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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,
histamine Ranitidine,
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 systems
recepto mechanism effect
r
5HT1A Adenylyl direct vasodilatation &
cyclase inotropic effect
stimulation
5HT1A Adenylyl inhibition of NE
B cyclase release
5HT1D inhibition
5HT1C Phospholipase indirect vasodilation
C activation via EDRF release
5HT2 Phospholipase vasoconstriction,
C stimulation ↑intracellular Calcium
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 & pain
most veins
B2 Arteriolar vasodilation ↑Capillary
via EDRF or H release; permeabilit
contraction of endothelialy, edema
cells in venules

B1 & B2Contraction of bronchial pain


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
Eicosanoi effects clinical uses
d
PGE2 & increase uterine induction of
PGF2a activity labor / abortion
PGE1 Relax vascular Maintain a patent
smooth muscle ductus arteriosus

PGE bronchodilates
PGF Bronchoconstrict
s
Clinical uses of Eicosanoids
eicosanoi effects clinical use
d
PGE & Decrease gastric Misoprostol –
PGI2 acid secretion; to reduce
sensitize afferent gastric
nerve endings in ulcerations
pain from NSAIDS
PGI2 Vasodilation Tx of 1º
pulmonary
HTN
TXA2 & Control of
PGI2 microcirculation
Clinical Application of
autacoid
Autacoids
agonist antagonist enzyme
inhibitor
Histamine Allergy Anti-allergy,
diagnostic Sedation, ulcer
challenge Rx
Serotonin Migraine Appetite
therapy stimulation,
GERD, HTN,
depression,
asthma
Angiotensin Hypertension hypertension

Prostanoids Ulcer Rx, Anti-


(PGE, PGF) stimulation inflammatory,
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 !