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8/14/2019 Pharma Chem Mediators
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Chemical
Mediators
inHealth &
DiseaseMa. Minda Luz M. Manuguid, M.D.
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Inflammatory Mediators &Antagonists
Autacoids Histamine
Serotonin
Angiotensin Prostanoids
Eicosanoids Prostaglandins
Leukotrienes
Chemokines & Cytokines
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AutacoidsAutacoids self remedy derived from Gr.
autos self & akos medicinal agent orremedy
diverse group of endogenous mediators involvedin 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
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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
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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 inbasophils & mast cells
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Histamine receptors
receptor agonist antagonist
H1 (~mine) 2-(m-fluorophenyl)-
histamine
Chlorpheniramine,Diphenhydramine,
MeclizineH2 (~dine) 4-methyl
histamineCimetidine,Ranitidine,Famotidine
H3 -methylhistamine
Thioperamide
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clinical use of Anti-histamines
H1 blockers anti-allergy,
anti-inflammatory,
anti-motion sickness.
common side effect: sedation
H2 blockers reduce secretion ofgastric acid. in peptic ulcer disease
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Serotonin
sources: vertebrates, molluscs, pineapple,banana,nuts, stings, venom; in man 80% in GIchromaffin cells, rest in platelets & CNS
functions: central chemical transmitter for
tryptominergic neurons in the brain; precursorfor melatonin; regulation of GI motility byincreasing 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
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5HT receptor subtypes &effector systems
recepto
r
mechanism effect
5HT1A Adenylylcyclase
stimulation
direct vasodilatation &inotropic effect
5HT1AB
5HT1D
Adenylylcyclase
inhibition
inhibition of NErelease
5HT1C PhospholipaseC activation
indirect vasodilationvia EDRF release
5HT2 Phospholipase
C stimulation
vasoconstriction,
intracellular Calcium
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5HT Antagonists
Ketanserin blocks 5HT2 receptors
lowers blood pressure by blocking 5HT-induced contraction ofvascular 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 vascularsmooth muscle
clinical use: prophylaxis for migraine & vascular headaches
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Kinins
synthesis: HMWK & LMWK are acted uponby plasma & tissue Kallikrein to produceBradykinin & Kallidin
metabolism: half-life=15 sec; inactivatedby 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
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Receptors & effectorsystems
B1 Contraction of arteries &most veins
pain
B2 Arteriolar vasodilation
via EDRF or H release;contraction of endothelialcells in venules
Capillary
permeability, edema
B1 & B2Contraction of bronchialsmooth muscle;stimulate nerve endings
pain
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KKK Antagonists
Receptor antagonists Non-selective: blocks both B1 & B2
Selective: blocks B1 effects
Kallikrein inhibitors Aprotinin
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the Renin Angiotensinsystem
precursor: Angiotensinogen
enzyme: Renin
Angiotensin I
converting enzyme: Kininase
Angiotensin II arteriolar vasoconstriction BP
aminopeptidase
Angiotensin III
angiotensinase
inactive peptide fragments
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Angiotensin II actions
stimulates synthesis & secretionof Aldosterone
stimulates the heart &sympathetic nervous system
increases ADH secretion
stimulates thirst center powerful vasoconstrictor
increases BP
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Angiotensin Antagonists
ACE inhibitors
Captopril
Enalapril
Lisinopril
Angiotensin II receptor blockers(ARBs)
Losartan Valsartan
Temisartan
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Eicosanoids
def. unsaturated fatty acidderivatives locally synthesized &released as needed, widely
distributed in the body, very shortduration of action, rapidlymetabolized to inactive products
receptors: DP1, DP2 (PGD2); EP1,EP2, EP3, EP4 (PGE2); FP (PGF2); IP(PGI2); TP (TXA2)
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Synthesis of Eicosanoids
Phospholipids
Phospholipase A2
Arachidonic acid
Lipooxygenase Cyclooxygenase
Leukotrienes ProstacyclinProstaglandins Thromboxane
