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