Title: PHARMACOLOGY of gastrointestinal tract II. Secretion and motility disorders
1PHARMACOLOGY of gastrointestinal tract
II.Secretion and motility disorders
2When is the medication necessary ?
- motility disorders (vomiting, reflux, abnormal
passages, irritable bowel syndrome, colic,
...)resorption disorders (disorders of GIT
enzymes secretion, malabsorption)peptic lesions
(ulceration GD)inflammatory disease (bowel,
hepatitis, ...) - excessive food intake (antiobesity drugs)
- gastrointestinal bleeding (prophylaxis and
treatment)
3Medicines for diseases of the gastrointestinal
tract
- pharmacotherapy of functional and motor
disordersantiemeticsprokineticantispasmodics - pharmacotherapy of peptic ulcer disease -
proton pump inhibitors - - antihelicobacterial treatment - histamine H2
receptor antagonists - chelates based on bismuth
salts,antacids
4Medicines for diseases of the gastrointestinal
tract
- pharmacotherapy of motoric and functional GIT
disorders. laxativesantidiarrheal
drugseubiotics, antihaemorrhoidaliapharmacother
apy of digestion disturbancessubstitution of
digestive enzymes
5Medicines for diseases of the gastrointestinal
tract
- nonspecific intestines inflammation
pharmacotherapy. anti-inflammatory
therapy - corticosteroids -
aminosalicylates - biological
treatmentpharmacotherapy of liver and bile
pathsbiol. treatmentinterferonsantispasmodics
hepatoprotectives
6Pharmacotherapy of functional gastrointestinal
disorders
- nausea and vomiting
- motility disorders of the proximal part of the
GITfunctional dyspepsiaspasm of hollow organs
(colic)gastroesophageal reflux disease
(heartburn, regurgitation) - motility disorders of the distal part of the
GITdiarrheaconstipation
7Nausea and vomiting
- nausea only subjective feeling
- vomiting can lead to metabolic disruption (loss
of potassium, water, HCl, negative energ.
balances), the risk of aspiration of vomit,
mucous rupture - bleedingthe need for
prevention and treatmentimportance especially in
oncology
8antiemetics
9Nausea and vomiting - control
- vomiting center (medulla oblongata)CAVE is not
protected by a HE barrier - easy penetration of
toxins!!signal receptionafferent neural
pathways - from the periphery and other
GIT tissues (larynx, stomach, myocardium,
...) - from the CNS (psychogenic stimuli,
intracranial hypertension, ...) - from
the vestibule. disorders (Meniere's ch., motion
sickness)afferent humoral stimuli -
toxins (bacterial, uremia, ...), drugs
(cytostatics, digoxin, morphine),
endocrine disorders (pregnancy, ...)effector
efferent pathways - n phrenicus -
diaphragm - Spinal nerves of
the stomach and esophagus
10Medication with frequent occurrence of nausea and
vomiting
- cytostatics (cisplatina,)
- analgesics (opiates, NSAD,)
- cardiotonics (digoxin,)
- antibiotics (erytromycin,)
- metformin
- antiparkinsonics (bromcryptin, L-DOPA, )
- antiepileptics (fenytoin, carbamazepin,)
- methylxantins (theophylin)
- anaesthetics (inhalatory and i.v.)
11Patophysiology of nausea and vomiting
cortex psych. impuls migraine, (ACH)
chemoreceptors alcohol, emetics, cytotox.
drugs, irradiation, gravidity, (DA,SE)
Centrum for vomit.
vestibul. apparat. kinet. impuls, hyperstimulatio
n (H, ACH)
- Antiemetics
- antag. SE rec. 5HT3
- antag. DA rec. D2
- antag. rec. H1
- anticholinergics
pharyng, stomach mechan. and chemical imp. (H)
12Antiemetics by mode of action
- neurotransmitter drugs with antiemetic effect
- serotonin serotonin rec. 5-HT3 antagonists
(setrons) - (ondansetron, granisetron,
...)histamine H1 histamine. rec. antagonists
(moxastin, ...)dopamine dopamine rec. D2
antagonists -
the type of neuroleptics (prochlorperazine,
...)
- type of prokinetics (metoclopramide
, ...)
acetylcholine
anticholinergics (scopolamine, ...)
