Autacoids 2011/2012

AUTACOIDS
Autacoids are biologically active substances of heterogenous chemical structures, which
may be involved in some pathological conditions, and are known as "Locally- acting
hormones".

Classification:
Autacoids are classified chemically into:
a) Amino Acid derivatives:
1. Histamine (derived from histidine).
2. Serotonin = 5-Hydroxytryptamine = 5-HT (derived from tryptophan).
b) Vasoactive Peptides:
1. Angiotensin.
2. Kinins: bradykinin and kallidin.
3. Substance P.
4. Endothelin.
5. Vasoactive Intestinal Peptide (VIP).
6. Atrial Natriuretic Peptide (ANP).
c) Eicosanoids (Fatty acid derivatives):
1. Prostaglandins.
2. Leukotrienes.
d) Others:
Cytokines as interferons

1- HISTAMINE

Synthesis:
histidine
L-Histidine ▬▬▬▬▬▬► Histamine
decarboxylase
Storage:
Histamine is stored in mast cells (with heparin), in basophils, and other cells. Histamine is
abundant in epidermis of skin, lungs, and GIT.
Release:
1-Antigen-antibody reactions (allergy or immunological reactions).
2-Physical and chemical injury.
3-Proteolytic enzymes.
4-Insect bites and snake venom.

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Autacoids 2011/2012

5-Drugs: some basic drugs as morphine, trimetaphan, curare, succinylcholine, and atropine
(large and toxic doses) may induce histamine release, and are known as "histamine
liberators"..
Pharmacodynamics:
Mechanism of action:
Histamine stimulates specific G-protein coupled receptors:

Receptor Signal transduction Sites Actions

H1 Gq 1. Smooth muscle fibers 1. Spasmogenic effect.
PLC→ ↑DAG and as bronchi, GIT, uterus. 2. Vasodilatation and
IP3→↑ Ca2+. 2. Endothelium of Blood increase capillary
vessels. permeability by
increasing synthesis of
nitric oxide.
3. Skin and sensory nerve 3. Itching, urticaria, triple
endings. response, pain.
4. CNS (post-synaptic). 4. Alertness.
H2 Gs→ activation of 1. Parietal cells of the 1. Stimulate secretion of
A.C.→ ↑c-AMP. stomach. HCl and pepsin.
2. Heart. 2. Increase cardiac
properties (+ve inotropic,
+ve chronotropic).
3. Blood vessels. 3. Vasodilatation.
4. CNS (post-synaptic). 4. Alertness.
H3 Gi CNS (pre-synaptic). ↓ Release of
A.C.→↓ c-AMP. neurotransmitters.
H4 Gi Inflammatory cells as CD4 Modulation of cytokines.
A.C.→↓ c-AMP. T lymphocytes-
Neeutrophils-Esinophils.

Pharmacological actions:
1-Stomach: histamine stimulates HCl and pepsin secretion from the parietal cells by acting
on H2-receptors (histamine is the most powerful secretagogue),
2-Smooth muscle fibres: histamine is spasmogenic on the bronchi, GIT and uterus by acting
on H1-receptors.
3-Skin:
 Itching (pain occurs if histamine is deeply injected).
 Triple response: localized redness (due to capillary V.D.) – spreading redness=flare due
to arteriolar V.D. - localized edema (wheal) due to increased capillary permeability.
 These actions are mediated by H1 receptors.

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Autacoids 2011/2012

4-CVS:
 Heart: myocardial stimulation, both directly by H2-receptor stimulation, and reflexly
following V.D. and hypotension.
 Blood vessels: V.D. by stimulation of H1- and H2 –receptors (mainly H1).
 ABP: Hypotension due to V.D. and increased capillary permeability, and anaphylactic
shock may occur in severe allergy.
5-Stimulation of catecholamines release from adrenal medulla: both directly and reflexly
following hypotension.
6-CNS: Arousal (H1-mainly).

Indications:
Histamine has no therapeutic uses nowadays.

Histamine Antagonists:
1. Pharmacological Antagonists:
a) H1-Antagonists = Antihistaminics = Antiallergic drugs.
b) H2-Antagonists: Cimetidine-Famotidine-Ranitidine-Nizatidine.
Used in treatment of peptic ulcer (see GIT pharmacology).

2. Physiological Antagonist:
"Adrenaline is the physiological antagonist of histamine" (2 different agents acting on 2
different receptors causing 2 opposing actions).

