CAM202: Drug Uses and Cellular Mechanisms

Question 1

Metoclopramide: uses and cellular mechanism

Answer 1

Anti-emetic action: Antagonist effect at D2 receptors present in the chemoreceptor trigger zone (CTZ) in the medulla.

At high doses, agonises 5HT3 (serotonin receptor) receptors (may contribute to anti-emetic effect)

Gastric Prokinetic action: Via muscarinic receptors (action unknown?). Also relaxes pyloric sphincter to aid gastric emptying.
(Maxalon) First-line anti-emetic. Dopaminergic antagonist
Used as an anti-emetic (e.g. commonly during chemotherapy).
Also used as a gastric prokinetic agent to facilitate gastric emptying in conditions causing gastric stasis (e.g. post-abdo-surgery).
Also shown to increase LOS tone, thus aiding in reflux.

Other uses: Gastric stasis, difficult SI intubation, G-O reflux

Question 2

Prochlorperazine: uses and cellular mechanism

Answer 2

Anti-emetic (for nausea and vomiting), also for vertigo. At higher doses is used as an anti-psychotic, but anti-emetic doses are less than 1/3 this level.

Dopaminergic Antagonist

Antagonise the D2 receptor in the chemoreceptor trigger zone (CTZ) of the medulla.

Also affects histamine and muscarinic receptors.

Question 3

Domperidone: uses and cellular mechanism

Answer 3

Dopaminergic Antagonist
Anti-emetic, gastric emptying disorders (via prokinetic gastric action), gastro-oesophageal reflue.

*Does not penetrate blood brain barrier, thus less likely to elicit CNS side effects

Antagonises D2 receptors at chemoreceptor trigger zone (CTZ) in medulla.

Also a D3 antagonist

Increased LOS tone, inhibiting reflux, increases gastric emptying (relaxes pyloric sphincter), increase duodenal peristalsis

Question 4

Thiethylperazin: uses and cellular mechanism

Answer 4

Anti-emetic (usually associated with chemotherapy, radiation, cytotoxics and anaesthesia)

Antagonises D2 receptor at chemoreceptor trigger zone (CTZ) in medulla

Question 5

Promezathine: uses and cellular mechanism

Answer 5

Used for: motion sickness, vertigo, labyrinthitis, pain, sedation, allergic conditions

Histamine receptor antagonist: blocks H1 receptors (located in smooth muscle, in heart, vascular endothelial cells, in CNS)

Due to affect on H1, prmezathine/cyckizine/cinnarizine/dimenhydrinate are more useful in “direct” nausea syndromes such as those listed above. Not useful against stimuli that take the chemoreceptor trigger zone (CTZ) pathway

Question 6

Cyclizine: uses and cellular mechanism

Answer 6

Used for: motion sickness, vertigo, labyrinthitis, pain, sedation, allergic conditions

Histamine receptor antagonist: blocks H1 receptors (located in smooth muscle, in heart, vascular endothelial cells, in CNS)

Due to affect on H1, prmezathine/cyckizine/cinnarizine/dimenhydrinate are more useful in “direct” nausea syndromes such as those listen above. Not useful against stimuli that take the chemoreceptor trigger zone (CTZ) pathway

Question 7

Cinnarizine: uses and cellular mechanism

Answer 7

Used for: motion sickness, vertigo, labyrinthitis, pain, sedation, allergic conditions

Histamine receptor antagonist: blocks H1 receptors (located in smooth muscle, in heart, vascular endothelial cells, in CNS)

Due to affect on H1, prmezathine/cyckizine/cinnarizine/dimenhydrinate are more useful in “direct” nausea syndromes such as those listen above. Not useful against stimuli that take the chemoreceptor trigger zone (CTZ) pathway

Question 8

Dimenhydrinate: uses and cellular mechanism

Answer 8

Used for: motion sickness, vertigo, labyrinthitis, pain, sedation, allergic conditions

Histamine receptor antagonist: blocks H1 receptors (located in smooth muscle, in heart, vascular endothelial cells, in CNS)

