This is not official study material of Dpt. of Pharmacology Drugs used in gastric ulcer disease Peptic ulcers – result of dysbalance between protective and harmful factors H+ pepsin Helicobacter pylori NSAIDs corticosteroids mucin, mucus HCO- 3 epitelium, mucous barrier perfusion in gastric mucosa Protective factors Harmful factors pepsin H+ Helicobacter pylori Epiel digestion nv.vagus gastrin histamine + gastritis O• radicals secretine PGE2 , PGI2 adenosine - stress NSAIDs smoking - HCO- 3 Prostaglandins + ULCUS (5-10 %) H+, K+ -ATP-dep. pump H+ K+ ClParietal cell LumenStimulation Histamine Gastrin Acetylcholin (nv. vagus) G H2 cAMP Ca2+ Ca2+ antacids anticholinergics antagonists H2 PG analogues proton pump i. PK AC Gs PgR Gi - + M1 AIMS of TREATMENT • supress pain • improve healing (mucosa reparation) • prevent relaps neutralization (antacids) supress harmfull factors (HCl, pepsin, H. pylori) mucosa resistence increase Drugs used in ulcer disease • Antacids • Inhibition of HCl secr. - H2 antagonists - H+ pump antagonists - anticholinergic drugs • Eradication of H. pylori • Cytoprotective drugs Antacids • symptomatic therapy • HCl neutralisation in stomach = increase in pH...decr. pepsin activity (pH optimum 2) Antacids • NaHCO3 (strong, rapid relief from pain) • CaCO3 (strong, rapid relief from pain, not for chronic treatment absorption of Ca2+) • MgO / Mg(OH)2 (laxative) • Mg [AlO2(OH)] Mg(OH)2 + Al2O3 • Al2O3 (gel, long-lasting, constipation) • Bi(OH)2NO3 (wek eff., supress H. pylori) Antacids Indications: dyspepsia, hyperacidity, pyrosis, reflux oesophaagitis symptomatic treatment of GIT disorders begining of antiulcerous therapy, rapid relief from pain ADE: absorption of Ca, Mg (cardiac complications) – Al – constipation, Mg - laxative – decr. absorption of other drugs Inhibition of HCl secretion 1) H2 antihistaminics 2) Proton pump inhibitors 3) Anticholinergics H2 antihistaminics Mechanism of action: competitive H2 receptor antagonisms selective supression of HIS-induced secretion inhibition of intrinsic factor secretion (B12) H2 antihistaminics cimetidine (Cimetidin, Primamet) withdrawn ranitidine (Apo- ranitidine, Ranisan, Ulcosan, Ranitan, Zantac, Histac) famotidine (Apo-Famotidin, Famosan, Quamatel, Ulfamid) nizatidine roxatidine H2 antihistaminics Indications: ulcer disease secondary ulcer disease prevention of peptic ulcer relapse Zollinger-Ellison syndrome ( ↑gastrin) reflux oesophafgitis hyperacidity, NSAIDs treatment H2 antihistaminics ADR: headache, myalgia, diarrhoea, constiption, CNS - confusedness, glossolalia endocrine - antiandrogenic efect (cimetidine) - impotence, gynekomastia blood – granulocytopenia, trombocytopenia, neutropenia..aplastic anemia (cimetidine, ranitidine) hepatotoxicity – ALT, AST Caution: passes placental barrier, Proton pump inhibitors • very strong effect • supress HCl secretion not concerning the origin of stimuli • enterosolvent coating, parenteral • administered as a pro-drugs Proton pump inhibitors • H+ conditionsactive metabolites • irreversible inhibition • Re-synthesis needed for regeneration Mechanism of action Proton pump inhibitors • omeprazole (Helicid, Apo-Ome, Gasec) • pantoprazole (Controloc, Pantoprazol) • lansoprazole (Lansul) • rabeprazole • constituent of H. pylori eradication in ulcer disease • ulcer disease in H2 antagonists failure • reflux oesophagitis • Zollinger-Ellison syndrome ( ↑gastrin) Indications Proton pump antagonists • dyspepsia, headache • rarely cytopenia • P450 inhibition ADR Proton pump antagonists Selective parasympatolytics Mechanism of action: acetylcholine antagonism in M1 receptors • convenient is selective inhibition • supress