Pharma Chem Mediators

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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Pharma Chem Mediators

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