GSS Past paper questions

Question 1

B1. What role do chief cells play in the GI tract?

Answer 1

• Cells found in the stomach
• Release pepsinogen, which is activated into the digestive enzyme pepsin when it comes into contact with acid produced by parietal cells
• For protein digestion
• Also releases chymosin
• Are activated when there is chymus present

Question 2

B2. Describe the peripheral and central receptor type(s) and mechanisms by which 5-HT can cause emesis. Include examples of anti-emetic drugs that block these receptors. (5 marks)

Answer 2

• 5-HT3 is thought to be a receptor responsible to trigger emesis
• Chemoreceptor trigger zone is thought to be responsible for triggering emesis
• Ondansetron and dolasetron are 5-HT3 antagonists
• Receptors found in CNS and parietal cells
• Ligand gated ion channel

Question 3

B3. Proton pump inhibitors (PPIs) such as omeprazole (shown below) are prescribed to limit gastric acid production. Describe the mechanism of acid secretion and explain why the pKa of PPIs is important for their effective use in treatment. (5 marks)

Answer 3

• Proton pumps are found on parietal cells and will pump H+ ions into the stomach
• Gastrin, histamine and acetylcholine activate the gastrin receptors, H2 receptors and Muscarinic receptors which all stimulate protons to be pumped out in exchange for potassium ions
• Once pumped out, H+ ions will form HCL with chloride ions
• This is stimulated when humans eat
• Omeprazole is a weak base so concentrates in acid canaliculi in parietal cells. Low pH will cause the conversion into active species (sulphenamide)
• Sulphenamide is a cation which cannot escape the canaliculi
• There is a higher pH elsewhere in the body so omeprazole is only turned to the active species in the stomach

Question 4

B4. Highlight the pharmacokinetic changes that may occur when administering drugs to patients with hepatic disease.

Answer 4

• Reduced drug clearance causing drug accumulation. Drug will be harder to go through elimination especially if there is cholestasis due to a blockage
• Reduced metabolism of the drug resulting in a higher amount of circulating drug. This is especially an issue for prodrugs
• Portal systemic shunting may occur
• Distribution of drug- Bilirubin build up will compete with drugs for protein binding sites causing enhanced clinical effect, and distribution may be affected by ascites
• Usually need to lower doses
• Liver capacity is so great that liver disease must be extensive before effects on drug handling are important

Question 5

B5. Describe the methods of absorption to systemic circulation when an active pharmaceutical ingredient is administered rectally. (5 marks)

Answer 5

• Rectal drug delivery via suppositories are waxy and composed of fats (semisynthetic glyceride base)
• Vehicle choice will depend on partition coefficient of vehicle and rate of drug release
• Other additives such as colloidal silica oxide may be added to increase viscosity and prevent sedimentation of drug in base
• Bypasses the liver so there is no first pass effect if API enters via middle and lower haemorrhoidal veins
• If it enters portal circulation via upper haemorrhoidal vein, first pass effect will take place
• There is no disintegration with a suppository unlike a tablet
  1. The suppository will melt and result in spreading caused by motility and pressure
  2. Sedimentation occurs
  3. Wetting- Partition coefficient plays a role here. Rectal wall has some water so drug slowly starts to become hydrated
  4. Dissolution occurs
• Factors that affect absorption  contents of the rectum, fluid available to dissolve the drug, motility of the rectal wall and the rectal mucous
• Other rectal formulations – enemas, fatty ointments

Question 6

B6. Name 5 factors than can influence the process of passive transport of a molecule into the skin. (5 marks)

Answer 6

• Age as hydration and blood flow to the skin decreases with age
• Presence of hormones
• Hydration of the skin
• Presence of damage such as cuts/wounds/scars
• Presence of hair follicles
• Skin thickness (e.g. thicker on your palms of your hand vs your eyelids)
• Concentration gradient
• Molecular weight of drug
• Log P (partitioning coefficient of drug)

Question 7

a) Outline the common complications associated with liver disease (6 marks).

Answer 7

• Ascites which is the accumulation of fluid in peritoneal cavity resulting in a swollen abdomen
• Jaundice due to a build-up of bilirubin from decreased biliary clearance
• Build-up of bilirubin also causes itching under the skin
• Hepatic encephalopathy – Occurrence of confusion, changes in mood and behaviour associated with liver disease. It is thought that it could be due to toxins reaching the brain and can result in a coma.
• Reduced drug metabolism
• Reduced drug elimination
• Enhanced activity of drugs due to increased bilirubin- more competition to bind to proteins
• Cirrhosis
• Variceal Bleeding and Portal Hypertension- Due to increased resistance to flow via portal veins via disruption of hepatic structure. Collateral vessels form to try and enable blood to bypass the liver however they are weak and can burst very easily resulting in bleeding.

Question 8

What is ascites and how is it treated?

