1. Chemical Mediators
in
Health & Disease
Ma. Minda Luz M. Manuguid, M.D.

2. Inflammatory Mediators & Antagonists
Autacoids
 Histamine
 Serotonin
 Angiotensin
 Prostanoids
Eicosanoids
 Prostaglandins
 Leukotrienes
Chemokines & Cytokines

3. Autacoids
Autacoids – “self remedy” – derived from Gr. autos
– “self” & akos – medicinal agent or “remedy”
diverse group of endogenous mediators involved
in homeostasis & in inflammation
occur in minute amounts
distinct biologic / pharmacologic activity
act as “local hormones”
mediators in aging, hypertension, allergy,
asthma, acid peptic disease, anxiety,
depression, hyperemesis

4. Receptors
Histamine: H1, H2, H3
Bradykinin: B1, B2
Serotonin: 5HT1A / 1B/ 1D/ 1E/ 1F/ 2A/
2B/
2C/ 3/ 4/ 5a/ 5b/ 6/ 7
Angiotensin: AT1A, AT1B, AT2
Prostanoids: DP, EP1, EP2, EP3, EP4,
FP, IP,
TP

5. Histamine
 actions:
 vasodilatation;
 ↑capillary permeability
 mediation of cellular responses, including allergic &
inflammatory reactions, gastric acid secretion
 pain & itch mediator
 bronchial & intestinal smooth muscle contraction
 location: occurs in practically all tissues, with
high amounts in the lungs, skin, GIT;
stored in basophils & mast cells

6. Histamine receptors
receptor agonist antagonist
H1 (~mine) 2-(m-
fluorophenyl)-
histamine
Chlorpheniramine,
Diphenhydramine,
Meclizine(Bonamine
)
H2 (~dine) 4-methyl
histamine
Cimetidine,
Ranitidine,
Famotidine
H3 ⍺-methyl
histamine
Thioperamide

7. clinical use of Anti-histamines
H1 blockers –
 anti-allergy,
 anti-inflammatory,
 anti-motion sickness.
 common side effect: sedation
H2 blockers – reduce secretion of
gastric acid.
 in peptic ulcer disease

8. Serotonin
 sources: vertebrates, molluscs, pineapple,
banana,
nuts, stings, venom; in man – 80% in GI
chromaffin cells, rest in platelets & CNS
 functions:
 central chemical transmitter for tryptominergic neurons in the
brain;
 precursor for melatonin;
 regulation of GI motility by increasing tone & peristalsis;
 hemostasis – vasospasm & platelet activation/aggregation;
 contraction of smooth muscle in the uterus, bronchi
 synthesis: Tryptophan (tryptophan 5-
hydroxylase)  5hydroxytryptophan(L-amino-
decarboxylase) 5HydroxyTryptamine (5HT,
Serotonin)

9. 5HT receptor subtypes & effector systems
recepto
r
mechanism effect
5HT1A Adenylyl cyclase
stimulation
direct vasodilatation &
inotropic effect
5HT1A
B
5HT1D
Adenylyl cyclase
inhibition
inhibition of NE release
5HT1C Phospholipase
C activation
indirect vasodilation via
EDRF release
5HT2 Phospholipase
C stimulation
vasoconstriction,
↑intracellular Calcium
5HT3 Calcium channel depolarization of

10. 5HT Antagonists
Ketanserin – blocks 5HT2 receptors –
 lowers blood pressure by blocking 5HT-induced contraction of
vascular smooth muscle & platelet aggregation;
 minor side effects: sedation, dry mouth, dizziness, nausea;
 clinical application: treatment of HTN & vasospastic disorders
Methysergide (1-methy-d-lysergic acid
butanolamide) -
 inhibits vasoconstrictor & pressor effects of 5HT on vascular
smooth muscle
 clinical use: prophylaxis for migraine & vascular headaches

11. Kinins
 synthesis: HMWK & LMWK are acted upon by
plasma & tissue Kallikrein to produce Bradykinin
& Kallidin
 metabolism: half-life=15 sec; inactivated by
kininase or converting enzyme
 functions:
 inflammatory mediators
 (also in rhinitis, hereditary angioneurotic edema, gout, endotoxic
shock, DIC);
 nociception;
 composition/volume of urine;
 BP regulation;
 fetal to neonatal adjustment

