2. Introduction - Anti-
emetics
• Two centres: vomiting centre (VC) and
chemoreceptor trigger zone (CTZ)
• Both near the floor of the fourth ventricle, close to
the vital centres
• VC is within the blood brain barrier (BBB)
• CTZ outside in the area postrema
• They are connected together
3. ANTIEMETIC
DRUGS
A group of drugs which are used to
control nausea and vomiting
Provide symptomatic relief
Removal of causative factor to have ultimate relief
4. Cerebral cortex
Smell
Sight Anticipatory
emesis Thought
Vestibula
r
nuclei
Motion
sickness
Cancer
chemotherap
y Opioids
Vomiting
Centre
(medulla)
Muscarinic, 5
HT3 &
Histaminic H1
Chemo & radio
therapy
Gastroenteritis
Pharynx &
GIT 5 HT3
receptor
Chemorecepto
r Trigger
Zone
(CTZ)
(Outside BBB)
Dopamine D2
5 HT3,
Opioid
Receptors
Muscarinic
Histaminic
H1
Pathophysiology of Emesis
8. D2 Antagonists
a. Substituted Benzamides
Metoclopramide, Trimethobenzamide
b. Butyrophenones
Domperidone , Droperidol
c. Phenothiazines
Prochlorperazine, Promethazine &
Thiethylperazine.
9. Metoclopramide
Chemistry: Substituted Benzamide
MOA: Dopamine D2 receptors antagonist
It is potent Antiemetic & Prokinetic agent
As Antiemetic
• It has potent Antiemetic & antinausea effect.
• Blocks D2 receptors in CTZ of the medulla (area postrema)
As Prokinetic agent
• It can selectively stimulate gut motor function.
• Blocks D2 receptor in GIT & blocks the normal inhibitory
effect of Dopamine on cholinergic smooth
muscle stimulation--- ↑ motility.
10. The Uses - Metroclopramide
Potent antiemetic controls / reduces vomiting due to
• Uremia
• Radiation
• Viral gastro enteritis, hepatic-biliary disease
• Anticancer drugs
• Migraine
• Post operatively & pre-operatively
11. Metroclopramide…
Pharmacokinetic
s
• Rapidly absorbed from GIT after oral administration.
• Undergoes a high degree first pass metabolism.
• It is excreted in the urine as free and as metabolites.
• It is also excreted in the breast milk.
• DOSE: 10-20mg orally or IV every 6 hrs
12. Adverse Effects - Metroclopramide
• Extrapyramidal reactions with facial and skeletal muscle
spasms- Restlessness, Dystonias , Parkinsonian symptoms.
-----More common in young and very old. Usually occur shortly
after staring treatment and subside with in 24 hours of stopping
the drug.
• Bowel upsets, Diarrhea
• Drowsiness and fatigue, dizziness, restlessness and anxiety.
• Galactorrhoea, Gynecomastia, impotence and menstrual
disorders – due to increased prolactin levels
14. Phenothiazines
Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine
Phenothiazines are antipsychotics with potent antiemetic
property due to D2 antagonism and anti-maucarinic
properties
Sedative property due to anti-histaminic property
Mainly used as anti-emetic in severe N& V
Main A/E: EPS , sedation , postural hypotension
15. Butyrophenones
Antipsychotic drugs , D2
antagonists
Droperidol
Central D2 antagonist
Main A/E: EPS , postural hypotension
QT prolongation may occur
Domperidone
• Does not cross BBB. Only blocks D2 in CTZ where BBB is leaky.
• May be used in N&V due to Levodopa, without affecting
its efficacy.
• No EPS.
• Used as antiemetic , prokinetic agent & for post partum lactation
stimulation.