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Eicosanoids
Mechanism of action activation of cellsurface receptors that are coupled by Gproteins to adenylyl cyclase (producingCAMP) or to phosphatidylinositol(producing IP3 & DAG 2nd messengers)
Physiologic effects: LTB4 chemotactic factor
PGE2 & PGI vasodilators PGE2 & PGF2a induce labor
PGE1 & derivatives smooth musclerelaxation, protect gastric mucosa
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Therapeutic uses ofEicosanoids
Eicosanoid
effects clinical uses
PGE2 &PGF2a increase uterineactivity induction oflabor / abortion
PGE1 Relax vascularsmooth muscle
Maintain a patentductus arteriosus
PGE bronchodilates
PGF Bronchoconstrict
s
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Clinical uses of Eicosanoids
eicosanoid effects clinical use
PGE &PGI2
Decrease gastricacid secretion;
sensitize afferentnerve endings inpain
Misoprostol to reduce
gastriculcerationsfrom NSAIDS
PGI2 Vasodilation Tx of 1pulmonaryHTN
TXA2 &
PGI2
Control of
microcirculation
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Clinical Application ofAutacoids
autacoid agonist antagonist enzymeinhibitor
Histamine Allergydiagnosticchallenge
Anti-allergy,
Sedation, ulcer
RxSerotonin Migraine
therapyAppetitestimulation,GERD, HTN,depression,asthma
Angiotensin Hypertension hypertension
Prostanoids(PGE, PGF) Ulcer Rx,stimulation Anti-inflammatory,
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Chemokines & Cytokines
Chemokines small proteins (90-130 AAs) containing 4conserved 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 theextracellular matrix & set up chemokine gradients for themigrating leukocytes to follow
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Chemokines & receptors
Examples of Chemokines: IL8 interleukin 8
RANTES regulated upon activation normal T
cell expressed & secreted MCP monocyte chemoattractant protein
serpentine receptors polypeptide chainsnakes through the cell membrane with
7 transmembrane segments CCR bind CC chemokines
CXCR bind CXC chemokines
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Cytokines
Soluble factors released bylymphocytes & monocytes :Interferons & Interleukins
have potent pro-inflammatoryproperties
IL 1, IL 6, TNF- : endogenouspyrogens
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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 3-5h); high dose zero order (half-life >15h)
excretion: kidney
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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
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Aspirin
hypersensitivity reactions
anaphylaxis
special precaution: use in children with
viral infection is associated with Reyessyndrome hepatic fatty degeneration& encephalopathy
overdose: metabolic acidosis;
dehydration; hyperthermia; collapse;coma; death
Tx of overdose: dialysis
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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---deathChronic toxicity: (3 gm/day): dizziness, nausea,
vomiting, diarrhea, drowsiness, hallucinations,convulsions, coma
Known effects: analgesic; anti-plateletaggregation; gastric irritant--- acute erosivegastritis
Unpredictable ADRs: hypersensitivity: rashes,urticaria, exfoliative dermatoses
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NSAIDs
representative drugs: Ibuprofen low potency; short acting; half-life = 2 hrs
Naproxen intermediate potency;
Indomethacin high potency; long-acting; half-life = 12-24hrs
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
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Acetaminophen /Paracetamol
mechanism of action: unclear; weakcyclooxygenase inhibition in peripheraltissues, more effective in CNS
effects: antipyretic, analgesic. (nosignificant anti-platelet aggregation oranti-inflammatory effects)
pharmacokinetics: well-absorbed &metabolized in the liver; half-life = 2-3hrs; unaffected by renal disease
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Acetaminophen
clinical use: analgesic;
antipyretic;
Aspirin substitute in hypersensitivitycases & in children with viral infection
toxicity:
negligible in therapeutic dosage; overdose hepatotoxicity (Use withcaution in Liver impairment)
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Acetaminophen
therapeutic dose: 0.5 gm q 4 hrs.(up to3gm/day)
toxic dose: 15-25 gm;
toxicity: nausea, vomiting, diarrhea;shock; hepatic injury
pathology: hepatic necrosis;
renal/myocardial damage
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Thank You !