2. • Autacoids: local hormone - like substance, not
formed by specific endocrine glands. They act and
metabolized locally near their synthesis & have a
brief duration of action. Autacoids may have
systemic effect by being transported via circulation
as hormones.
3.
4. I. Prostaglandins
• There are two major pathways in the synthesis of
eicosanoids from arachidonic acid.
1- Cyclooxygenase pathway:
• All eicosanoids with ring structures that is, PGs,
thromboxanes and prostacyclins are synthesized from
cyclooxygenase pathway.
• Two isoforms of cyclooxygenase enzyme are described:
• Constitutive cyclooxygenase-1 (COX-1) is responsible
for the physiological functions of PGs.
• While, induced cyclooxygenase-2 (COX-2) causes
elevated production of pathological PGs in the sites of
disease and inflammation.
5.
6. • Effects of Prostaglandins & Thromboxanes
• A.Smooth Muscle
1. Vascular: TXA2 and PGF2α are potent
vasoconstrictor. PGI2 and PGE2, promote vasodilation
2. Gastrointestinal tract: Most of the prostaglandins
activate gastrointestinal smooth muscle.
3. Airways: Respiratory smooth muscle is relaxed by
PGE2 and PGI2 and contracted by PGD2, TXA2, and
PGF2α.
7. • Effects of Prostaglandins & Thromboxanes
B. Platelets
• PGI2 (vascular endothelium) is a potent inhibitor of
platelet aggregation.
• TXA2 (platelet) is a powerful inducer of platelet
aggregation.
C. Kidney
• PGE2 and PGI2 maintain renal blood flow and
glomerular filtration rate. They regulate water and
sodium excretion.
8. • Effects of Prostaglandins & Thromboxanes
D. Eye
• PGF2α lowers intraocular pressure by increased
outflow of aqueous humor from the anterior chamber.
E. Reproductive Organs
1. Female reproductive organs: PGE2 and PGF2α play a
role in ovulation and fertilization. Uterine muscle is
contracted by PGF2α, and PGE2.
2. Male reproductive organs: Men with a low seminal
fluid concentration of prostaglandins are relatively
infertile.
9. • Effects of Prostaglandins & Thromboxanes
F. Central and Peripheral Nervous Systems
Fever: PGE2 increases body temperature.
G. Inflammation and pain
• prostanoids are associated with inflammation. They
enhance edema formation and leukocyte infiltration.
• Prostaglandins are powerful pain mediators
(peripheral nerves excitation)
10. • Therapeutic uses of prostaglandins
1.Abortion: Several of the prostaglandins find use as
abortifacients. The most effective option available
involves oral administration mifepristone
(antiprogestational effects) followed at least 24
hours later by the synthetic prostaglandin E1
analog misoprostol administered vaginally (Figure
.2).
2.Peptic ulcer: misoprostol inhibit the secretion of
gastric acid and enhance mucosal protective
mechanism in patients with NSAIDs-induce peptic
ulcer.
11. • Therapeutic uses of prostaglandins
3. Facilitation of Labor control postpartum
hemorrhage: Dinoprostone and carboprost can
effectively initiate and stimulate labor
4. Male Reproductive System:Intracavernosal
injection with alprostadil (PGE1 analog) is a
second-line treatment for erectile dysfunction.
12. Therapeutic uses of prostaglandins
5. CVS:
A-pulmonary Hypertension: PGI2 (epoprostenol) is
approved.
B. Peripheral arterial disease: PGE1 and PGI2
compounds in Raynaud’s phenomenon.
C. Patent Ductus Arteriosus: it is important to
maintain the patency of the neonate’s ductus
arteriosus until corrective surgery can be carried
out. This can be achieved with alprostadil (PGE1).
13. • INHIBITION OF EICOSANOID
1.Corticosteroids inhibit phospholipase A2 activity,
thus preventing the release of arachidonic acid.
2.NSAIDs (indomethacin, ibuprofen) block both
prostaglandin and thromboxane formation by
reversibly inhibiting COX activity. Aspirin is an
irreversible COX inhibitor.
14. LEUKOTRIENES are synthesized by the 5-lipoxygenase.
LTA4 is an unstable intermediate and it converts to LTB4
or “ LTC4, LTD4 and LTE4” so called "slow reacting
substance of anaphylaxis" (SRS-A).
• Leukotrienes antagonists
• Montelukast and Zafirlukast are selective leukotriene
receptor antagonists. They are given orally for the
prophylaxis and chronic treatment of bronchial asthma.