3. Inhibitors of Histamine release:

a) Glucocorticoids: inhibit antibody formation and antigen-antibody reaction, and
accordingly inhibit histamine release.
b) Mast Cell Stabilizers = Degranulation inhibitors as disodium cromoglycate=cromolyn,
and nedocromil (see pharmacology of Respiratory system).

4. Desensitization.

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Autacoids 2011/2012

H1-Antagonists (Antihistaminics-Antiallergics)

 All antihistaminics are competitive antagonists with histamine on H1-receptors.

 All antihistaminics are "Antiallergic drugs" used in treatment of allergic conditions such
as: skin rash- urticaria- angioneurotic edema-anaphylactic shock (remember: adrenaline
is life-saving in anaphylactic shock).
Pharmacokinetics:
1. They can be given orally, parenterally, and topically as skin ointment-eye drops-nasal
drops-and ear drops.
2. "First generation" antihistaminics can pass easily B.B.B. whereas "Second generation"
drugs poorly penetrate B.B.B.
3. Pass placental barrier and may be teratogenic in experimental animals (Cyclizine-
Meclizine).
4. Metabolized by the liver and excreted in urine, and are partly excreted in breast milk.

N.B.:
1. Antihistaminics are not essential in treatment of bronchial asthma because the role of
histamine is insignificant.
2. Treatment of anaphylactic shock: Adrenaline (Life saving) + Corticosteroid +
Antihistaminic.
Classification:
First Generation=Sedating Antihistaminics. Second Generation= Non-
sedating Antihistaminics
●Pass B.B.B. and cause sedation and drowsiness, ●Poor passage through B.B.B. and do
but toxic doses cause hallucination, excitation and not have CNS actions, i.e. No sedation
convulsions. They have anti-emetic (by blocking H1 and no antiemetic action.
and M receptors in the medullary vomiting centre)
and anti-parkinsonian (by blocking M receptors in
basal ganglia) actions.
-6 hours) due to rapid -24 hours) due to
metabolism by hepatic microsomal enzymes. slower metabolism by hepatic
microsomal enzymes (mainly CYP
3A4).
Actions: Actions:
1. Antihistaminic action: antagonize the actions of 1. Antihistaminic action: antagonize
histamine on H1-receptors in blood vessels, the action of histamine on H1-
bronchi, GIT, and skin. receptors in blood vessels, bronchi,
and skin.

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Autacoids 2011/2012

2. Atropine-like actions leading to: 2. No atropine-like action

a) Antiemetic action including in motion accordingly:
sickness. a) No antiemetic action.
b) Antiparkinsonian action. b) No antiparkinsonian action.
c) Urine retention (contraindicated in BPH). c) Not contraindicated in BPH.
d) ↑IOP (contraindicated in glaucoma). d) Not contraindicated in
glaucoma.

3. Some have Na+-channel blocking action 3. No Na+-channel blocking action.

(Membrane stabilizing action) leading to
Local anaesthetic action and Antiarrhythmic
action (Quinidine-like action); e.g: Antazoline.

4. Some have Antiserotonin action leading to 4. No antiserotonin action.

stimulation of appetite; e.g.Cyproheptadine.

5. α-blocking action. 5. No α-blocking action.

 Examples:  Examples:
 Diphenhydramine, Dimenhydrinate,  Astemizole.
Promethazine  Cetrizine.
 (antiemetics and antiparkinsonian).  Loratadine.
 Meclizine and Cyclizine (antiemetics but  Terfenadine (was withdrawn as
contraindicated in pregnancy, being it may cause fatal arrhythmias).
"teratogenic").  Fexofenadine (is the active
 Chlorpheniramine maleate (in common cold metabolite of terfenadine but is
medications)-Antazoline (antiarrhythmic). safe, sometimes it is referred to
 Clemastine and Chemizole. as "Third Generation"
 Cyproheptadine (also antiserotonin) - antihistaminic).
Mepyramine (in experimental
pharmacology)- Ketotifen (also
antiserotonin and a mast cell stabilizer) –
Hydroxyzine – Carbinoxamine.

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Autacoids 2011/2012

First Generation=Sedating Antihistaminics Second Generation=Non-sedating

Antihistaminics
 Therapeutic uses:  Therapeutic uses:
1. Treatment of allergic conditions (allergic Treatment of allergic conditions
rhinitis, rash, urticaria, angioneurotic (rash, urticaria, angioneurotic
edeme, and anaphylactic shock). edema, and anaphylactic shock).
2. Antiemetics in motion sickness, vertigo
and Meniere's disease.
3. Parkinsonism (Diphenhydramine).
4. Arrhythmias (Antazoline).
5. Anxiety and insomnia (situational).

