ملخص

Autacoids regulate certain aspects of gastrointestinal (GI), uterine and renal function.

Differ from hormones and neurotransmitters
Short duration of action
Usually involved in response to injury
Sites of action restricted to the synthesis area

Classification of autocoids

Fatty acid derivatives

Endogenous peptides

Aminoacid derivatives

Eicosanoids

Kinins, Angiotensin
Substance P&others


Histamine
Serotonin

Histamine present in

Lung , skin, Alimentary tract ,Blood vessels.
It is stored in mast cells and basophils

Fate :

1. Methylation (major metabolic pathway)
2. Oxidation by histaminase enzyme.
It can not pass B.B.B. but it is present in brain.

Histamine relased in response to :Injury (as physical trauma)

Proteolytic enzymes
Snake venom
Antigen/antibody reaction.

action

Histamine receptors
1-1.Spasmogenic effect on smooth muscles
but arterioles are dilated
2-Hypotension due to arteriolar dilatation
3-Stimulation of adrenaline release from
adrenal medulla
4-Skin
Itching occurs if histamine is released in the skin and induces pain when deeply injected.


H1 receptors: which present mainly in smooth muscles
1. Increase gastric acid secretion and pepsin.
2. Stimulation of heart → tachycardia by direct action on histamine (H2) receptors and by reflex action as a result
of hypotension.

H2 receptors: Present in stomach (responsible for HCl),

heart and some vessels.

H3 receptors:

Present presynaptic in brain and in myentric plexus

Note : If injected intradermally, it produces triple response:

Redness due to capillary dilatation.
Spreading flare due to arteriolar dilatation
Wheal formation due to increased capillary permeability

The effects of histamine can be antagonized by:

1. Physiological antagonism, e.g. adrenaline.
2. Competitive antagonism.
3.Prevention of histamine release by glucocorticoids


Antihistaminic drugs
A- First generation:
They have sedative effect, atropine like action and antiemetic action
Dimenhydrinate, diphenhydramine and promethazine

They are antiemetic but teratogenic

Meclizine and cyclizine

Anti-arrhythmic action

Antazoline

It has antiserotonin and appetite stimulant action.

Cyproheptadine (periactin)

B-Second generation

Second generation H1-blockers have minimal CNS actions
They have minimal sedative effect, no atropine like action, no anti-emetic, no anti-serotonin & long duration
Fexofenadine, terfenadine
Terfenadine is withdrawn due to risk of cardiac arrhythmias and is replaced by its active
metabolite fexofenadine (considered as a third generation)


Adverse effects of anti-histaminic:

Actions of anti-histaminic:

1-Sedation, drowsiness and fatigue.

1. H1 blocking action antagonizing spasmogenic effect on smooth muscle

2-Hallucination, excitement, convulsions and coma in toxic doses.

2. C.N.S. depressant action → sedation

Second generation excluded from central action.
3- Dry mouth, anorexia and nausea, blurred vision & urine retention.

3.Dimenhydrinate, diphenhydramine, meclizine,

cyclizine and promethazine:
Antiemetic action and antimotion sickness

4.Diphenhydramine, promethazine, cyproheptadine and Chlorpheneramine : Atropine like action

5.Diphenhydramine Antiparkinsonian action

6.Cyproheptadine Antiserotonin action

7. Antazoiline Quinidine like action, membrane stabilizing action and local anaesthetic action.

Uses :

1. Allergic disorders as:
2. Motion sickness
3. Cardiac arrhythmia
4. Parkinsonism
5. Common Cold Sedation & dries the secretions

Eicosanoids

include:
the prostaglandins
thromboxanes
leukotrienes
hydroperoxyeicosatetraenoic acids (HPETEs)
hydroxyeicosatetraenoic acids (HETEs).

eicosanoids are NOT synthesized in advance and stored in granules – when needed, they can be produced very quickly from arachidonate released from membranes
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.