13ANTIEMETICS - SETRONS
- SEROTONERGIC 5-HT3 rec. ANTAG.
- competitive or non-compet. blockade
most effective antiemetics -
blockade of the signal/ - excitement in the periphery of the
- gastrointestinal tract,
- aswell as in the chemo-
- receptor center
- very valuable in oncology
serotonin5HT
14Setrons and emetic reflex
GIT peripheral emetic 5- HT3 rec.
CNS
central emetic rec. 5- HT3
aferent fiber of n. vagus
15Possible inhibition of serotoninergic rec. -
antiemetics a psychopharmacs
antidepres. inhib. MAO
triptans
anxiolytics
anxiolytics
atyp. anti- psychotics
setrone
SSRI antidepress.
16Structural formulas of serotonine and setrons
ondansetron ZOFRAN, granisetron KYTRIL ,
tropisetron NAVOBAN,
17ANTIEMETICS - SETRONS
- ondansetron (Zofran)
- competit. bound displacement through ? Ser
concentration - granisetron (Kyril)
- noncompetive, more reliable effect, longer
duration (1 day) - palonosetron (Aloxi)
- noncompet., most reliable and the longest effect
(5 days) - ADVE headaches, intestinal motility disorders
(especially constipation, abd. cramps, diarrhea),
fatigue, sleepiness and insomnia - Indications vomiting in oncology
18ANTIEMETICS - SETRONS
- palonosetron, ondansetron, ... - oxidase
polymorphic CYP2D6 substrates - risk of
effect failure in fast/extensive
metabolisers or the co-medication with
CYP2D6 inducersgranisetron - is not a
substrate of CYP2D6 oxidase - reliable effect
19ANTIEMETICS neurokinine antag.
- aprepitant (Emend)
- comb. effect substance P antag. (block
neurokininového rec.) 5-HT3 rec.inhibitor. -
significant antiemetic effect, potentiates the
effect of setronsIndications Vomiting in
Oncology comb. effect antag. substance P
(blockade of neurokinine rec.) inhib. 5-HT3
rec. - potentiates the effect of setrones
- indication vomiting in oncology
- setron dexametason aprepitant
20ANTIEMETICS
- H1 rec ANTAGONISTS
- effectively inhibits stimuli from the vestibule.
apparatus - kinetosis and treatment of dizzinessside effects
(ADVE) sleepiness, dry mouth, ...moxastin
(KINEDRYL) embramin (Medrin)diphenhydramine
21ANTIEMETICS
D2 rec. DOPAMINERGIC ANTAGONISTS inhibit mainly
emetic stimuli from the periphery GIThave
prokinetic properties - increase gastrointestinal
motility, psychosedative or supportive
effects type of neuroleptics - also
psychosedataion thietylperazin (Torecan),
prochlorperazine, ... type of prokinetics -
increased motility of the aesophagus and
stomach metoclopramide (Cerucal) ?
penetration through HE barrier, extrapyramidal
disorders domperidone (Motilium) - does not
penetrate to the CNS
22Dopamine receptors
23ANTIEMETICS with complex effect
- Thietylperazin (Torecan)
- Blockade of - dopamin D2
- - histamine H1
- - muskarin
- Remarcable antiemetic and antivertiginous effect
- p.o., i.m., supp. application
24ANTIEMETICS
- ANTICHOLINERGICS
- muskarin rec. blockade
- also spazmolytic effect
- only adjuvant treatment
- scopolamin (adjuvant treatment ), atropin
25Antiemetics indication considering cause of
nausea and vomiting
- Vestibular vomiting and kinetosis
antihistaminics (moxastin), combinations with
anticholinergics - GIT affection
- - with spasms anticholinergics (scopolamin)
- - with kinetik disorders DA dopaminergic
rec. (metoklopramid, domperidon, ev.
thiethylperazin) - Vomiting in oncology selective serotonin 3 rec.
(5HT3) inhib. (ondansetron, granisetron,
palonosetron), combination with neurokinin rec.