• Zileuton is a potent selective 5-lipoxygenase inhibitor
that blocks leukotriene formation and was approved for
use in bronchial asthma but has been withdrawn due to
its liver toxicity and frequency of administration.
15. Histamine
• Synthesis:
• It is formed by decarboxylation of the amino acid
histidine.
• Storage:
• Most tissue histamine is stored in granules in mast
cells or basophils. Mast cells are especially rich at
skin, nose, mouth and blood vessels.
• Non-mast cell histamine is found in: brain
(neurotransmitter) and enterochromaffin-like (ECL)
cell of the fundus of the stomach.
16. 3.Release of histamine:
- Immunologically: degranulation mediated by
antigen-antibody reactions.
- Chemically: e.g., morphine.
- Mechanically: thermal (heat or cold).
- Other stimuli: bacterial toxins, bee stings, venoms
and trauma.
17. B. Mechanism of action
• Histamine exerts its biologic actions by binding
with specific receptors located on the surface
membrane (G-protein coupled receptors).
Receptor Distribution
H1 Smooth muscle, endothelium, brain and heart
H2 Gastric mucosa, cardiac muscle, mast cells
H3 Presynaptic: inhibiting histamine release.
18. • Histamine actions:
• Nervous System:
• Stimulates sensory nerve endings mediating pain and
itching.
• Cardiovascular regulation, thermal and body weight
regulation, and arousal.
• Cardiovascular System:
• Vasodilatation [H1(low doses), H2 (high doses)] with
decrease systolic and diastolic blood pressure, this is
associated with reflex tachycardia. Histamine induced
edema by H1 receptors that contract the postcapillary
vessels with the separation of the endothelial cells.
19. • Histamine actions:
• Bronchial Smooth Muscles: Bronchoconstriction (H1 R)
• GIT: H1 contracts smooth muscles, H2 increases
gastric acid secretion.
• Histamine is involved in major allergic conditions
inside the body
• Triple Response: Intradermal injection of histamine
leads to reddening appears due to dilation of small
vessels, followed soon by an edematous wheal at the
injection site and a red irregular flare surrounding the
wheal.
20. Antihistaminics:
1. Physiologic antagonists: especially epinephrine
2. Release inhibitors reduce the degranulation of
mast cells:
Cromolyn, nedocromil and beta 2 agonists.
3. Histamine receptor antagonists
A. H1-RECEPTOR ANTAGONISTS
Mechanism: reversible competitive binding to the H1
receptor.
23. Therapeutic uses
A. Allergic Reactions:
Allergic rhinitis, Urticaria, Angioedema and Atopic
dermatitis.
B. Motion Sickness and Vestibular Disturbances
first-generation H1 antagonists are effective
agents. Also, useful in Méniére’s syndrome,
C. Nausea and Vomiting of Pregnancy
D. Adjuvants in bronchial asthma and anaphylaxis
E. Cyproheptadine is an appetizer (increases body
weight)
24. • Side effects:
1. Sedation interferes with the daytime activities.
2. Anti-muscarinic side effects: Dry mouth,
palpitation,
constipation, urinary retention, blurred vision.
3. Photosensitization on topical use on skin.
4. GIT: nausea, vomiting and epigastric distress.
5. In acute poisoning with H1 antagonists:
hallucinations, excitement and convulsions.
25. • Histamine H2-Receptor Blockers:
• Have little affinity for H1 receptors. They block the
actions of histamine at H2 receptors, their chief
clinical use is as inhibitors of gastric acid secretion
in the treatment of peptic ulcers; cimetidine,
ranitidine, famotidine and nizatidine.
26. SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT)
• Serotonin is produced from tryptophan.
• Sites:
• 90% of the serotonin is found in enterochromaffin
cells in GIT.
• Platelets are able to uptake serotonin by active
carrier mechanism.
• Brain serotonin is involved in mood, sleep,
appetite, temperature regulation, the perception of
pain, the regulation of blood pressure, and
vomiting.
27. • Serotonin Agonists:
1. 5-HT1A-receptor agonist: buspirone used as an
antianxiety drug.
2. 5-HT1D agonists: Sumatriptan, naratriptan and
rizatriptan. They are effective in TTT of acute migraine.
3. Serotonin reuptake inhibitors: A number of important
antidepressant drugs e.g., fluoxetine act to increase
activity at serotonin by inhibiting the reuptake carrier for
5-HT.
4. 5HT4-receptor agonists: metoclopramiide and Cisapride,
prokinetic agents that increase gastric motility and
facilitate gastric emptying.
