICS - prominent in current
therapy
GASTRIC ULCER
- H2 receptor antagonists reduce
symptoms and promotes healing for
benign gastric ulcers
GASTROESOPHAGEAL REFLUX
-high
dosage
of
H2
receptor
antagonists along with proton pump
blockers

HYPERSECRETORY DISEASE
ZOLLINGER ELLISON SYNDROME
- associated with acid hypersecretion
w/c is caused by gastrin-secreting
tumor disorder and is often fatal
- H2 receptor antagonists control
symptoms

TOXICITY: H2 RECEPTOR
ANTAGONISTS

diarrhea
dizziness
somnolence
headache
rash
CIMETIDINE has the most adverse
effects
NIZATIDINE has the fewest side
effects

 PREGNANCY

harmful effects on the fetus have not

been observed
since these drugs can cross the
placenta, they should only be
prescribed when absolutely required
DRUG-DRUG INTERACTION
CIMETIDINE is particularly effective in
inhibiting the cytochrome P450 drug
metabolizing system therefore
influencing the metabolism of other
drugs
reduces liver blood flow and the
combination of effects on blood flow
and metabolism tend to the clearance
of certain drugs