CO2- 3 and mucus secretion • Similar action with H2 antagonists pirenzepine Indications: peptic ulcer disease dyspepsia after NSAIDs treatment stress ulcer prevention CI: glaucoma, prostate hypertrophy, micturition disorders Selective parasympatolytics Cytoprotectives Mucus- protective eff. on the na mucosa of stomach Sucralfate Bismuth salts Alginic acid Cytoprotectives Sucralfate – octasulfate of sucrose + aluminium hydroxide strong mucoprotective eff. protective barrier set up Binds pepsin and bile acids Incr. prostaglandins synthesis Effects (Sucrolan, Venter,Ulcogant) Sucralfate – octasulfate of sucrose + aluminium hydroxide not absorbed  mild ADR dyspepsia, Al- constipation Rarely plasmatic Al elevation Decr. bioavailability of other drugs - TC, phenytoin,digoxine, cimetidine... ADR Bismuth salts – basic salts of bismuth and citric acid Chelatation of proteins on ulcer surface  protective barrier PG secretion stimulation antibacterial action (eradication of H. pylori) Mechanism of action Alginic acid Proves protective barrier-gel on the surface of stomach mucous Effect lasts app. 2.5 h Eicosanoids PGE1, PGI2 – main natural protective factors synthetised in gastric mucosa Incr. mucus and HCO3 production, perfusion Unstable, only derrivatives administered as prevention of harmfull effects of NSAIDs Cytoprotective and antisecretive drugs Antiulceróza Rioprostil, enprostil, misoprostol Misoprostol methylester PGE1 long-lasting effect abortive ! ADE- dysepsia, nausea, flatulence Eradication of H. pylori (G- bacteria) decrease frequency of relapses to 0-10 % complex therapy – together with H+ pump inhibitors Combination of 2 antibiotics metronidazole + amoxycilin metronidazole + claritromycin metronidazole + tetracyclin Antiemetics, prokinetics Initiation of vomitting A) Chemoperception area (area postrema) apomorphine, digitalis, nicotine,CuSO4 ,toxins, uremia B) Formatio reticulraris – (CNS center of vomitting) sympathetic and parasympathetic inervation kinetosis incr. Intracranial pressure pregnancy psychogenic factors inflammation, peritoneal distension delayed gastric emptying B) formatio reticularis C) Efferent nerves VIII-X – pylorus sfincter contraction - cardia opening - abdominal muscles contraction - reflux peristaltic moevements in oesophagus Initiation of vomitting Antiemetics Influence of neurotransitters on vomitting dopamine - D2 receptors histamine - H1 receptors serotonin - 5HT3 receptors acetylcholine - M receptors enkephalins (+opioids) - , - receptors GABA Antiemetic drugs • anticholinergic drugs • antihistaminics (H1) • neuroleptics • 5HT3 antagonists • cannabinoids • neurokinine antagonist • prokinetic drugs (incr. motility) • Ca++ channel blockers • ginger extracts (zingiber off.) Anticholinergic drugs Scopolamin (TTS) • acts centrally + peripherally • for kinetosis in the dose 0.5 mg • ADE: sedation, constipation, urine retention and others anticholinergic ADE Antihistaminics • H1 antihistaminics of the 1.st generation – anticholinergic action, pass through BBB • sedative action  convenient use in kinetosis • insufficient action in severe vomitting after chemotherapeutics (oncology) Antihistaminics Drugs used in practice difephehydramin theoclate = dimenhydrinate (Travel-Gum, +cinnarizin = Arlevert, +Paracetamol = Migraeflux) moxastine theoclate = mefenhydrinate (Kinedryl) embramine theoclate = mebrofenhydrinate (Medrin) promethazine (Prothazin) Antihistaminics theoclates (salts of H1 antagonist + 8-chlortheophylline) - weak sedation, low occurence of ADE - augmented antivertiginous effect - prolonged T1/2 ADR: ADE: sedation, fotosensitivity, allergy, dry mouth, urine retention