 Adverse effects:  Adverse effects:

1. Sedation and drowsiness. Cardiac arrhythmias especially in
2. Excitement, hallucinations, convulsions, overdose or if given with HME
and may be coma in acute toxicity. inhibitors as erythromycin and
Excitation is more common in children. ketoconazole.
3. Teratogenicity (Cyclizine and Meclizine).
4. Allergic reactions.
5. Atropine-like adverse effects as dry
mouth, constipation, urine retention,
tachycardia, and elevation of IOP.

 Contraindications:
1-Car drivers. 2-Pregnancy. 3-Glaucoma. 4-BPH.

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Autacoids 2011/2012

2- EICOSANOIDS
They include:
1. Prostaglandinds (prostanoids).
2. Leukotrienes.

They are not stored in the body but are synthesized and rapidly metabolized, they have very
short duration

Cell Membrane Phospholipids

Phospholipase A2 Phospholipase C
(inhibited by cortisol)
DAG
DAG lipase

Arachidonic Acid
Cyclooxygenases (COX) 5-lipooxygenase (LOX)
(inhibited by NSAIDs) (inhibited by Zileuton)

Prostaglandins G2 and H2 5-HPETE and HETE

Prostaglandin Prostacyclin Thromboxane A2

synthetase synthetase synthetase Leukotrienes
(A4, B4,C4,D4,E4,F4)
PGs E,F PGI2 TXA2
(prostacyclin) (Thromboxane A2)

DAG: Diacyl glycerol. 5-HPETE: 5-Hydroperoxyeicosatetraenoic acid. HETE:

Hydroxyeicosatetraenoic acid.

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Autacoids 2011/2012

Mechanism of action:
PGs act on specific G-protein coupled receptors, known as EP-FP-DP-IP-and TP which are
stimulated by PGE2-PGF2α-PGD2-PGI2-and TXA2, respectively.
Actions of PGs:
1. CNS:
a) Pain (algesic action): PGs stimulate pain transmission in the thalamus and sensitize
pain receptors to serotonin and kinins.
b) Fever (pyrctic action): PGs elevate the set point of hypothalamic heat regulating
centre (HRC):
Pyrogens
↑ production of PGE2 H.R.C.

2. Inflammation:
PGs are very potent inflammatory mediators.

3. Eye:
PGF2α increases drainage of aqueous humor through the uveoscleral pathway
and accordingly decreases IOP. It does not change the size of the pupil.

4. Female reproductive system:

a) Uterus: PGs –especially PGF2α and PGE2 stimulate uterine contractions
(oxytocic action) leading to induction of abortion and pregnancy and controlling
post- partum hemorrhage.
b) PGs play an important role in fertilization and ovulation.

5. Male reproductive system:

a) PGE1 enhances erection.
b) PGE and F may have a role in male fertility.

6. GIT:
a) Stomach: PGE and PGI are Cytoprotective by: reducing HCl secretion – increasing
mucus secretion – increasing bicarbonate in duodenum – increasing blood flow to
promote healing of damaged mucosa.
b) Small intestine:
PGs increase motility leading to colics and diarrhea.

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Autacoids 2011/2012

7. Bronchi:
Some PGs are bronchodilators as PGE and I, but others as PGF2α and TXA2 cause
bronchospasm.

8. CVS actions:
a) Some PGs, as PGE and PGI, are vasodilators but TXA2 and PGF2α cause V.C.
b) PGE2 maintains the patency of Ductus Arteriosus during fetal life.
c) Recently it is assumed that PGE2 induces angiogenesis which may be the cause of
cancer colon.
d) Platelets: PGI2 inhibits platelet aggregation and TXA2 stimulates platelet aggregation.

9. IX-Kidney:
PGs increase renal blood flow by V.D. of renal blood vessels. PGI2 increases renin
release.

N.B.:
PGI2 is synthesized from the intact endothelium of blood vessels causing V.D. and
inhibition of platelet aggregation, whereas TXA2 is synthesized from platelets in cases of
injury of blood vessels and is "hemoststic" by causing V.C. and stimulation of platelet
aggregation.

Actions of Leukotrienes:
LTs act on specific G-protein coupled receptors known as "cysteinyl leukotriene
receptors", and induce inflammatory reaction in bronchi leading to bronchial asthma in
susceptible persons (especially LTC4 and D4). LTB4 may have a role in Rheumatoid Arthritis.
N.B.:Leukotrienes have no therapeutic uses.