16. Selective 5-HT3 Antagonists
Ondansetron, Granisetron , Dolasetron & Palonosetron
MOA
Antiemetic action is restricted to emesis caused by vagal stimulation
(e..g post operative) & chemotherapy
Palonosetron: newer with greater affinity for 5-HT3 receptor
& comparatively longer half life
No effect on Dopamine / muscarinic receptors
17. Ph. K - Selective 5-HT3
Antagonists
• High first pass metabolism
• t1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron)
40 hrs (Palonosetron)
• Given once or twice daily – orally or intravenously
• Excreted by liver & kidney
• No dose reduction in renal insufficiency but needed in
hepatic insufficiency (Ondansetron)
18. The Uses - Selective 5-HT3
Antagonists
• Chemotherapy- Induced Nausea & vomiting
• Primary Agents - prevention of acute
chemotherapy induced Nausea & vomiting
Effective alone in most of the cases.
Efficacy is enhanced
in combination. Can be given I/V 1/2 hr before
chemotherapy
• To prevent Delayed Nausea & vomiting
occurring after 24 hrs of Cancer
chemotherapy
in combination with
Dexamethasone & NK1
19. A/Es - Selective 5-HT3
Antagonists
• Excellent safety profile
• Headache, Dizziness & constipation
• All three drugs cause prolongation of QT interval, but
more pronounced with dolasetron.
DIs
Hepatic clearance may decrease by enzyme inhibitors
20. H1antihistamines & Muscarinic Antagonists
H1antihistamines
Meclizine, Cinnarizine, Cyclizine & Diphenhydramine &
its salt Dimenhydrinate.
• They have anticholinergic & H1 antagonist sedating properties
(1st generation).
• They produce specific depression of conduction
in vestibulocerebellar pathway.
MuscarinicAntagonist
Hyoscine (Scopolamine).
21. H1antihistamines & Muscarinic Antagonists…
Theraputic Uses
• Vestibular system is important in motion sickness
via cranial nerve VIII - rich in Cholinergic M1
& Histamine H1receptors
• Most effective drugs for motion sickness
• Effective for nausea & vomiting associated with
motion sickness.
• Vestibular disorders ( Meniere’s disease)
• (hyoscine) – used as transdermal patch for motion sickness
• Meclozine is long acting so useful in sea sickness
• Cinnarizine also has antivertigo effect. Act by inhibiting
influx of calcium to vestibular sensory cells
from endolymph
23. • MOA: Act as antiemetic & appetite stimulant in addition
to psychoactive action. MOA not clear.
• Cancer chemotherapy induced Nausea & vomiting
with Phenothiazines – synergistic effect but
AEs are added – not used as better drugs are
available
• Nabilone
• closely related THC analog
26. Neurokinin-1 (NK1 )Antagonists
Aprepitant, Fosaprepitant
Given orally BA = 65% , Crosses BBB.
t ½ : 11 hrs, Metabolized by hepatic CYP3A4.
MOA
Act as Antiemetic: Selectively block NK1 receptor in area
postrema.
No effect on Serotonin , Dopamine or Corticoid receptors
27. Aprepitant
• Non peptide, selective, Neurokinin type 1 (NK
1) receptors antagonist
• Block substance P from binding to NK1 receptor
• Broader spectrum and activity in delayed emesis (In
Preclinical studies)
• Augment the antiemetic activity of 5HT3 receptor
antagonists and dexamethasone
• Inhibit both acute and delayed CINV
28. Uses
Used in combination with 5HT3 antagonists &
Corticosteroids for prevention of acute & chronic
nausea and vomiting from Cancer chemotherapy
Neurokinin-1 (NK1 )Antagonists
29. A/Es
• Fatigue, dizziness & diarrhoea.
• Enzyme inhibition
• Metabolized by CYP3A4 & may inhibit metabolism of many anticancer
drugs (Docetaxel, Paclitaxel, Etoposide, Vinblastine, Imatinib) ---- ↑ levels ---
toxicity.
• Metabolism of Aprepitant may be inhibited by Ketoconazole, Ciprofloxacin,
Clarithromycin, Nafazodone, Ritonavir, Nelfinavir, Verapamil & Quinidine)
• Aprepitant ↓ INR in patients taking warfarin.
