W11 Pharm Chem of GI Drugs Flashcards
What are the General Drugs used for the GI
System? (8)
- Antacids
- H2 Receptor Antagonists
- Promotility Agents
- Laxatives
- Anti-diarrheal Drugs
- Antibiotics
- Corticosteroids
- Proton Pump Inhibitors
What are the Specialised Drugs used for the GI
System? (7)
- Immunosuppressants
- Antispasmodics
- Mucolytic Agents
- Aminosalicylates
- Other Antagonists (e.g. H1)
- Enzymes (e.g. Dornase Alfa)
- Monoclonal Antibodies
What are antacids?
Some examples of these drugs?
- Used to treat heartburn / indigestion /
upset stomach - Works by neutralising stomach acid
- Most commonly contain magnesium
hydroxide or aluminium hydroxide (or
a combination of both)
Aluminium/Magnesium Hydroxide
Calcium/Magnesium Carbonate
Sodium Bicarbonate
What are H2 Receptor Antagonists?
Some examples of these drugs?
- Used to treat acid-peptic disease (duodenal ulcers, gastric ulcers, gastroesophageal reflux disease, common heartburn)
- Block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach
e.g. Famotidine, Ranitidine, Cimetidine, Metiamidem Roxatidine, Burimamide
(types of antihistamine)
What are Promotility Agents?
What are their 2 moA?
Some examples of these drugs?
- Used to treat conditions with slow movement of matter through the digestive system
(gastroparesis, constipation) - Two main mechanisms of action:
1. Enhancing the effect of acetylcholine (smooth muscle contraction)
2. Blocking the effect of an inhibitory neurotransmitter, e.g. dopamine
e.g. Metoclopramide (substituted benzamide)
Domperidone, Droperidol ( Butyrophenes)
Cispride, Mosapride, Tegaserod
What are laxatives?
What are their moA? (3)
- Used to treat constipation and conditions with limited movement through the digestive system
- Accelerate fecal passage or decrease fecal consistency
- Mechanisms of action:
- Increase fluid retention by hydrophilic or osmotic mechanisms
- Decrease absorption of fluid by manipulation of electrolyte transport
- Stimulation of propulsive contractions / inhibition of non-propulsive contraction
e.g.
1. Stimulant- Senna, Biscodyl tablets, Phenolphthalein, Castor oil,
2. Bulk-forming- Methycellulose, Polycarbophil,
3. Osmotic- Lactulose, Phosphate enema, magnesium sulphate
What are the 2 main types of
Antidiarrheal Drugs?
- Antimotility agents (loperamide, diphenoxylate, codeine)
- Anticholinergic agents (atropine, scopolamine)
What are antibiotics?
Examples?
Used to treat bacterial infections that may develop with GI system issues
Amoxicillin, Erythromycin, Metronidazole
What is the structure change in active corticosteroids?
Cortisone- Cortisol, Prednisone- Prednisolone
Carbonyl (=O) is converted to Alcohol (-OH)
Proton Pump Inhibitors (PPIs)
Structures?
What does the moA involve?
Name some examples?
- Used primarily for gastric ulcer treatment, e.g. omeprazol
- Racemic prodrug (omeprazole) converted to active metabolite (cyclic sulfenamide) in parietal cells
- Inhibits gastric acid secretion by inhibiting H+, K+ -ATPase
- Mechanism of action involves a disulphide bond with the enzyme
Omeprazole (inactive)- Active cyclic sulphonamide- Omeprazole-enzyme complex
Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Esomeprazole (E-enantiomer)
What are Proton Pumps?
- Proton pumps regulate the flow of cations into
and out of the cell, to maintain cell functions - If protons are not excreted efficiently, the cell
process could slow down (equilibrium, Le
Chatelier’s Principle) - Ion channels control the flow of other ions into
and out of the cell – work via ion gradient
e.g. H2O + CO2 = H2CO3= H+ + HCO3-
Chemical Properties of PPIs?