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Autacoids 2011/2012

Therapeutic uses of PG analogs:

Therapeutic use Drugs used

a) Gynecological and obstetrical uses: Dinoprostone
1. Induction of abortion in the second (PGE2 analog, given as vaginal
trimester. suppository).
2. Induction of labor.
3. To control post-partum hemorrhage. Carboprost
(PGF2α analog, given IM or intra-
amniotic which may cause
b) Treatment of erectile dysfunction. anaphylactic shock or CV collapse.

Alprostadil
c) GIT use: (PGE1 analog, given as urethral
suppository of intracavernous
Prophylaxis and treatment of peptic ulcer,
injection).
especially iatrogenic ulcer caused by NSAIDs
and Steroids.
Misoprostol
(PGE1 analog, given orally-may cause
d) CVS uses: colics and diarrhea, and bone pains-
1. To maintain the patency of ductus causes abortion in pregnant
arteriosus before surgical correction of females).
congenital heart diseases in neonates.
2. Treatment of pulmonary hypertension. Alprostadil.
3. Inhibition of platelet aggregation, e.g. during
hemodialysis. Epoprostenol
4. Treatment of peripheral vascular diseases (PGI2 analog, given by IV infusion).
(PVD).
Latanoprost
e) Ophthalmic use: (PGF2α analog, given as eye drops)
Treatment of open angle glaucoma.

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Autacoids 2011/2012

Inhibitors of Eicosanoid Synthesis

1. Glucocorticoids(Cortisol): inhibit PLA2 by stimulation of synthesis of a protein known as

"Lipocortin" and accordingly inhibit synthesis of eicosanoids ( arachidonic acid, PGs,
and LTs).

2. NSAIDs: (e.g. aspirin, indomethacin, ibuprofen).They inhibit cyclooxygenases (non-

selective COX inhibitors) and accordingly inhibit PGs synthesis. They have analgesic,
antipyretic, and anti-inflammatory actions but may cause peptic ulcer and renal
ischemia especially with prolonged use of large doses.

3. Dazoxiben and Aspirin(Infantile dose): selectively inhibit TXA2 synthase an accordingly

inhibit platelet aggregation.

4. Leukotrienes inhibitors: are used in prophylaxis of bronchial asthma and include:

a) 5-LOX inhibitors: Zileuton inhibits synthesis of leukotrienes.
b) LT-Receptor Antagonists: Montelukast and Zafirlukast .

Important Notes:
1. There are 3 types of cyclooxygenase enzyme:
a) COX1: is"constitutive" and is involved in synthesis of PGs that cause cytoprotection of
the stomach and renal V.D.
b) COX2: is "inducible"stimulating synthesis of PGs involved in pain, fever, and
inflammation. Celecoxib and Rofecoxib are selective COX2 inhibitors
c) COX3: in CNS (formation of PGs causing pain and fever). Paracetamol
(Acetaminophen) and Dipyrone are selective COX3 inhibitors .

2. NSAIDs and Glucocoricoids cause peptic ulcer (iatrogenic ulcer) due to inhibition of
synthesis of cytoprotective PGs. It can be prevented and treated by PG analogs as
Misoprostol (but it is contraindicated in pregnancy as it can lead to abortion).

3. NSAIDs –but not glucocorticoids-may induce attacks of bronchial asthma in asthmatics

because they shift arachidonic acid into synthesis of LTs.

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Autacoids 2011/2012

ERGOT ALKALOIDS
Source:
Ergot alkaloids are derived from ergot fungus which grows parasitically on rye grains.
Chemistry:
 Derivatives of lysergic acid.
 L-isomers are more active.
 Classified into:
1. Amino Acid Alkaloids: Ergotamine – Ergotoxine-Ergosine.
2. Amine Alkaloids: Ergometrine (ergonovine).

1-Ergotamine:
Pharmacokinetics:
 Poorly absorbed orally, absorption is enhanced by adding caffeine (Cafergot).
 Ergotamine can also be given S.L., inhalation, I.M., I.V., and rectal.
 Passes B.B.B.
 Partly metabolized by the liver and partly excreted in urine.