28. • Serotonin Antagonists:
1. Ketanserin is a 5-HT 2 & alpha-adrenecepter blocker.
Cyproheptadine ( H 1 blocker) & 5-HT2 blockers. They
may be of value in the treatment of carcinoid turmors.
2. Ondansetron, granisetron and alosetron are 5-HT 3
blockers used in treatment of vomiting associated with
cancer chemetherapy and posteperative vomiting.
3. 5-HT2A-receptor antagonist: methyscrgide used for
prophylaxis against migraine attacks. Risperidone is
another antagonist used for management of
schizophremia.
4. Alosetron, another 5-HT 3 antagonist, was used in
irritable bowel syndrome in women.
29. "Angiotensins"
• These are polypeptides that increase the blood pressure.
• Biosynthesis and metabolism:-
• Renin ACE
Angiotensinogen Angiotensin I Angiotensin II
1. Receptors:
• AT1-receptors: present in the vascular, myocardial tissue,
brain, kidney and adrenal cells (which release
aldosterone). They stimulate cell growth & proliferastion.
• AT2-receptors: present in the adrenal medulla, kidney
and CNS. Hey may have a role in vascular activity,
eliciting antigrowth antiproliferative and vasodilator
responses.
30. • Actions:
1- Regulation of blood pressure and fluid and electrolyte
balance. This action is achieved via:
a) Direct vasoconstriction of arterioles
b) Aldosterone production salt and water retention.
2- Sympathetic nervous system stimulation.
• Therapeutic uses: not approved for clinical use.
• Adverse effects: hypertension, edema, electrolyte
imbalance.
31. • Renin-angiotensin system antagonists:-
I- ACE inhibitors: e.g. captopril, enalapril, lisinopril ….. etc.
• Mechanismof action: inhibit angiotensin converting
enzyme, thus no angiotensin II will be formed.
• Actions:
1- Decrease salt and water retention.
2- Inhibit sympathetic nervous system hyperactivity.
3- Accumulation of bradykinin ( produces vasodilatation).
Used clinically as antihypertensives, in congestive heart
failure and portal hypertension with liver cirrhosis and
diabetic nephropathy.
32. II- Direct Renin Inhibitors
• Beta1-adrenoceptor antagonists:
• Renin is released from the juxtaglomerular cells via B1 –
receptors stimulation. When blocked by propranolol,
rennin release is reduced.
• Aliskiren: it is selective renin inhibitor, it decreases
plasma renin activity and level of ang. I and II is
reduced. It is effective in treatment of hypertension,
heart failure.
III-Angiotensin- receptor antagonists:
• e.g. losartan and valsartan
• Used clinically the same as ACEIs with no side effect (dry
cough and angioedema).
33. • Therapeutic Uses of ACE Inhibitors
• Hypertension Advantages: inexpensive - less electrolytes
disturbance- no hyperuricemia, hyperglycemia or
hyperlipidemia – no sexual dysfunction – no postural
hypotension.
• Congestive heart failure:- they reverse ventricular
remodeling by decrease in preload/afterload, and prevent
the growth effects of angiotensin II on myocytes.
• Acute Myocardial Infarction:- They reduce overall
mortality when treatment is begun early.
• Diabetic nephropathy:- they reduce glomerular capillary
pressure and glomerular injury. They decrease mesangial
cell proliferation and matrix production.
34. • Adverse Effects of ACE Inhibitors:
• Hypotension occur after the first dose of an ACE inhibitor.
• Dry Cough: due to accumulation of bradykinin in lungs.
• Hyperkalemia In patients with renal insufficiency or taking
K+-sparing diuretics, K+ supplements.
• Acute Renal Failure: in patients with bilateral renal artery
stenosis.
• Fetopathic Potential: in the second and third trimesters.
• Angioedema swelling in nose, lips, tongue.(↑ bradykinin).
• Rash , Proteinuria and Neutropenia
• Drug Interactions
• NSAIDs reduce the antihypertensive action of ACEIs.
35. II- Direct Renin Inhibitors
• Beta1-adrenoceptor antagonists:
• Renin is released from the juxtaglomerular cells via B1 –
receptors stimulation. When blocked by propranolol,
rennin release is reduced.
• Aliskiren: it is selective renin inhibitor, it decreases
plasma renin activity and level of ang. I and II is
reduced. It is effective in treatment of hypertension,
heart failure.
III-Angiotensin- receptor antagonists: e.g. losartan
and valsartan. Used clinically the same as ACEIs with no
side effect (dry cough and angioedema due to no
bradykinin accumulation).