- PPIs are weak bases (pKa about 4.0)
- Free bases at blood pH (7.4)
- Ionized in strongly acidic environments (pH <4)
- Only region in the body is secretory canaliculus
of parietal cells (pH = 2) - Can take orally, get carried around in the blood
until the un-ionised weak bases (lipophilicity)
cross the cell membrane of the parietal cell - Protonation occurs:
-Drug too polar to cross back across membrane
(1000 –fold accumulation of the drug) - The protonation activated the drug
Activation of PPIs
What are the steps? (10)
- Protonation takes place on the benzimidazole ring
- Nitrogen of the pyridine ring then acts as a
nucleophile – uses its lone pair of electrons
to forma a bond with the electron deficient
2-carbon of the benzimidazole ring - The spiro structure is formed – aromatic
character of the imidazole portion of the
ring is lost - The ring wants to re-aromatise
- The lone pair of e- from the nitrogen
reform the double bond and cleave the S-C
bond, forming sulfenic acid - Sulfenic acids are highly reactive – rapid
reaction of an intramolecular attack by the
NH group of the benzimidazole on the
sulfenic acid, displacing the hydroxyl group - The cationic, tetracyclic, pyridinium
sulfenamide is formed and is an irreversible
enzyme inhibitor - It forms a covalent bond to an accessible
cysteine residue on the proton pump - Cys-813, Cys-821, Cys-892 all have the
potential to be attacked, depending on the
drug - Omeprazole prefers Cys-813 and Cys-892,
pantoprazole only reacts with Cys-813
How are PPIs metabolised?
- Metabolised by cytochrome P450 enzymes
- Primarily S-mephenytoin hydroxylase (CYP2C19) and nifedipine hydroxylase (CYP3A4)
- 3% of white European people are slow metabolisers of PPIs
- Pantoprazole is also metabolised by
sulfotransferase, whereas omeprazole and
lansoprazole are not
Immunosuppressive Drugs:
What is the main drug class?
- Thiopurines are the main class of
drugs used to maintain remission if
corticosteroids are needed following 2 or more exacerbations in a 12-month period - Should only be used if aminosalicylates are not effective
- Methotrexate is the second line option after thiopurines
- Thiopurines are known to increase the risk of non-melanoma skin cancer
What are the types of antispasmodics?
- Divided into two main classificaions:
-Antimuscarinics
-Smooth Muscle Relaxants
e.g. Buscopan (hyoscine butylbromide) which is similar in structure to Ipratropium bromide (SAMA), a smooth muscle relaxant
Examples of Mucolytic agents?
Strands with disulphide bonds are broken
N-acetylcysteine, Erdosteine, Carbocysteine
What are Aminosalicylates? (used to treat)
Examples?
- Specialist drug treatment for ulcerative colitis
- Also considered for mild-moderate proctitis
and proctosigmoiditis - Usually prescribed topically (suppository or
enema) - Prescribed for oral use if remission not
achieved in 4 weeks
5 ASA, Sulfalazine, Olsalazine, Balsaladize
Aminosalicylates MoA?
- 5-aminosalicylic acid (5-ASA) activates a class
of nuclear receptors involved in the control of
inflammation, cell proliferation, apoptosis and
metabolic function (peroxisome proliferator-
activated receptors) - The receptors are highly expressed in colon
epithelial cells - Oral administration of 5-ASA tablets / capsules
is ineffective as it is absorbed in the small
bowel due to slow transit time so effective
concentrations do not make it to the distal gut - Hence: Prodrug
Properties of Aminosalicylates?
- The prodrugs are stable at more extreme pH levels
- They can therefore reach the gut without being broken down
- The enzyme azoreductase (produced by the bacteria in the gut) can break down the
prodrug – azo cleavage reaction - This releases the active molecule (5-ASA
H1 Receptor Antagonists: Function?
Suppress histamine-mediated effects
of anaphylactoid or anaphylactic
reactions e.g. Chlorphenniramine
Tripolidine, Mepyramine, Neobenodine
Enzymes (dornase alfa): function?
Recombinant human deoxyribonuclease (rhDNase)
* Cleaves (via hydrolysis) extra-cellular long-chain DNA in the sputum
* Reduces mucous viscosity
Monoclonal Antibodies: function
- Immune system proteins created in the lab
- Type of targeted drug therapy
- Primarily used in cancer therapy as the antibodies can be designed to recognise and
find specific proteins on cancer cells
Monoclonal antibodies bind to their target, once they do they make it harmless.