Pharmacodynamics:
 Mechanism of action:
Partial agonist at α1-receptors and 5-HT receptors.
 Pharmacological actions:
1. V.C. of blood vessels e.g. cerebral, coronary, and peripheral blood vessels.
2. Oxytocic action (stimulates contraction of the uterus).
3. CNS actions:
4. Stimulation of C.T.Z. leading to nausea and vomiting.
5. Stimulation of C.I.C. leading to bradycardia.
6. Inhibition of V.M.C. and R.C. especially in acute toxicity (Ergotism).
Therapeutic uses:
Acute attacks of migraine headache as it causes cerebral V.C.
Adverse effects: Contraindications:
1-Tingling, numbness and gangrene of 1- P.V.D.
fingers. 2- Angina pectoris.
2- Anginal pains. 3- Hypertension.
3- Elevation of ABP. 4- Pregnancy.
4- Abortion. 5- Bradycardia.
5- Nausea and vomiting. 6-Liver and kidney diseases.
6- Bradycardia.

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Autacoids 2011/2012

(Ergotism) :
It is acute ergot toxicity due to toxic doses of ergotamine or due to eating contaminated
rye grains; it is manifested by nausea, vomiting, bradycardia, hypertension, tingling and
numbness, abortion in pregnant females, and CNS manifestations as hallucinations,
convulsions, coma and death due to depression of R.C. and V.M.C.).

Dihydroergotamine
Is similar to ergotamine causing cerebral V.C. and is used in treatment of acute attacks of
migraine.

2- Ergotoxine:
More antagonistic action on α1-receptors than ergotamine, and inhibits V.M.C. leading to
V.D.

Dihydroergotoxine
Has more antagonistic action on α1-receptors and weaker agonistic action than ergotoxine
leading to V.D.
Uses:
1. P.V.D.
2. Cerebral ischemia (cerebro-vascular insufficiency).

3-Ergometrine (Ergonovine):
Pharmacokinetics:
Completely absorbed orally and has short duration of action.
Pharmacodynamics:
1. Weak α1-agonist → weak V.C. but NO α-blocking action.
2. Partial agonist on 5-HT receptors.
3. No CNS actions.
4. Powerful oxytocic action.
Therapeutic uses:
1. Prevention and treatment of post-partum hemorrhage.
2. Involution of the uterus after labor.
3. Diagnosis of Prinzmetal angina (=variant=vasospastic angina): ergometrine is given by
4. I.V.infusion during angiography and it induces coronary V.C. in Prinzmetal angina.

Methylergometrine(Methergin) :
more potent oxytocic than ergometrine, used in prevention and treatment of post-partum
hemorrhage and to help involution of the uterus after labor.

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Autacoids 2011/2012

Migraine Headache
Definition:
Paroxysmal severe unilateral pulsating headache usually accompanied by nausea and
vomiting and preceded by "aura" characterized by visual disturbances.

Pathophysiology:
5-HT causes V.C. of cerebral (cranial) blood vessels→ Aura.
Accumulation of metabolites and release of inflammatory mediators→ V.D. and edema
of the wall of cranial blood vessels

Treatment of acute attacks:

1. Analgesics as NSAIDs (as aspirin) and paracetamol may be tried in mild cases.
Antiemetics as metoclopramide and domperidone are useful if the attack is
accompanied with vomiting
2. Ergotamine is given orally, inhalation, S.L., I.M., I.V., or rectally.
Caffeine may be added to ergotamine to increase oral absorption and potentiat
its action (caffeine causes cerebral V.C.). Antiemetics (as metoclopramide) may be also
added.
N.B.: the dose of ergotamine should never exceed 6 mg. per attack and 10 mg. per week.
Never give ergotamine within 24 hours after administration of triptans to avoid severe
systemic V.C.

3. Dihydroergotamine.
4. Triptans: Sumatriptan, Rizatriptan, Zolmitriptan
5. HT1D-agonist causing cranial V.C.
Contraindications: ischemic heart diseases (angina)- Hypertension- PVD.

Prophylactic treatment:
1. Propranolol (the most commonly used drug).
2. Anti-serotonin drugs: Methysergide (long use causes fibrosis of the serous membranes
as retroperitoneal fibrosis which may lead to renal failure) – Cyproheptadine (in
resistant cases, it is also H1-antagonist) – Pizotifen and Ketotifen (as cyproheptadine).
3. Clonidine (in small doses).
4. Calcium channel blockers: Flunarizine- Verapamil.
5. Tri-Cyclic Antidepressants (TCAs) as Amitriptyline.

Drugs that should be avoided:

Some drugs increase frequency of migraine attacks as Oral contraceptives (estrogen).

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