(aprepitant) inhib. corticoids (dexametazon)
26Antiemetics indication considering cause of
nausea and vomiting
- Vomiting following opioids dopaminergic antag.
and histaminic H2 rec. antag. (thietylperazin),
ev. anticholinergika
(skopolamin) - Vomiting in pregnancy in light hyperemesis -
diet, in severe parent. fluid, setrons
(ondasetron), antihistaminic agents, antag. DA
(thietylperazin, metoklopramid) or corticoids,
larg interindividual differences in responses
but empiric treatment is important
27Prokinetic drugs
28PROKINETIC DRUGS
- regulate gastrointestinal propulsive motility
- increase peristaltic movements of the esophagus
- stimulation of gastric motility and emptying
- accelerate passage through the intestine
-
29PROKINETIC DRUGS principle of treatment
- ? ACH
- (inhib. of degradation)
? DA stimulation receptor (blockade)
30PROKINETIC DRUGS
- Antagonists at peripheral dopamine rec. D2
- dopamine stimulates GIT peristaltic movements
- Agonists of acetylcholine in plexus myentericus
- acetylcholine stimulates GIT peristaltic
movements - acetylcholinesterase inhibitors - ? ACH in
synapses
31Prokinetic drugs D2 rec. antagonists
- ? ton. aesophag. sfincter
- - convenient in GE reflux
- ? stomachal evacuation
- - in gastroparesis
- ? effect in lower GIT part disorders (intestine)
32Prokinetic drugs antagonists of D2receptors
- indication
- symptomatic gastroesophageal reflux (in comb.
with inhibitory drugs. of gastric secretion)-
Duodenogastric reflux- Dysmotility type of
functional dyspepsia- Nausea and vomiting
associated with cytotoxic therapy- Postoperative
gastroparesis - metoclopramid (Cerucal, Degan)
- frequent ADRs 10-20also central -
extrapyramidal disorders (tremor, ...),
drowsinessperipheral - diarrheahyperprolactinemi
a - galactorrhoea, breast pain, abnormal
cyclecheap, fast and short acting - 1-2 pm, but
many ADV. Effectsshould not be used for a long
time (weeks)
33Prokinetic drugs D2 rec. antagonists
-
- domperidon (Motilium)
- more selective effect on D2 reconly peripheral
antagonistic eff. on D2 rec.does not penetrate
the HE barrier? effect antiemetic, prokinetic
effect ? ?ADRs central type, remains
hyperprolactinemia, the risk of
arrhythmiasfewer ADRs weaker antiemet. effect,
longer working 4-6 hours
34Prokinetic drugs with dual effect
- itoprid (Ganaton)
- Peripheral antagonist at D2 receptor
- acetylcholinesterase inhibitor (Inh. ACHE)
- ADVERSE eff. diarrhea, hypersalivation or
hyperprolactinemia - more expensive than others, highly effective,
well tolerated, "gold standard rapid onset of
effect in approx. 30 minutes, duration of eff.
for 6-8 hrs
35Prokinetic drugs effect mostly in the proximal
GIT part
- INDICATIONS
- ??? aesophageal reflux
-
- ?? stomach evacuation
- functional dyspepsy
- gastroparesis
- ? intestinal motility
- (postoperative paralytic ileus)
- KI GI obstruction, GIT bleeding
36Treatment of lower parts of GIT
- prokinetic drugs less effective in the
intestine, itoprid - neostigmin acetylcholin esterasis inhib.
shortlasting infusion risk of
arrhythmias - erytromycin prokinetic peptid motilin in
subantibiotical or ATB doses in intestinal
paresis and gastroparesis - botulotoxin A neurotoxin inhibits presynapt.
ACH release (chemical dennervation), for
intestinal emptying disorders
37Prokinetic drugs dopamine D2 antagonists
- indications- Symptomatic gastroesophageal
reflux (in combination with drugs inhibiting
gastric secretion)- Duodenogastric reflux-
Dysmotility type of functional dyspepsia- Nausea
and vomiting associated with cytotoxic therapy-
Postoperative gastroparesis
38Spasmolytic drugs
39SPASMOLYTIC DRUGS 1. neurotropic
- parasympatholytics
- - atropine-like quarternary structure
(potassium) - hydrophilic - N-butyl scopolamine, oxyphenonium, poldin,
fenpiverin, otilium etc. - Use used for smooth muscels contraction,
especially in tubular organs of the GIT - to
prevent spasms of the stomach, intestine or
urinary bladder, GIT dyskinesis - Combinations
40Spasmolytic drugs 2. musculotropic
- musculotropic direct effect in the muscle
- -papaverine-like
- papaverine, drotaverine, alverine, mebeverine,
pitofenon, pinaverine (GIT Ca channel blocker)
etc. - Use to prevent spasms of the stomach, intestine
or urinary bladder, GIT dyskinesis.. - Combinations
413. Spasmoanalgetic drugs
- A) Combinations analgesics spasmolytics
- pitofenon, fenpiverine etc.