Answer 8

• Accumulation of fluid in peritoneal cavity resulting in a swollen abdomen
• Three possible mechanisms:
1. Underfill resulting in a reduction in circulating plasma and lack of blood flow, and pressure builds up
2. Overfill- increased plasma volume
3. Peripheral artery vasodilation
• Treated with diuretics e.g. spironolactone
• Limit sodium and fluid intake (max of 4-6g/day)
• Can also drain if there is a large volume but every 2L you drain, replace with 100mL of albumin to maintain circulating volume
• Monitor Us + Es including potassium as you can become hyperkalaemia if being treated with a potassium sparing diuretic
• Monitor urine output to ensure kidneys are functioning
• Monitor weight loss due to the loss of the fluid
• Avoid high sodium preparations such as Gaviscon

Question 9

What is hepatic encephalopathy and how is it treated?

Answer 9

Hepatic Encephalopathy
• May be due to toxins reaching the brain
• From stage 1 (impaired attention, irritability) to Stage 4 (coma)
• Lactulose that produces loose stools increasing urea and ammonia excretion from GI tract. This is due to lactulose increasing acidity to produce NH4+ which will not get reabsorbed so gets excreted instead
• Phosphate enema
• Metronidazole
• Rifamixin (abx that inhibits bacteria that produces ammonia in colon)
• Monitor symptoms and look for improvement in mood, sleep, general wellbeing

Question 10

Why does variceal bleeding and portal hypertension occur and how is it treated?

Answer 10

• Due to increased resistance to flow via portal veins (takes blood to the liver) via disruption of hepatic structure. Collateral vessels form to try and enable blood to bypass the liver however they are weak and can burst very easily resulting in bleeding.
• Terlipressin, a synthetic analogue of vasopressin:
- constricts portal veins
- in bolus every 4-6 hours until there is stable Prothrombin Time and BP
• Monitor sodium, potassium, fluid balance, BP and Prothombin Time
• Monitor for s/e such as ischaemia (blue hands and feet)

Question 11

What is TIPPS?

Answer 11

TIPPs- Transjugular intrahepatic portosystemic shunting
• To allow blood to flow normally through the liver to reduce portal hypertension
• High risk procedure
• To shrink the varices that have developed around the stomach reducing risk of variceal bleeding

Question 12

Reservoir bases for diffusion systems?

Answer 12

• Insoluble polymer membrane
• Fick’s law: J= -D (dc/dx)
• Permeation occurs across a membrane
• E.g. IUD

Question 13

Matrix devices for diffusion systems?

Answer 13

• Drug dissolved/dispersed in an insoluble polymer matrix
• Use hydrophilic polymer for hydrophobic drugs
• As drug is dissolved, matrix is emptied
• Water enters pores in matrix
• Vaginal rings
• Implantable pumps

Question 14

Give four advantages of the modified release systems

Answer 14

1. Reduces frequency of dosage and thus increases compliance
2. Maintains therapeutic effect over night
3. Reduces total amount of drug administered over the treatment period
4. Improves treatment of chronic illness and reduces side effects

Question 15

Topical Corticosteroids

Answer 15

• Drugs related to natural hormones produced by the body e.g. cortisol
• Mild  very potent
• Regulate the expression of many genes with a net ant-inflammatory effect
• Reduces production of inflammatory mediators inc cytokines, interleukins, prostaglandins
• Inhibit cell migration to sites of inflammation
• Promote death of apoptosis by WBCs recruited to inflammation site
• Biochemical effects can be genomic and non-genomic (faster involving receptors and non-specific actions)

Question 16

Advantages of Topical Steroids

Answer 16

• Non-invasive
• Can combine therapy with general body care e.g. moisturising for greater patient appeal
• May be delivered at controlled rates over a period of time so they can be infused more slowly into the body e.g. HRT

Question 17

Disadvantages of Topical Steroids

Answer 17

• May worsen ulcerated lesions
• Not curative and if you stop them, may cause rebound exacerbation
• Should try and avoid long term use
• Thinning of the skin, stretch marks
• Can cause dermatitis

Question 18

Genomic action of corticosteroids?

Answer 18

• Due to transcriptional mechanisms (activation and repression). Direct DNA binding with steroid-receptor complex to the promoter regions of genes associated with up-regulation or down-regulation
• Specific binding to cytoplasmic nuclear receptors
• Blocks cytokine production
• Induces inhibitory regulars e.g. SLAP
• Glucocorticoid receptor has 3 domains: amino, carboxyl and DNA binding domain. Two zinc fingers are in the centre
• There are also phosphorylation sites and regions of hormone-independent/dependent activation related to transcription

Question 19

B1. Briefly describe the FOUR main functions of the liver

Answer 19

1. Drug metabolism breaks down the drug by CYP enzymes (if this did not occur, there would be a potentially dangerous high level of the drug in circulation)
2. Production of bile  needed for emulsifying ingested fats and helps absorption of fat soluble vitamins
3. Drug clearance  via biliary clearance
4. RBC breakdown  produces bilirubin. Kuppfer cells are the phagocytic cells which are involved in this
5. Conversion of vitamin D3 to calcitriol which then goes on to the kidneys, the net effect it increasing calcium absorption in the blood