Due to affect on H1, prmezathine/cyckizine/cinnarizine/dimenhydrinate are more useful in “direct” nausea syndromes such as those listen above. Not useful against stimuli that take the chemoreceptor trigger zone (CTZ) pathway

Question 9

Nabilone: uses and cellular mechanism

Answer 9

Synthetic cannabinoid

Used as an anti-emetic; also has analgesic effect useful for neuropathic pain

Inhibits nausea-invoking stimuli at the chemoreceptor trigger zone (CTZ)

Question 10

Aprepitant: uses and cellular mechanism

Answer 10

Anti-emetic: Used for severe nausea and emesis associated with chemotherapy

Action: substance P inhibitor, thus works by antagonising neurokinin-1 (NK-1) receptors, which are found in the vomiting centre in high concentrations.

Question 11

Ondansetron

Answer 11

Short acting Anti-emetic: post-op, chemo/radiation therapy associated nausea/vomiting.

This is because cytotoxic agents used in chemotherapy etc. cause release of serotonin from enterochromaffin cells in gut

Selectively bind and antagonise 5-HT3 receptors (serotonin receptors) in nausea/vomiting centre in brainstem

By 5-HT3 receptors, has both CNS and PNS response

*All 5-HT receptors are G protein coupled except 5-HT3 which are receptor/ligand gated (Na+/K+ channel)

Normal conditions:
Enterochromaffin cells in gut store most bodies of serotonin and release it in response to noxious stimuli. This increases gut motility and diarrhoea to rid body of noxious irritant. If high levels of serotonin are circulating in the blood, they act on the 5HT3 receptors in the chemoreceptor trigger zone (CTZ), initiating vomiting.

Question 12

Dolasetron: uses and cellular mechanisn

Answer 12

Long acting anti-emetic (long acting version of ondansetron)

Used for post-op, chemo/radiation therapy associated nausea/vomiting.

This is because cytotoxic agents used in chemotherapy etc. cause release of serotonin from enterochromaffin cells in gut

Selectively bind and antagonise 5-HT3 receptors (serotonin receptors) in nausea/vomiting centre in brainstem

By 5-HT3 receptors, has both CNS and PNS response

*All 5-HT receptors are G protein coupled except 5-HT3 which are receptor/ligand gated (Na+/K+ channel)

Normal conditions:
Enterochromaffin cells in gut store most bodies of serotonin and release it in response to noxious stimuli. This increases gut motility and diarrhoea to rid body of noxious irritant. If high levels of serotonin are circulating in the blood, they act on the 5HT3 receptors in the chemoreceptor trigger zone (CTZ), initiating vomiting.

Question 13

Hyoscine: uses and cellular mechanism

Answer 13

(scopolaramine)

One of the most potent anti-motion sickness treatments

Muscarinic antagonist: binds the M1 (‘neural receptor’), inhibiting the generation of slow EPSP.

Normal Action:
Activation at M1 upregulates phospholipase C, inositol triphosphate and intracellular Ca++. This leads to release of neurotransmitters that lead to vomiting?

Binding of hyoscine to M1 prevents this pathway

Question 14

Xylitol, Sorbitol, Mannitol: uses and cellular mechanism

Answer 14

Are all polyols used for constipation

Polyols are sugar alcohols that occur naturally in apples, pears and stone fruits.

Act as natural laxatives by bulking up faeces as they are poorly absorbed by the GIT (act like dietary fibre)

*Can also cause bloating and wind due to gas produced with fermentation in large intestine

Question 15

Methylcellulose, Bran, Sterculia Agar, Ispaghula Husk, Psyllium Powder: uses and cellular mechanisms

Answer 15

Are bulking purgatives used for constipation

They are polysaccharide polymers that are not broken down in the upper portions of the GIT

Thus, they for a bulk hydrated mass that increases peristalsis and faecal consistency

• Take 2-3 days to work
• Important to maintain fluid intake and introduce doses gradually. Rapid increase in dose can cause flatulence and distension.

