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
AutacoidsAutacoids – “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 amountsdistinct biologic / pharmacologic activityact as “local hormones”mediators in aging, hypertension, allergy,
asthma, acid peptic disease, anxiety, depression, hyperemesis
Receptors
Histamine: H1, H2, H3Bradykinin: B1, B2Serotonin: 5HT1A / 1B/ 1D/ 1E/ 1F/ 2A/
2B/ 2C/ 3/ 4/ 5a/ 5b/ 6/ 7
Angiotensin: AT1A, AT1B, AT2Prostanoids: 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-fluorophenyl)-histamine
Chlorpheniramine, Diphenhydramine, Meclizine(Bonamine)
H2 (~dine) 4-methyl histamine
Cimetidine, Ranitidine, Famotidine
H3 ⍺-methyl histamine
Thioperamide
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, Serotonin)
5HT receptor subtypes & effector systems
receptor
mechanism effect
5HT1A Adenylyl cyclase
stimulation
direct vasodilatation & inotropic effect
5HT1AB5HT1D
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
activation
depolarization of sensory 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 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
KKK Antagonists
Receptor antagonists Non-selective: blocks both B1 & B2
Selective: blocks B1 effectsKallikrein 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 & PGF2a
increase uterine activity
induction of labor / abortion
PGE1 Relax vascular smooth muscle
Maintain a patent ductus arteriosus
PGE bronchodilates
PGF Bronchoconstricts
Clinical uses of Eicosanoidseicosanoid
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
Alprostadil
vasodilaton Induce penile erection
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
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
Analgesics/Anti-inflammatory agents &
AntipyreticsAspirin (ASA)NSAIDS: non-steroidal anti-
inflammatory agents Ibuprofen Naproxen Indomethacin
Acetaminophen
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./dayLethal dose: 2-4 gm./day in children
10-30 gm./day in adultsAcute 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 injurypathology: hepatic necrosis;
renal/myocardial damage
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