- B) Analgesics with spasmolytic effectiveness
metamizol /NOVALGIN/, pethidin /DOLSIN/ - Brand names ALGIFEN, SPASMOPAN,
- Use symptomatic painful spasms of GIT or urinary
tract (bladder, kidney colics), spastic migraine,
dysmenorrhea, instrumental checkup
42(No Transcript)
43Drugs used for therapy of GIT disorders A/
motility stimulation - prokinetic drugs (upper
GIT tract)- laxatives (back/lower GIT tract))
B/ motility inhibition - spasmolytic
(sfincters)- antidiarhoics
44Humoral control of GIT motility and secretion
- endocrinne peptides
- - gastrin (secretion)
- - other. vazoact. peptides (motility)
- paracrinne local mediators
- stimulatory - acetylcholine (?motilitysecretion)
- - serotonin (stimulated
by acetylcholine)
- relaxant - NO (? motility)
- - dopamine (? motility)
- - encephalins (opioid rec. -
? motility)
45drugs used in the treatment of obesity
46Obesity
- metabolic syndrome, risk factors include
- high blood pressure,
- obesity (abdominal type),
- high glycaemia (insulinoresistence),
dyslipidemia...
47The evolution of mankind
Human life style..
48Antiobezitics
- anorectics - acts centrally (?
appetite)phentermin (Adipex) - - Sympatomimet. amines - NA and DA
release - Serotonin reuptake
inhibitorsblockers pancreatic lipase -
operating at enterocyte level, increased fat
in the stoolsendocannabinoids - Blocking
cannabinoid rec. 1 (rec. EC-1) - Acting
centrally in the CNS (? appetite) and
peripherally in adipocytes (lipid control.,
and carbohydrates. metabol.)
49Anorectic drugs - sympatomimetic amines
- stimulate the release of noradrenaline dopamine
in the hypothalamusdecreases appetite and
stimulation of thermogenesisfor the risk of
dependence and pulmonary hypertension they are
not recommended!!Indications clinically
very significant obesity withheld for more than 3
monthsPhentermine (Adipex)
50Anorectics increasing serotonine availability
- interfere with reverse serotonin absorption and
norepinephrine in the hypothalamus ? ? serotonin
norepinephrine in the CNS
51Anorectics increasing the availability of
serotonin
- decrease appetite (through serotonin influence)
and increase thermogenesis (? stimulation)positiv
e effect on lipidogram and hypertensionlittle
risk of addictionindication in clin. confess.
obesity (especially in DM)Side effects
insomnia, dry mouth, constipationCIs for the
treatment of inhibitors. MAOIs (antidepressants)
and serotonin agonists (antimigren.)sibutramine
(Meridia, Reductil)
52Inhibitors of lipase
- inhibit gastric. and pancreatic lipase - lipid
degradation and inhibit resorption - increased lipid excretion in faeces not absorbed
- flatulence, diarrhea (often imperative) - an
educational
53Inhibition of intestinal lipase
54Lipase inhibitors - orlistat
- peptide derivative of lipstatin
Streptomycesvirtually not absorbed - reduce resorption of trigycerides about 30Side
effects diarrhea, abdominal pain,
flatulenceorlistat (Xenical)
55The pathway to the fit-centre
56Laxatives
57Daily balanced secretion and absorption of
liquids in the GIT
58Constipation - aetiology
- functional - ? motility (dyspepsia ?