Question 16

Saline Purgative and Lactulose: uses and cellular mechanism & what each contain

Answer 16

Osmotic laxatives used for constipation

Indicated for long-term treatment of constipation. Ideally combined with polyol-containing fruit juice.

These contain poorly absorbed solutes which create an osmotic gradient, drawing fluid into the lumen of the intestinal tract, which accelerates movement of faeces down into the colon.

Faeces entering colon tends to be larger than normal, which causes local distension of the colon wall resulting in increased : purgation

Saline purgative contains magnesium sulphate and magnesium hydroxide. Onset of action is 0.5-3 hrs orally, and 2-30mins rectally

Lactulose contains a semi-synthetic disaccharide of fructose and galactose. Onset: oral 1-3 days, rectal 5-30minds.

Question 17

Docusate sodium, Arachis oil (enema), Liquid parafin: uses and cellular mechanism

Answer 17

Stool softeners used in constipation

Act like detergents in the intestine and have weak stimulant laxative actions

Onset orally 2-3 days, rectally 5-20 mins

Question 18

Bisacodyl, Senna and Dantron: uses and cellular mechanism

Answer 18

Stimulant purgatives used for constipation

Bisacodyl:
Also used in bowel prep.
Increases electrolyte concentration in bowel thus increases water secretion. Also increases peristalsis, possibly by acting on the enteric nervous system

Often given as a suppository which works in 15-30 mins

Senna and Dantron:
Anthraquinone laxatives

Act directly on the myenteric plexus of the ENS to increase peristalsis and defecation.

Oral onset 6-12 hours, rectally 5-6 minutes

Question 19

Loperamide: uses and cellular mechanism

Answer 19

Anti-diarrhoea agent

Opiate. First-line treatment for traveller’s diarrhoea
Actions are quite specific to the gut.

Action: activates opiate receptors in the gut wall, which increases gut rhythmic contraction, particularly in the LI. Simultaneously decreases propulsive activity and contracts the pyloric, iliocolic and anal sphincters. This gives a net constipating action and may shorten the duration of the illness.

Does not cross BBB to cause CNS side affects.

Alleviates cramps created by propulsive nature of diarrhoes, but can potentially cause cramps by causing constipation?

Question 20

Atropine, Hyoscine, Propantheline and Dicyclverine: uses and cellular mechanisms

Answer 20

Anti-diarrhoea agents

Spasmolytics.

Indicated in irritable bowel syndrome and diverticular disease

Are muscarinic antagonists that inhibit the action of the PSNS (prevent Ach from binding)

Bind to M receptors in the gut and decrease motility and gastric secretions.

Normal Muscarinic receptor pathway in smooth muscle: ACh binds to M receptor, upregulating phospholipase C, inositol triphosphate and intracellular Ca++, thus resulting in increased SMC contraction

Question 21

Kaolin, Pectin, Chalk, Charcoal, Methyl Cellulose and Magnesium Aluminium Silicylate: uses and cellular mechanism

Answer 21

Anti-diarrhoea agents

Are adsorbents.

Absorp micro-organisms and toxins, altering intestinal flora.
Coat and protect intestinal mucosa.

• Efficacy not well established as not many studies have looked into it, but they are still widely used.
• Often mixed with other drugs: e.g. kaolin mixed with morphine (opiate) - enhances anti-diarrhoeal effect

Question 22

Sulfasalazine: uses and cellular mechanisms

Answer 22

First-line treatment in Ulcerative Colitis.
Also used for rheumatoid arthritis, and other autoimmune diseases. Limited role in Crohn’s disease.

Effective in inducing remission in UC, and reducing frequency of relapses - but do not prevent relapse.
Continual use cannot occur do to side effects. Medication starts/stops

= conjugate of two different drugs: 5-ASA and sulfapyridine

Action: exact mechanism unknown. Exerts local inflammatory actions within bowel.
Activates PPAR leading to transcription of genes associated with insulin resistance.