Question 20

B2. Briefly describe how THREE chemical changes, which occur to the prodrug omeprazole, result in the inhibition of gastric acid secretion

Answer 20

• S enantiomer is more active
• Omeprazole is a weak base (pka 4) which means it will reside in the acidic canaliculi in the parietal cells
• In low pH environments, it will undergo acidic protonation which will trigger the conversion to its active species sulphenamide via a spiro intermediate. This is a permanent cation that cannot escape the canaliculi
• Elsewhere in the body there is a higher pH so this conversion does not occur
• It inhibits the proton pump in the parietal cells prevent proton secretion into the stomach

Question 21

B3. What gastrointestinal organs are involved in neutralising the acidic chyme entering the duodenum?

Answer 21

• Chyme consists of broken down food, water, and HCL and digestive enzymes
• I cells in the duodenum of the small intestine secretes cholecystokinin (CKK) which causes the gallbladder to contract, releasing alkaline bile into duodenum
• CCK also triggers the release of digestive enzymes and bicarbonate from the pancreas which will neutralise acidic chime
• Secretin is secreted by the S cells in duodenum to inhibit gastric acid secretion and stimulates bile production in the liver
• Movement of chyme into the duodenum will result in a negative feedback so the stomach stops contracting and will stop any more chyme entering the small intestine.

Question 22

B4. What is the volume of fluid which is found in the normal rectum and what is its pH? How do these two properties influence the absorption of drugs into the blood stream?

Answer 22

pH= 7.4. If drug is ionised at this pH, then it will not get absorbed into the blood stream via the membrane. Drug absorption on rectal administration is based in the pH partition theory

Volume of fluid = 3mL. The volume will help in the dissolution stage of rectal drug delivery, however if there is not enough fluid, dissolution may not occur and this could result in drug falling out and not being absorbed into the blood stream

Question 23

B5. Briefly describe the differences between liposomes, transferosomes and niosomes

Answer 23

• Liposomes = lipid vesicles (with/without cholesterol) that can trap drugs, location is dependent on if drug is lipophilic or hydrophilic
• Transferomes =Phospholipid + surfactant to delivery drug, driving force is xerophobia (avoids dry environment)
• Niosomes = Prepared mainly from non-ionic surfactants as a drug vehicle

Question 24

B6. Describe the chemical composition of the mucilaginous laxatives

Answer 24

• Same as bulk forming laxatives
• E.g. Isphagula husk contains psyllium and indigestible vegetable material which attracts water and swells up in the colon
• Mucilage is obtained from psyllium which is a white fibrous material that is hydrophilic so attracts water. As it attracts water, it forms a mucilaginous gel increasing volume
• This increases peristalsis and promotes soft stool
• Used to treat constipation
• Methylcellulose and bran works by a similar principle
• Takes several days for it to work

Question 25

C3. Discuss the importance of endocrine cells in regulating gastrointestinal function

Answer 25

• Enteroendocrine cells are specialised cells of the GI tract and pancreas and are spread as single cells throughoutt the tract
• They produce hormones in response to stimuli either to enter the blood stream for systemic effect/be local messengers/activate nervous responses
• I cells in the small intestine (duodenum mainly) secrete cholecystokinin (CCK) which stimulates the release of bile to emulsify fat to aid digestion, and also stimulates the production of bile from the liver
• G cell releases gastrin via gastrin releasing peptide which stimulate gastrin receptors on parietal cells, which helps to breakdown the chyme when the body receives food. The pH of the stomach is 2
• S cells in the small intestine secrete secretin which stimulates exocrine pancreatic secretion of biocarbonate to neutralise the acidic chyme when it enters the duodenum and also inhibits stomach contraction to stop more chyme entering the small intestine
• Enterochromaffin cells release histamine which activate the H2 receptors on parietal cells, and through cAMP dependent pathway, stimulates gastric acid secretion through proton pumps
• D cells in the stomach, duodenum and pancreatic islets release somatostatin to inhibit enterochromaffin cells, parietal cells and G cells to prevent gastric acid secretion- this is when there is no chyme in the stomach so food does not need to be broken down by acid secretion
• On the enterchromaffin cells, there are M3 muscarinic receptors which when triggerered by acetylcholine, stimulates the cell to secrete more histamine and thus acid secretion. These receptors are also found on the parietal cells

Question 26

3 stages of acid secretion?

Answer 26

1. Cephalic phase: occurs before food enters. Causes ECL cells to secrete histamine
2. Gastric Phase: swallowed food and semi-digested protein activates gastric activity. Stimulates stretch and chemoreceptors in gastrin wall as well as G cells
3. Intestinal Phase: duodenum responds to arriving chyme and moderates gastric activity. It initially enhances gastric secretion but then soon inhibits it