Cox I present normally ,, Cox II present in stress

HPETEs and HETEs are precursor of leukotrine
Leukotrine produce bronchiospasm 100 times more than histamine

Effects of prostaglandins

1-Mediate inflammation
cause vasodilation and increase vascular permeability
2-Regulate pain and fever
3-PGE2, PGF2 stimulate uterine muscle contractions during labor
4-Prostaglandins of the PGE series inhibit gastric acid secretions
5-Regulate platelet aggregation: PGI2 = potent inhibitor of platelet aggregation
Note : TXA2 contracts arteries and veins and bronchi, and causes platelet aggregation.
PGI2 de-aggregate platelets clumps & reduces myocardial infarct size & ischemic organ damage
6-PGE2 inhibits reabsorption of Na+ and water in the collecting duct. PGI2: vasodilatation and regulation of glomerular filtration rate

Inhibitors of eicosanoid

Dazoxiben
Monteleukast and Zafirleukast
Zileuton
Selective COX II inhibitors
Non steroidal anti-inflammatory drugs (NSAIDs)
Glucocorticoids


a selective inhibitor of thromboxane A2 synthesis
Block leukotriene receptors.
inhibits 5-lipoxygenase enzyme.
Inhibit COX II
Inhibit COX I and COX II
My cause induce peptic ulcer due to inhibition of PGs generation by gastric mucosa.
inhibit the activity of phospholipase A2

Clinical Uses of Eicosanoids Inhibitors:

1-Asthma: Leukotrien antagonists or
Lipoxegenase inhibitor
2-Anti-inflammatory and RA (NSAIDs)
3-Antiplatelet action (Aspirin),
4-Dazoxiben used as prophylaxis against blood coagulation
5-Dysmenorrhea (NSAIDs)
Therapeutic uses of PGs :

1-Induce abortion & labour.

2-Treatment of Impotance
3-Treatment of glaucoma
4-To decrease platelet aggregation
5-Treatment of petic ulcer
6-Treatment of pulmonary hypertension


BIOGENIC AMINESSEROTONIN

It is formed in argentaffm cells in GIT (mainly) and brain.

90% of body serotonin is present in entrochromaffin cells of gut 8% in platlate and 2% in CNS
. It is stored in platelets and inside vesicles in nerve endings. Synthezied from amino acid Tryptophan .

Neurotransmitter in the CNS

Precursor of melatonin
Induces sleep, Intestinal motility
Involved in Temperature regulation
Affects mood and behavior (humans)
Deficiency causes depression
Hemostasis : 5-HT2 receptors → aggregation of platelets and vasoconstriction
Carcinoid syndrome (tumor of serotonin producing cells) large amounts released leading to diarrhea, bronchoconstriction and edema
Does not pass B.B.B

Serotonin metabolized by MAO to produce 5-hydroxyindole acetic acid this increased in in carcinoid tumor & reserpine therapy and decreased in patients treated with MAO inhibitors
Clinical conditions in which
5-HT (serotonin ) plays a role include
Actions of serotonin
migraine
1. Cardiovascular system :Stimulation of heart and increased platelet aggregation.
Vaso.Cons. of B.V. especially veins and V.D. of skeletal
muscle vessels
mood disorders anxiety


2.Spasmogenic effect on smooth muscles.

vomiting

3. Antidiuretic effect due to V.C. of afferent renal arterioles.

carcinoid syndrome

4. Ganglion stimulant action and stimulation of sensory nerve endings(pain).

Serotonin antagonist:

4.Clozapine
3. Ketanserin
2.Cyproheptadine (periactin)

1.Methysergide (Deseril):

5HT2A/2C antagonist: for schizophrenia
1. It blocks 5-HT2→VD. &↓ platelet aggregation
2. It blocks ά1 receptors →VD.
3.Useful in hypertension and PVD

It antagonizes, H1, serotonin and muscarinic receptors

Stimulates the appetite.


used in prophylaxis of migraine headache and in carcinoid syndrome

5HT4 in gut smooth muscles, they increase ACh release in gut.

5HT3 Located in enteric neurons
and in CNS.

5HT2,A,B,C. present in smooth muscles, platelets and C.N.S.

5HT1A,B,D,E,F. present in C.N.S.

Agonists of

5-HT4-receptors
in the intestine and stimulates
peristalsis and secretion.

Effects are excitatory, causing

GI motility and vomiting
Antagonists of 5-HT3-
receptors are very
powerful antiemetics
in CNS produces excitement
in blood vessels - contraction
and platelet aggregation
Antagonists of
5-HT2-receptors are used:
for prophylaxis of migraine as they produce vasodilatation


cause neural inhibition
Buspirone
anxiolytic agent
partial agonist of the
5-HT1A-receptors
5-HT1D-receptors are
found in some blood
vessels
They produce vasoconstriction it is agonist used in acute attacks of migraine (Sumatriptan)

In acute attack of migraine use , V.C and in prophylaxis use V.D

Ergot Alkalbids

Ergotamine

Contraindications:
Peripheral vascular diseases.
* Coronary heart diseases.
* Hypertension.
* Pregnancy.
* Liver and kidney diseases.