Neurokinin-1 (NK1 )Antagonists
30. Therapeutic Uses of Anti-emetics
• Motion sickness: Hyoscine
• Vestibular disorders( Menieres, disease): Cinnerazine
• Vomiting due to Uremia, Radiation, Viral gastro enteritis,
Liver disease, Migraine, Prochlorperazine
, Metroclopramide
• Vomiting due to pregnancy ( hyperemesis gravidarum),
Meclizine with vit. B6 (Navidoxine)
31. • Vomiting due to Cytotoxic Anticancer drugs: 5HT3
Antagonists Metroclopramide,
Cannabinoids, corticosteroids , Aprepitant
• Anticipatory Vomiting due to Cytotoxic Anticancer
drugs. Benzodiazepines (Diazepam)
• Post Operative Vomiting: Metoclopramide ,
Prochlorperazine , Dimenhydrinate, 5HT3
Antagonists (Ondensetron)
34. DIARRHOEA
Loose bowel movements resulting into the frequent passage
of water, uniformed stools with or without mucous and blood.
Classification
Osmotic diarrhoea
Something in the bowel is drawing water from the body into
the bowel.
Eg; Sorbitol is not absorbed by the body but draws water
from the body into the bowel, resulting in diarrhoea.
35. Secretory diarrhoea
Occurs when the body is releasing water into the bowel,
many infections, drugs causes secretory diarrhoea.
Exudative diarrhoea
Diarrhoea with the presence of blood and pus in the stool.
This occurs with inflammatory bowels disease (IBD), such as
crohn’s disease or ulcerative colitis etc.
36. Acute diarrhoea
Sudden onset in a previously healthy person
Lasts from 3 days to 2 weeks
Self-limiting
Resolves without sequelae
Chronic diarrhoea
Lasts for more than 3 weeks.
Associated with recurring passage of diarrhoeal stools, fever,
loss of appetite, nausea, vomiting, weight loss, and chronic
37. CAUSES OF DIARRHOEA
Acute Diarrhoea
Bacterial
Viral
Drug induced
Nutritional
Protozoal
Chronic Diarrhoea
Tumours
Diabetes
Addison’s disease
Hyperthyroidism
Irritable bowel syndrome
E. Coli bacteria Rotavirus
38. DRUG THERAPY
i. Specific antimicrobial drugs
ii. Non specific antidiarrhoeal drugs
ORAL
REHYDRATION
THERAPY
39. Specific anti microbial drugs
A. Antimicrobials are of no value
Due to non infective causes such as
Irritable bowel syndrome
Colic disease
Pancreatic enzyme deficiency etc
Rota virus causes acute diarrhoea, specially in children
40. B. Antimicrobials are regularly useful
cholera
Tetracyclines,
chloramphenicol
etc
Clostridium
difficile
Vancomycin,
metronidazole etc
amoebiasis
Metronidazole,
dioxonid
furoate
42. 2.Anti secretory
Agents which reduce the secretion
Eg; aspirin, sulphasalazine, bismuth sub salicylate, atropine
etc.
3.Antimotility drugs
Increase small bowel tone and segmenting activity.
Helps reabsorption of water by delaying intestinal transit
time
Eg: codeine, loperamide, diphenoxylate etc
43. Functions of Antidiarrhoeal Drugs
Decrease irritation to the intestinal wall
Block GI muscle activity to decrease movement
Affect CNS activity to cause GI spasm and stop
movement
Relief of symptoms and fluid & electrolyte loss
44. Many OTC antidiarrhoeal drugs, contain limited amounts
of opioids (loperamide) aluminium hydroxide, kaolin and
pectin.
PRECAUTIONS
Care should be taken when using antidiarrhoeals if the
cause of the diarrhoea is bacterial as this allows the
bacterial toxin to remain in the body.
Excess use may cause constipation
45. Non Specific Antidiarrhoeal Drugs
Adsorbents
Coat the walls of the GI tract
Bind to the causative bacteria or toxin, which is then
eliminated through the stool
Examples: bismuth subsalicylate, kaolin-pectin, activated
charcoal.