12. Receptors & effector systems
B1 Contraction of arteries &
most veins
pain
B2 Arteriolar vasodilation via
EDRF or H release;
contraction of endothelial
cells in venules
↑Capillary
permeability,
edema
B1 &
B2
Contraction of bronchial
smooth muscle; stimulate
nerve endings
pain

13. KKK Antagonists
Receptor antagonists
 Non-selective: blocks both B1 & B2
Selective: blocks B1 effects
Kallikrein inhibitors
 Aprotinin

14. the Renin – Angiotensin system
 precursor: Angiotensinogen
 enzyme: Renin
 Angiotensin I
 converting enzyme: Kininase
 Angiotensin II – arteriolar vasoconstriction ↑BP
 aminopeptidase
 Angiotensin III
 angiotensinase
 inactive peptide fragments

15. Angiotensin II actions
 stimulates synthesis & secretion of
Aldosterone
 stimulates the heart & sympathetic
nervous system
 increases ADH secretion
 stimulates thirst center
 powerful vasoconstrictor  increases
BP

16. Angiotensin Antagonists
ACE inhibitors –
 Captopril
 Enalapril
 Lisinopril
Angiotensin II receptor blockers
(ARBs)
 Losartan
 Valsartan
 Temisartan

17. Eicosanoids
 def. unsaturated fatty acid derivatives
locally synthesized & released as needed,
widely distributed in the body, very short
duration of action, rapidly metabolized to
inactive products
 receptors: DP1, DP2 (PGD2); EP1, EP2,
EP3, EP4 (PGE2); FP (PGF2); IP (PGI2);
TP (TXA2)

18. Synthesis of Eicosanoids
Phospholipids
 Phospholipase A2
Arachidonic acid
 Lipooxygenase ▪ Cyclooxygenase
Leukotrienes Prostacyclin
Prostaglandins
Thromboxane

19. Eicosanoids
Mechanism of action – activation of cell surface
receptors that are coupled by G proteins to
adenylyl cyclase (producing CAMP) or to
phosphatidylinositol (producing IP3 & DAG 2nd
messengers)
Physiologic effects:
 LTB4 – chemotactic factor
 PGE2 & PGI – vasodilators
 PGE2 & PGF2a – induce labor
 PGE1 & derivatives – smooth muscle relaxation, protect gastric
mucosa

20. Therapeutic uses of Eicosanoids
Eicosanoi
d
effects clinical uses
PGE2 &
PGF2a
increase uterine
activity
induction of labor /
abortion
PGE1 Relax vascular
smooth muscle
Maintain a patent
ductus arteriosus
PGE bronchodilates
PGF Bronchoconstricts

21. Clinical uses of Eicosanoids
eicosanoi
d
effects clinical use
PGE &
PGI2
Decrease gastric acid
secretion; sensitize
afferent nerve
endings in pain
Misoprostol –
to reduce
gastric
ulcerations from
NSAIDS
PGI2 Vasodilation Tx of 1º
pulmonary HTN
TXA2 &
PGI2
Control of
microcirculation
Alprostadi vasodilaton Induce penile

22. Clinical Application of Autacoids
autacoid agonist antagonist enzyme
inhibitor
Histamine Allergy
diagnostic
challenge
Anti-allergy,
Sedation, ulcer Rx
Serotonin Migraine
therapy
Appetite stimulation,
GERD, HTN,
depression, asthma
Angiotensin Hypertension hypertension
Prostanoids
(PGE, PGF)
Ulcer Rx,
stimulation of
labor
Anti-inflammatory,
anti-platelet, anti-
asthma

23. Chemokines & Cytokines
Chemokines – small proteins (90-130 AAs)
containing 4 conserved Cysteines
 CC chemokines: 2 consecutive cysteine pairs
 CXC chemokines: 2 cysteine pairs separated by other AA
 over 50, produced by a wide variety of cell types
 major regulators of Leukocyte traffic; chemotactic; bind to
proteoglycans on the endothelial cell surface & within the
extracellular matrix & set up chemokine gradients for the
migrating leukocytes to follow