etc.. Caution: prevent combination with other sedative drugs (opioids, hypnosedatives, neuroleptikcs) pass BB, placenta Neuroleptics • inhibit vomitting center in f. reticularis • strong antiemetic effect • except of thietylperazine ineffective in kinetosis • lower doses than in psychosis • sufficient effect in nausea ad vomitting after antineoplastic treatment X weaker effe. Compared to procinetics + i 5HT3 receptors (setrones) Phenothiazines prochlorperazine perphenazine thiethylperazine (Torecan inj., drg., supp.) Neuroleptics ADE: sedation, tiredness, dry mouth, constipation, fotosensitivity, extrapyramidal symptoms. Thiethylperazine can be administered in 1st. trimester of pregnancy Butyrophenons haloperidol droperidol – prior to general anaesthesia, severe vomitting in cytostatic treatment ADE: haloperidol- somnolence, tiredness, hypoglycemia, constipation droperidol- rare – neuroleptic syndrom (10% mortality) Neuroleptics 5HT3 receptor antagonists • in the peripheral tissues - block n. vagus stimulation • in the vomitting center (f. reticularis) • absence of sedative eff. • more eff. in cytostatic treatment than prokinetics and glucocorticoids ADE: constipation, headaches, vertigo, ALT,AST 5HT3 receptor antagonists Palonosetron (Aloxi) ondansetron (Emeset, Emetron) granisetron (Kytril) dolasetron (Ansemet) tropisetron Neurokinin receptor antagonist Antiemetics NK-1 receptors in brain stem, area postrema, n. tractus solitarii in medula oblong. NK1-rcp vagal endings in oesophagal sfincter NK1- agonist is substance P, and neurokinine neuropeptide, 11 AMK) Aprepitant – antag. NK1 rcp., binds substance P NK1 rcp antag. = anxiolytic, antidepressant actions, supresses proliferation Prokinetics Peristalsis stimulation GIT (proximal part) partial antagonists of D2 and 5HT receptors Indications: nausea, vomitting, reflux. oesophagitis, prevention of bile reflux, improvement of gastric emptying Prokinetics Metoclopramide (Cerucal, Degan, Pramidin) Cisapride (Prepulsid) Domperidone (Motilium) Alizapride (levo)Sulpiride – antipsychotic drug, antiemetikum (Prosulpin, Sulpirol, Dogmatil)  psychoaffective disorders with somatic symptoms Cannabinoids Dronabinol Nabilon - Not in clin. practice, unknown mechanism of action, acting centrally + peripherally Antivertiginous Ca++ channel blockers cinnarizine flunarizine vasodilation, antivertiginous eff. structurally related to anti-H1 Indications : vertigo due to impaired cerebral perfusion Stugeron, Cinnabene, Arlevert (+ dimenhydrinate) Antiemetics Corticosteroids - nonspecific – membrane stabilizing effects - decrease of sy.PG  combined with metoclopramide in nausea after cytostatic treatment Dexamethasone, Methylprednisolone Ginger - Zingiber officinale - zingiberol and gingerol  mild nausea symptoms in pregnancy  peripheral action Indications of antiemetic drugs PREGNANCY: thietylperazin (Torecan supp, inj. drg.) vit. B6 (pyridoxine) ginger POSTOPERATIVE :domperidone metoclopramide KINETOSIS, VERTIGO antihistaminics (anti H1, H3) - phenothiazines (anti H1 and PSL) - parasympatolytics - Ca blockers AFTER CYTOSTATICS, IRRADIATION: 5-HT3 rcp antagonists, combination metoclopramide + corticosteroids Emetics Indication: weaning alcohol addicts,treatment of overdose (consciousness) Apomorphine - stimulation of D2 rec. in area postrema (in medulla oblongata) - 5-10 mg s.c.  intense vomitting ADE: vertigo, sedation, hypotension, euphoria, coma Emetics Emetin Cephaelis Ipecacuanha – radix (roots) 10-15 mg  vomitting 1-2 mg  expectorative eff. Disulfiram Inh. aldehyddehydrogenase  acetate, ketones  vomitting center stimulation Alcohol + Cephalosporins, Metronidazol, Sulphonylureas