46. Side Effects
Increased bleeding time
Constipation, dark stools
Confusion, twitching
Hearing loss, tinnitus, metallic taste, blue gums
47. Anti secretory
Agents which reduce the secretion
Decrease intestinal muscle tone and peristalsis of GI tract
Result: slowing the movement of faecal matter through the
GI tract
Examples: belladonna alkaloids, atropine, sulphasalazine,
hyoscyamine
49. Antimotility drugs
Decrease bowel motility and relieve rectal spasms
Decrease transit time through the bowel, allowing more
time for water and electrolytes to be absorbed
Examples: codeine, loperamide, diphenoxylate
51. Metabolism of Sulphasalazine
Sulphasalazine
[H]
Gut
N
H2
OH
O
OH
5- Amino salicylic acid
+
H
O
S
N
N
O
Prodrug, having low solubility and poorly absorbed from
ileum.
The azo bond split by column bacteria into Sulfa pyridine
and 5-amino salicylic acid.
Blocks cyclooxgenase and lypooxygenase pathway and
reduce mucosal secretion.
52. CONSTIPATION
Constipation is the infrequent and/or unsatisfactory
defecation fewer than 3 times per week.
Abnormally infrequent and difficult passage of faeces through
the lower GI tract
Symptom, not a disease
Disorder of movement through the colon and/or rectum
53. CAUSES OF CONSTIPATION
Diet
Lack of exercise
Age
Irregular bowel habits
Drug induced
Disease States/Conditions
Spasm of sigmoid colon
Dysfunction of myenteric plexus
54. SYMPTOMS OF CONSTIPATION
Infrequent defecation
Nausea
Vomiting
Anorexia
Feeling full quickly
Stools that are small, hard, and/or difficult to
evacuate
Rectal bleeding
Weight loss (in chronic constipation)
55. • Mild action,
elimination of soft
stools but formed
stools.
Laxative or
aperients
• Stronger action
resulting in more
fluid evacuation.
Purgative or
cathartic
LAXATIVES
Drugs that promote evacuation of bowels.
Based on intensity of action
58. 4. Osmotic purgative
Magnesium salts, lactulose
etc
Bulk Forming Laxatives
Improve stool consistency and frequency with regular use
Ensure good fluid intake to prevent faecal impaction
Onset of action 2-3 days
Side Effects may include bloating, flatulence, distension
59. Stool Softeners
May be useful with anal fissures of haemorrhoids
Liquid paraffin is not recommended for treatment of
constipation
- risk of aspiration and lipid pneumonia
- long term use may result in depletion of Vitamins
A, D, E and K
60. Stimulant Laxatives
Increase intestinal motility by stimulating colonic nerves
Useful with opioids
Onset of action 8-12 hours
Development of tolerance is reported to be uncommon
Generally considered 2nd
line therapy in elderly due to risk
of electrolyte disturbances
Other adverse effects include cramping, diarrhoea,
dehydration
61. Osmotic Laxatives
Increase fecal water content
Result: bowel distention, increased peristalsis,
and evacuation
Improving stool frequency
Onset of action – up to 48 hours
Metabolized by bacteria flatulence
62. CONCLUSION
Good nutrition and hygiene can prevent most
diarrhoea.
Patients should be instructed to increase fluid intake
and participate in regular exercise to prevent
constipation.
63. REFERENCE
1.Text Book of Medicinal chemistry by V.Alagarsamy;volume-II
;page no:1137
2.Bently and Driver’s text book of pharmaceutical chemistry 8th
edition revised By L M ANTHERDEN page No. 724, 625.
3.Essentials of medicinal pharmacology by K D TRIPATHI 6th
edition page No. 651
4.Clinical Pharmacy and Therapeutics, 4th
edition by Roger
Walker, Cate Whitelsia Page No: 824- 832
5. www.wickipedia.org
![Metabolism of Sulphasalazine
Sulphasalazine
[H]
Gut
N
H2
OH
O
OH
5- Amino salicylic acid
+
H
O
S
N
N
O
Prodrug, having low solubility and poorly absorbed from
ileum.
The azo bond split by column bacteria into Sulfa pyridine
and 5-amino salicylic acid.
Blocks cyclooxgenase and lypooxygenase pathway and
reduce mucosal secretion.](https://image.slidesharecdn.com/mergedpresentationcholadeck1-250616055911-03d4b30d/85/merged_presentation_choladeck-1-pptx-chat-51-320.jpg)
