AUTACOIDS

a. Endogenous substance with complex

physiologic and pathophysiologic function
b. Include : histamine, prostaglandin,
bradykinin, vasoactive peptide
c. As a local hormone
 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.)
Rec. Distribution Posr rec. Prototype
subtype mech

H1 Smooth musc. IP3, DAG Diphenhidr

amine

H2 Stomach, heart, C AMP inc. Cimetidine

mast cell

H3 Nerve ending, cAMP dec. -

CNS

H4 Cell of C AMP dec. -

hemapoetic Ca2+ inc.
origin
Antihistaminika - H1

sedative nonsedative
difenhydramin terfenadine
embramin astemizol
prometazin cetirizin
cyproheptadin loratidin
bisulepin
dimetinden
azatadin
klemastin
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.

Distribution:
- 1st generation drugs: body and CNS •
- 2nd generation drugs: not in CNS •

Clinical effects at H1 & other receptors:

1. Antiallergic
due to blockade of peripheral H1 receptors → –
useful only in mild allergic reactions

2. Sedation:
-blockade of H1 and M receptors in CNS
-common effect, "sleep aids“, newer H1 antagonists:
limited sedation
3. Antinausea & antiemetic actions
- blockade of H1 receptors

4. Cholinergic receptor blockade

urinary retention, blurred vision, dry mouth, –
constipation

5. Adrenergic receptor blockade

orthostatic hypotension –

6. Local anesthesia:
- block Na+ channels like lidocaine

N.B. NOT effective in bronchial asthma

-other mediators involved
-local concentrations too low
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.
EICOSANOIDS
Overview

 Eicosanoids are a large group of

autocoids with potent effects on virtually
every tissue in the body
 these agents are derived from
metabolism of 20-carbon, unsaturated
fatty acids (eicosanoic acids).
 The eicosanoids include:
1. the prostaglandins
2. thromboxanes
3. leukotrienes
4. hydroperoxyeicosatetraenoic acids
(HPETEs)
5. hydroxyeicosatetraenoic acids (HETEs).
Biosynthesis

 Arachidonic acid, the most common

precursor of the eicosanoids, is formed by two
pathways:
1. Phospholipase A2-mediated production
from membrane phospholipids; this
pathway is inhibited by glucocorticoids.
2. Phospholipase C.
Stimulus
Eicosanoids are synthesized by two
pathways:

1. The prostaglandin H synthase

(COX, cyclooxygenase) pathway produces:
A. thromboxane
B. the primary prostaglandins
 prostaglandin E, or PGE
 prostaglandin F, or PGF
 prostaglandin D, or PGD)
C. prostacyclin (PGI2)
2. The lipoxygenase pathway produces:
 HPETEs
 HETEs
 leukotrienes
▪ The eicosanoids all have short plasma half-
lives (typically 0.5—5 min).
▪ Most catabolism occurs in the lung.
▪ Metabolites are excreted in the urine.
▪ Thromboxane A2 (TXA2) is rapidly hydrated
to the less active TXB2.
▪ PGI2 is hydrolyzed to 6-keto-PGF1α.
 Various eicosanoids are synthesized
throughout the body
 synthesis can be very tissue specific:
 PGI2 is synthesized in endothelial and
vascular smooth muscle cells.
 Thromboxane synthesis occurs primarily in
platelets.
 HPETEs, HETEs, and the leukotrienes are
synthesized predominantly in mast cells,
white blood cells, airway epithelium, and
platelets.
Actions:
 Vascular smooth muscle
 PGE2 and PGI2 are potent vasodilators in
most vascular beds.
 Thromboxane is a potent vasoconstrictor.
 Inflammation
 PGE2 and PGI2 cause an increase in blood
flow and promote, but do not cause, edema.
 HETEs (5-HETE, 12-HETE, 15-HETE) and
leukotrienes cause chemotaxis of
neutrophils and eosinophils.
 Bronchial smooth muscle
 PGFs cause smooth muscle contraction.
 PGEs cause smooth muscle relaxation.
 Leukotrienes and thromboxane are potent
bronchoconstrictors and are the most likely
candidates for mediating allergic
bronchospasm.
▪ Uterine smooth muscle.
▪ PGE2 and PGF2a
▪ cause contraction of uterine smooth muscle
in pregnant women.
▪ The nonpregnant uterus has a more
variable response to prostaglandins
▪ PGF2a causes contraction
▪ PGE2 causes relaxation.
 Gastrointestinal tract
 PGE2 and PGF2a
 increase the rate of longitudinal contraction in
the gut and decrease transit time.
 The leukotrienes
 are potent stimulators of gastrointestinal
smooth muscle.
 PGE2 and PGI2
 inhibit acid and pepsinogen secretion in the
stomach.
 Prostaglandins
 increase mucus, water, and electrolyte secretion
in the stomach and the intestine.
 Blood
 TXA2
 is a potent inducer of platelet aggregation.
 PGI2 and PGE2
 inhibit platelet aggregation.
 PGEs
 induce erythropoiesis by stimulating the renal
release of erythropoietin.
 5-HPETE
 stimulates release of histamine
 PGI2 and PGD
 inhibit histamine release.
Therapeutic uses

Induction of labor at term.

 Induction of labor is produced by:
 infusion of PGF2a (carboprost tromethamine)
[Hemabate] or
 PGE2 (dinoprostone) [Prostin E].
Therapeutic abortion:
A.Inducing abortion in the second trimester:
▪ Infusion of carboprost tromethamine or
▪ Administration of vaginal suppositories
containing dinoprostone
B. inducing first-trimester abortion:
 these prostaglandins are combined with
mifepristone (RU486)
Maintenance of ductus arteriosus

 is produced by PGE1 [Prostin VR] infusion

 PGE1 will maintain patency of the ductus
arteriosus, which may be desirable before
surgery.
Treatment of peptic ulcer.

 Misoprostol [Cytotec]
 a methylated derivative of PGE1
 is approved for use in patients taking high
doses of nonsteroidal antiinflammatory
drugs (NSAIDs) to reduce gastric
ulceration.
Erectile dysfunction:
▪ Alprostadil (PGE1) can be injected directly into the
corpus cavernosum or administered as a
transurethral suppository to cause vasodilation and
enhance tumescence.
Adverse effects of eicosanoids

▪ local pain and irritation

▪ bronchospasm
▪ gastrointestinal disturbances: nausea,
vomiting, cramping, and diarrhea.