Chemical Mediators

in
Health & Disease
Ma. Minda Luz M. Manuguid, M.D.
Inflammatory Mediators &
Antagonists
Autacoids
 Histamine
 Serotonin
 Angiotensin
 Prostanoids
Eicosanoids
 Prostaglandins
 Leukotrienes
Chemokines & Cytokines
 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
 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
 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
 Histamine receptors
receptor agonist antagonist
H1 (~mine) 2-(m- Chlorpheniramine,
fluorophenyl)- Diphenhydramine,
histamine Meclizine
H2 (~dine) 4-methyl Cimetidine, Ranitidine,
histamine Famotidine

H3 ⍺-methyl Thioperamide
histamine
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
 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 receptor subtypes & effector
receptor
systems
mechanism effect
5HT1A Adenylyl cyclase direct vasodilatation &
stimulation inotropic effect
5HT1A Adenylyl cyclase inhibition of NE release
B inhibition
5HT1D
5HT1C Phospholipase C indirect vasodilation via
activation EDRF release
5HT2 Phospholipase C vasoconstriction,
stimulation ↑intracellular Calcium
5HT3 Calcium channel depolarization of sensory
activation nerves
 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
 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
 Receptors & effector systems
B1 Contraction of arteries & most pain
veins

B2 Arteriolar vasodilation via ↑Capillary

EDRF or H release; permeability,
contraction of endothelial edema
cells in venules
B1 & Contraction of bronchial pain
B2 smooth muscle; stimulate
nerve endings
 KKK Antagonists
Receptor antagonists
 Non-selective: blocks both B1 & B2
Selective: blocks B1 effects
Kallikrein inhibitors
 Aprotinin
 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
 Angiotensin II actions
 stimulates synthesis & secretion of
Aldosterone
 stimulates the heart & sympathetic
nervous system
 increases ADH secretion
 stimulates thirst center
 powerful vasoconstrictor  increases BP
 Angiotensin Antagonists
ACE inhibitors –
 Captopril
 Enalapril
 Lisinopril
Angiotensin II receptor blockers (ARBs)
 Losartan
 Valsartan
 Temisartan
 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)
 Synthesis of Eicosanoids
Phospholipids
 Phospholipase A2
Arachidonic acid
 Lipooxygenase ▪ Cyclooxygenase
Leukotrienes Prostacyclin
Prostaglandins
Thromboxane
 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
 Therapeutic uses of Eicosanoids

Eicosanoid effects clinical uses

PGE2 & increase uterine induction of labor /
PGF2a activity abortion
PGE1 Relax vascular Maintain a patent
smooth muscle ductus arteriosus
PGE bronchodilates

PGF Bronchoconstricts
 Clinical uses of Eicosanoids
eicosanoid effects clinical use
PGE & Decrease gastric acid Misoprostol – to
PGI2 secretion; sensitize reduce gastric
afferent nerve endings ulcerations from
in pain NSAIDS
PGI2 Vasodilation Tx of 1º
pulmonary HTN
TXA2 & Control of
PGI2 microcirculation
Alprostadi vasodilaton Induce penile
l erection
 Clinical Application of Autacoids
autacoid agonist antagonist enzyme inhibitor

Histamine Allergy Anti-allergy,

diagnostic Sedation, ulcer Rx
challenge
Serotonin Migraine Appetite stimulation,
therapy GERD, HTN,
depression, asthma
Angiotensin Hypertension hypertension
Prostanoids Ulcer Rx, Anti-inflammatory,
(PGE, PGF) stimulation of anti-platelet, anti-
labor asthma
 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
 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
 Cytokines
Soluble factors released by lymphocytes &
monocytes : Interferons & Interleukins
 have potent pro-inflammatory properties
 IL 1, IL 6, TNF-⍺ : endogenous pyrogens
 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
 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
 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
 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
 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
 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
 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)
 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
Thank You !