Adverse effects
Nausea and vomiting, anginal pain, tingling and numbness, gangrene and abortion.

Used in Acute attack of migraine headache Due to its V.C. effect, given in first stage to prevent second stage

Actions:

1.Partial agonist on α -receptor.
2.Partial agonist on serotonin receptors.
3.Contract smooth muscles of uterus (oxytocic action).

Diagnosis of variant angina.

Ergonovine (Ergometrine) produces prompt V.C. of coronary vessels in Prinzmetal's or variant angina

.Ergometrine

dihydrogotoxin
Ergotoxine
dihydroergotamine

It has potent oxytocic action

No α -blocking effect or C.N.S. action
Partial agonist on 5-HT receptors.


is
more V.D. than ergotoxin
As ergotamine but with
vasodilator effect

vasoconstricon

Prevention and treatment of postpartum hemorrhage and in subinvolution of uterus
used in cerebral ischemia
used in cerebral ischaemia and peripheral vascular disease..
Used
in Acute attack
of migraine

Renin production is

Decreased by
Renin production is increased by
Angiotensinogen production is increased by
Angiotensin II.
Vasopressin
Hyperkalemia


1. Decreased renal perfusion
2. Decreased Na in macula densa
3. Sympathetic stimulation

corticosteroids (mainly glucocorticoids), estrogens, thyroid and angiotensin II

Actions of Angiotensin

1. Pressor effect on blood vessels

2. Increases proximal Na tubular reabsorption, inhibits renin release and increases angiotensinogen production
3. Increases biosynthesis and release of aldosterone from adrenal cortex.
4. Stimulates catecholamine release from adrenal medulla and facilitates sympathetic transmission.
5. Positive inotropic effect on heart
6. Spasmogenic effect on smooth muscles.
7. Stimulates drinking (dispogenic effect), increases vasopressin and ACTH

Therapeutic uses

In treatment of hypotension especially due to overdose of α – blockers

Drugs affecting renin / angiotensin system

1. Drugs inhibiting renin secretion:
- β-blockers.
- α 2 agonists
2. Angiotensin converting enzyme inhibitors
captopril

Adverse Effects

Hypotension
Renal Insufficiency (if bilateral renal artery stenosis)
Hyperkalemia
Cough (20 %)kinin related
Angioedema kinin related
With captopril especially: neutropenia, nephrotic syndrome, skin rash, taste disturbances
Vasodilatation and decrease in blood pressure via:
ANG II Bradykinin (vasodilator) Activity of sympathetic nervous system Blood volume ( Na+ reabsorption)

Angiotensin receptor blockers

Losartan

Compete with angiotensin II for AT1 receptors ,They are pure antagonists.

Therapeutic uses: similar to ACE.I used in hypertension.
Side effects Similar to ACE.I. but not dry irritant cough

Kallidin and Bradykinin They act on (B1&B2) receptors

Action of kinin
1-Vasodilatation of vascular bed (10 times more potent than histamine).
2- They relax arterioles but veins are contracted
3- They decrease B.P. and increase H.R
4- Increase capillary permeability
5- Spasmogenic action on GIT and bronchi
6 -Potent algesic on nerve endings

Trasylol (aprotinin) is

a kallikrein inhibitor used to minimize bleeding in patients undergoing coronary bypass
aspirin is a kinins inhibitor
while ACE inhibitors enhance the action of kinins

Atrial natriuretic peptide (ANP)

Vasoactive intestinal polypeptide (V1P)


Endothelin

Substance-P

Released from atrium and increase the glomerular filtration rate →↑Na excretion in urine
Inhibit renin and aldosterone secretion.

Relaxes smooth muscles,

Potent V.D.→ coronary V.D and postive inonotropic and chronotropic effect

potent Vaso.Const.

present in 1. C.N.S. (acts as a chemical transmitter)
2. Gut (acts a local hormone).
It has a vasodilator effect on the arterioles but spasmogenic on veins, intestinal and bronchial muscles.