24. Chemokines & receptors
Examples of Chemokines:
 IL8 – interleukin 8
 RANTES – regulated upon activation normal T cell expressed &
secreted
 MCP – monocyte chemoattractant protein
“serpentine receptors” – polypeptide chain
“snakes through” the cell membrane with 7
transmembrane segments
 CCR – bind CC chemokines
 CXCR – bind CXC chemokines

25. Cytokines
Soluble factors released by lymphocytes
& monocytes : Interferons & Interleukins
 have potent pro-inflammatory properties
 IL 1, IL 6, TNF-⍺ : endogenous pyrogens

26. Analgesics/Anti-inflammatory agents &
Antipyretics
Aspirin (ASA)
NSAIDS: non-steroidal anti-inflammatory
agents
 Ibuprofen
 Naproxen
 Indomethacin
Acetaminophen

27. Aspirin
Acetyl salicylic acid
 irreversibly inhibits cyclooxygenase
 effects: ↓manifestations of inflammation;
analgesia; ↓body temperature
 pharmacokinetics: readily absorbed; hydrolyzed
in blood & tissues to Acetate & Salicylate (the
active molecule);
 elimination: low-dose – 1st
order (half-life 3-5 h);
high dose – zero order (half-life >15h)
 excretion: kidney

28. Aspirin
 clinical use:
 low dose = < 300mg/d = anti-platelet aggregation
 intermediate = 300-2400 mg/d = antipyretic, analgesic
 high dose = 2400-4000 mg/d = anti-inflammatory
 toxicity:
 G I disturbances
 ↑risk of bleeding
 ↓prothrombin synthesis
 tinnitus, vertigo, hyperventilation, respiratory alkalosis

29. Aspirin
 hypersensitivity reactions
 anaphylaxis
 special precaution: use in children with
viral infection is associated with Reye’s
syndrome – hepatic fatty degeneration &
encephalopathy
 overdose: metabolic acidosis;
dehydration; hyperthermia; collapse;
coma; death
 Tx of overdose: dialysis

30. Aspirin
Therapeutic dose: 0.5-1.0 gm./day
Lethal dose: 2-4 gm./day in children
10-30 gm./day in adults
Acute toxicity: initial alkalosis--- fluid & electrolyte
imbalance--- metabolic acidosis--- death
Chronic toxicity: (3 gm/day): dizziness, nausea,
vomiting, diarrhea, drowsiness, hallucinations,
convulsions, coma
Known effects: analgesic; anti-platelet
aggregation; gastric irritant--- acute erosive
gastritis
Unpredictable ADRs: hypersensitivity: rashes,
urticaria, exfoliative dermatoses

31. NSAIDs
 representative drugs:
 Ibuprofen – low potency; short acting; half-life = 2 hrs
 Naproxen – intermediate potency;
 Indomethacin – high potency; long-acting; half-life = 12-24 hrs
 pharmacokinetics: good absorption after oral
intake; excretion – kidney
 toxicity:
 GI disturbances, ↑ risk of bleeding;
 significant risk of renal damage at high therapeutic dose, esp. in
the presence of pre-existing renal disease

32. Acetaminophen / Paracetamol
 mechanism of action: unclear; weak
cyclooxygenase inhibition in peripheral
tissues, more effective in CNS
 effects: antipyretic, analgesic. (no
significant anti-platelet aggregation or anti-
inflammatory effects)
 pharmacokinetics: well-absorbed &
metabolized in the liver; half-life = 2-3 hrs;
unaffected by renal disease

33. Acetaminophen
 clinical use:
 analgesic;
 antipyretic;
 Aspirin substitute in hypersensitivity cases & in children
with viral infection
 toxicity:
 negligible in therapeutic dosage;
 overdose  hepatotoxicity (Use with caution in Liver
impairment)

34. Acetaminophen
therapeutic dose: 0.5 gm q 4 hrs.(up to
3gm/day)
toxic dose: 15-25 gm;
 toxicity: nausea, vomiting, diarrhea; shock;
hepatic injury
pathology: hepatic necrosis; renal/myocardial
damage