ileus)mechanical obstructionmetabolic disorders - dehydrationinnervation disorder, autonomic
dysfunction,iatrogennic after use of some
medicinal products
59Pharmacologically induced constipation
- anticholinergic drugs and sympatomimetic drugs
- opioids
- Ca channell blockers (e.g. verapamil)
- diuretics
- antacids
- antihistamine drugs
- psychotropic drugs
- NSA
- Ferrum salts
60Indications of laxatives
- painful emptyingtorpid constipation bothersome
for the patientexamination before procedures
requiring intestinal emptyingalleviation of
congestion induced by medicines or during
pregnancyacceleration passages in intoxication
Contraindications of laxatives
inflammatory bowel diseaseacute abdomenchronic
abuse of laxatives
61Laxatives
- contact
- - senna, bisacodyl, fenolftalein, natrium
picosulphate - osmotic
- lactulosis, sulphate and magnesium hydroxide,
glycerine, chloride channel activators - volume
- methylcelulosis
- softening
- paraffin oil
62Volume laxatives
- mechanism of action
- Increase of volume of stool hydrophilic ?
stimulating of peristalsis by increase of volume,
need of liquid intake, volume laxatives arent
absorbed - Side eff. flatulency
-
- seed coat of ribgrass english plantain
Plantaginis ovatae testa, Ispaghula Husk) - tea, effect in 24 hrs., maximal eff. after 2
- 3 days - methylcellulose, agar
63Stimulating laxatives
- mechanism of action increase of peristaltic
movements - stimulation of nerves in colon (primary eff.)
- inhibition of Na pump - inflow of electrolytes to
- lumen secondary stimulation of peristaltic
movements in small intestine colon - rapidity of action 4 - 12 hrs, supp. tens of
min. - SEgt intestinal cramps, second. slack of intestine
- possible damage of mucosa, appl. only for days
64Laxative - stimulating, contact
- a/ bisacodyl (low toxicity)
- tablets for night, morning effect
- Supp. morning dosage eff. after 15 min. 1 hr.
- b/ senna
- natural glycosides
- Short-term treatment
- c/ phenolphthalein
- Eff. in colon - after 10 - 14 hrs (dosage in
evening) - enterohepatal circulation eff. for several days
- SE Colouring of urine and stool, rash
65Laxative drugs stimulating, contact
- antraquinone
- derivat. of anthracen bound to glycides
(glycosides) - not changed passage to colon, where bacterias
hydrolyze vazbu a uvolní antraceny - stimul. of plexus myentericus
- blocking of active transport of natrium
- ? dual stimulation peristaltics
- nástup za 6-12 hodin
- nepodávat v tehotenství, exkrece do mléka!!!
66Laxative drugs - osmotic
- Lactulosis (favorite)
- Non resorbable disacharide
- cleavage in colon to ? resorbable fructosis and
galactosis ? absorption of water - Effect after 12-24 hrs.
- Glycerol
- suppositories effect after 15 - 30 minutes
- Hydroxide and magnesium sulphate
- ? solubility, non resorbable, absorption of water
67Laxatives - osmotic
- macrogol - polyethylenglykol (Fortrans)
- effective laxative used espec. before examination
of colon - Non resorbable macromolecule
- Application espec. with salinic laxatives
- advantageous before colonoscopy and surg.
procedures - effective, but low tolerable laxative
/convulsions/ - effect after 1-3 hr.
68Chloridový kanál aktivne reguluje sekreci Na a
vody do lumen streva
69Aktivátory chloridového kanálu nová skupina
osmotických laxativ
- aktivací chloridového kanálu se zvýší pasivní
sekrece natria a vody do lumen streva - úprava zácpy u vetšiny nemocných s chron. zácpou,
šetrný prístup vhodný i k dlouhodobé lécbe - lubiproston (v registracním rízení)
70Principles of therapy of habitual constipation
(functional)
- I. step
- increase of roughage (fiber)
- increase of physical activity
- rehearsal of defecation reflex
- low amount of osmotic laxatives
- II. step
- Increase dosis of osmotic laxative, or
- add contact laxative (bisacodyl)
- III. step
- add laxative according optim. individ. effect
71Antidiarrheal agents
72Causes of acute diarrhea (lt14 days)
- infection
- Medicinal products (drugs)
- ischemic colitis
- thrombosis of a. mesenterica or v. mesenterica
- Diverticulitis acuta
73Causes of chronic diarheas (gt14 days)
- inflammatory - non specific and iradiation
colitis - osmotic - disorders of absorption - pancreat.
