Chemical Mediators
in
Health & Disease
Ma. Minda Luz M. Manuguid, M.D.
Inflammatory Mediators & Antagonists
Autacoids
 Histamine
 Serotonin
 Angiotensin
 Prostanoids
Eicosanoids
 Prostag...
Autacoids
Autacoids – “self remedy” – derived from Gr. autos
– “self” & akos – medicinal agent or “remedy”
diverse group ...
Receptors
Histamine: H1, H2, H3
Bradykinin: B1, B2
Serotonin: 5HT1A / 1B/ 1D/ 1E/ 1F/ 2A/
2B/
2C/ 3/ 4/ 5a/ 5b/ 6/ 7
A...
Histamine
 actions:
 vasodilatation;
 ↑capillary permeability
 mediation of cellular responses, including allergic &
i...
Histamine receptors
receptor agonist antagonist
H1 (~mine) 2-(m-
fluorophenyl)-
histamine
Chlorpheniramine,
Diphenhydramin...
clinical use of Anti-histamines
H1 blockers –
 anti-allergy,
 anti-inflammatory,
 anti-motion sickness.
 common side ...
Serotonin
 sources: vertebrates, molluscs, pineapple,
banana,
nuts, stings, venom; in man – 80% in GI
chromaffin cells, r...
5HT receptor subtypes & effector systems
recepto
r
mechanism effect
5HT1A Adenylyl cyclase
stimulation
direct vasodilatati...
5HT Antagonists
Ketanserin – blocks 5HT2 receptors –
 lowers blood pressure by blocking 5HT-induced contraction of
vascu...
Kinins
 synthesis: HMWK & LMWK are acted upon by
plasma & tissue Kallikrein to produce Bradykinin
& Kallidin
 metabolism...
Receptors & effector systems
B1 Contraction of arteries &
most veins
pain
B2 Arteriolar vasodilation via
EDRF or H release...
KKK Antagonists
Receptor antagonists
 Non-selective: blocks both B1 & B2
Selective: blocks B1 effects
Kallikrein inhib...
the Renin – Angiotensin system
 precursor: Angiotensinogen
 enzyme: Renin
 Angiotensin I
 converting enzyme: Kininase
...
Angiotensin II actions
 stimulates synthesis & secretion of
Aldosterone
 stimulates the heart & sympathetic
nervous syst...
Angiotensin Antagonists
ACE inhibitors –
 Captopril
 Enalapril
 Lisinopril
Angiotensin II receptor blockers
(ARBs)
 ...
Eicosanoids
 def. unsaturated fatty acid derivatives
locally synthesized & released as needed,
widely distributed in the ...
Synthesis of Eicosanoids
Phospholipids
 Phospholipase A2
Arachidonic acid
 Lipooxygenase ▪ Cyclooxygenase
Leukotriene...
Eicosanoids
Mechanism of action – activation of cell surface
receptors that are coupled by G proteins to
adenylyl cyclase...
Therapeutic uses of Eicosanoids
Eicosanoi
d
effects clinical uses
PGE2 &
PGF2a
increase uterine
activity
induction of labo...
Clinical uses of Eicosanoids
eicosanoi
d
effects clinical use
PGE &
PGI2
Decrease gastric acid
secretion; sensitize
affere...
Clinical Application of Autacoids
autacoid agonist antagonist enzyme
inhibitor
Histamine Allergy
diagnostic
challenge
Anti...
Chemokines & Cytokines
Chemokines – small proteins (90-130 AAs)
containing 4 conserved Cysteines
 CC chemokines: 2 conse...
Chemokines & receptors
Examples of Chemokines:
 IL8 – interleukin 8
 RANTES – regulated upon activation normal T cell e...
Cytokines
Soluble factors released by lymphocytes
& monocytes : Interferons & Interleukins
 have potent pro-inflammatory...
Analgesics/Anti-inflammatory agents &
Antipyretics
Aspirin (ASA)
NSAIDS: non-steroidal anti-inflammatory
agents
 Ibupro...
Aspirin
Acetyl salicylic acid
 irreversibly inhibits cyclooxygenase
 effects: ↓manifestations of inflammation;
analgesi...
Aspirin
 clinical use:
 low dose = < 300mg/d = anti-platelet aggregation
 intermediate = 300-2400 mg/d = antipyretic, a...
Aspirin
 hypersensitivity reactions
 anaphylaxis
 special precaution: use in children with
viral infection is associate...
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: ...
NSAIDs
 representative drugs:
 Ibuprofen – low potency; short acting; half-life = 2 hrs
 Naproxen – intermediate potenc...
Acetaminophen / Paracetamol
 mechanism of action: unclear; weak
cyclooxygenase inhibition in peripheral
tissues, more eff...
Acetaminophen
 clinical use:
 analgesic;
 antipyretic;
 Aspirin substitute in hypersensitivity cases & in children
wit...
Acetaminophen
therapeutic dose: 0.5 gm q 4 hrs.(up to
3gm/day)
toxic dose: 15-25 gm;
 toxicity: nausea, vomiting, diarr...
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Pharma chemmediators

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Pharma chemmediators

  1. 1. Chemical Mediators in Health & Disease Ma. Minda Luz M. Manuguid, M.D.
  2. 2. Inflammatory Mediators & Antagonists Autacoids  Histamine  Serotonin  Angiotensin  Prostanoids Eicosanoids  Prostaglandins  Leukotrienes Chemokines & Cytokines
  3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 13. KKK Antagonists Receptor antagonists  Non-selective: blocks both B1 & B2 Selective: blocks B1 effects Kallikrein inhibitors  Aprotinin
  14. 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. 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. 16. Angiotensin Antagonists ACE inhibitors –  Captopril  Enalapril  Lisinopril Angiotensin II receptor blockers (ARBs)  Losartan  Valsartan  Temisartan
  17. 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. 18. Synthesis of Eicosanoids Phospholipids  Phospholipase A2 Arachidonic acid  Lipooxygenase ▪ Cyclooxygenase Leukotrienes Prostacyclin Prostaglandins Thromboxane
  19. 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. 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. 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. 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. 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. 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. 25. Cytokines Soluble factors released by lymphocytes & monocytes : Interferons & Interleukins  have potent pro-inflammatory properties  IL 1, IL 6, TNF-⍺ : endogenous pyrogens
  26. 26. Analgesics/Anti-inflammatory agents & Antipyretics Aspirin (ASA) NSAIDS: non-steroidal anti-inflammatory agents  Ibuprofen  Naproxen  Indomethacin Acetaminophen
  27. 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. 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. 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. 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. 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. 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. 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. 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

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