insuf., - secretory - carcinoid syndr., ZE syn.,
- motility disordes - irritable bowel syndrome,
neurologic disord. - artefact - abuse of laxatives
74Antidiarrheal therapy
- Diarrhea is compensatory physiologic response of
organism, it is appropriate to treat according to
cause and not to treat only symptoms - Mechanisms of therapy
- Decrease exposition by toxins (adsorbent therapy)
- decelerate motility prolongate time for
reabsorption of electrolytes (opioids,
anti-motility drugs) - elimination of infectious pathogens if applicable
(ATB) - Colonization of bowel with physiol. flora
(probiotics)
75Anti-diarrheal therapy - adsorbent drugs
- Non absorbable, povrchove velmi aktivní látky
schopné na povrch navázat toxiny a tak je
inaktivovat - effective espec. during bowel infections
- Carbo adsorbens, kaoline
- diosmectitum - Smecta magnesium-aluminium
silicate, high adsorbent capacity - favorite
76Antidiarrheal therapy antisecretory drugs and
antimotility drugs
- direct stimulation of opioid recept. type ?
- deceleration of passage and secretion in colon
- loperamid (Imodium) opioid, analogue of
pethidine - is not resorbed
- induces decreased tonus of muscles of small
intestine - increases tonus of m. sphincter ani
- decreases secretion in gastrointestinal tract
- tinct. opii
77Protiprujmová lécba antisekrecní léky a
antimotilika
- ? nabídky endogenních opiátu enkefalinu
- blokáda enkefalinázy (degradace enkef.) ?
nabídku enkef., stimulace opiových recept. - (napr. racecadotril není v CR)
78Antidiarrheal therapy
- bowel germicidal agents (bowel antiseptics)
- non absorbable chemotherapeutics
- non absorbable antibiotics
- antibacterial effect predominantly on pathogens
(salmonela, shigela), less on physiol. flora - antimycotic effect (candida)
- antiprotozoic effect (amoeba,..)
79Anti-diarrheal therapy - chemotherapeutic
- cloroxine (Endiaron)
- - quinolone chemotherapeutic agent
- - effect on G- and G
- - if used longer (gt4 wks) neurotoxic
- - appropriate for prophylaxis
- nifuroxazide (Ercefuryl)
- suitable for prophylaxis
- fluoroquinolones - cipro-, norfloxo- or ofloxacin
80Antidiarrheal therapy antibiotics
- rifaximin (Normix)
- - bakteriostatic and bactericidal ATB
- with G and G- spectrum
- - is not resorbed
- - rapid risk of resistance (relatively)
- - for treatment, less suitable for prevention
81Travelers diarrhea - treatment
- Non specific treatment
- rehydratation, diet
- bowel adsorbents - carbo adsorbens, diosmectit
(Smecta) - antimotility loperamide (Imodium)
contraindication if diarrhea with blood is
present (dysenteria) or with temperature - probiotics
82Cestovatelský prujem - lécba
- kauzální u bakteriálních prujmu
- ATB jen u težších prubehu (teploty,) ci pri
nutnosti zamezit šírení - chloroxin (Endiaron), nifuroxazid (Ercefuryl)
- fluorochinolony - ciprofloxacin, norfloxacin,
ofloxacin - rifaximin (Normix)
- kauzální u virových (zejm. deti)
- metronidazol, event. dle etiologie
83- probiotika (eubiotika) - lyofilizovaná,
životaschopná kultura nepatog. kmenu E.coli ci
Saccharomyces - modulace strevní mikroflory, obnovení fyziol.
osídlení strev - indikace probiotik podpurná lécba
- dráždivý tracník, ch. prujem bez org. príciny,
meteorismus - zácpa, zejména funkcní
- nespec. strevní zánety, infekcní kolitida,
snížení dysmikrobie po ATB
84substituce tráv. enzymu a HCl
85Léciva k substitucní lécbe poruch trávení
- acida (kys. chlorovodíková, kys. citronová) pri
achlorhydrii s dyspepsií - pankreatické enzymy
- obsah amyláz, proteát a lipázy - multienzymy
- substutuce zevní sekrece
- úcinné jen vyšší dávky
- v kyselém prostredí inaktivovány (acidorezist.
tbl., event. komb. s anacidy
86Thank you for attention