Other proposed actions of 5-ASA inflammatory action include:
Inhibition of leuketrienes (inflammatory protein) and thromboxane A2 (platelet adhesion); decrease in IgM, rheumatoid factor, IL6, IL1, TNFa and NK-kB concentrations

Sulfasalazine is poorly absorbed in the SI. In the colon, bacterial actions break the conjugation between sulfapyridine and 5-ASA (the active metabolites).

Question 23

Mercaptopurine and Azathioprine: uses and cellular mechanisms

Answer 23

Purine Synthesis Inhibitors. Immunosuppressants. Used in chronically active, severe, resistant inflammatory bowel disease, where the patient suffers frequent relapses and cannot function without steroids.

Also used as post-transplant anti-rejection agent

*Also used when patient cannot use steroids

Both are metabolised into 6-TGN (6-thioguanine nucleotide), which inhibits purine synthesis, which in turn inhibits DNA synthesis and cell proliferation. Primarily affects lymphocyte and leukocyte proliferation.

Onset is slow: 3-6 months
Drug does build up and have an effect for some time; thus remission time can reach ~2 years

Patients tend to take drug for 12 months at a time

Important side effects: Bone marrow suppression and Liver Toxicity - thus regular FBCs and LFTs are necessary throughout treatment

Question 24

Methotrexate: uses and cellular mechanism

Answer 24

Indicated in severe, resistant Crohn’s and other auto-inflammatory conditions

Action: folic acid antagonist. Inhibits DNA synthesis and cell replication by competitively inhibiting the conversation of folic acid into folinic acid, with cytotoxic, immunosuppressive and anti-inflammatory action

Action takes several months

Question 25

Infliximab

Answer 25

(Remicade)

Used for a range of autoimmune disorders

Plaque Psoriasis
Rheumatoid arthritis
Psoriatic arthritis
Ankylosing Spondylitis
**Crohn's disease in adults and children - indicated in moderate to severe and fistulating crohn's that is refractory to standard treatment
**Ulcerative Colitis

Infliximab is a monoclonal antibody against TNF-alpha. TNF-alpha is a cytokine that induces mucosal inflammation.

Patients with Crohn’s and UC tend to have increased levels of TNF-a - Infliximab treats this excess

Most effective administration is infusion at 2 weeks, 6 weeks, and then every 8 weeks.

If cease drug, remission will end*

Half-life is 10 days, but infliximab antibodies are detectable for ~6 months

Question 26

Prednisolone, Hydrocortisone, Budesonide: uses and cellular mechanisms

Answer 26

All corticosteroids - glucocorticoids

First line treatment in Crohn’s disease**

Glucocorticoids enter the cell and bind to intracellular receptors. The receptors either induce or repress transcription factors for particular genes, resulting in synthesis of particular genes and suppression of others.

Actions on inflammatory cells:
1. Secondary to decreased transcription factors coding for cell adhesion and cytokine release, results in decreased immigration of neutrophils from blood vessels, and reduced activation of neutrophils and macrophages.

2. Decreased activation of T helper cells, and reduced clonal expansion of T cells secondary to decreased transcription factors for production of Il-2 and its receptor (IL-2 s responsible for causing clonal expansion of T cells)
   * Note: clonal expansion: process of all cells being daughter cells from single parent cell, resulting in all cells sharing the same exact antigen.
3. Decreased fibroblast function and less production of collagen and glycosaminoglycans, resulting in reduced fibrosis due to wound repair/healing
4. Reduced activity of osteoblasts and increased activity of osteoclasts, resulting in increased chance of osteoporosis

Actions on mediators of inflammatory and immune responses:
Decreased expression of COX2 resulting in decreased prostanoids
Decreased generation of many cytokines
Decreased complement in plasma
Decreased NO
Decreased histamine release from basophils
Dereased IgG production
Increased production of anti-inflammatory factors

Question 27

Cimetidine, Ranitidine, Famotidine, Nizatidine: uses and cellular mechanism

Answer 27

Gastric Acid Secretion Agents: Histamine Antagonists

Used in: Peptic ulcer disease, GO-reflux disease, Dyspepsia, Stress Ulcer prophylaxis

*Parietal cells = stomach epithelial cells that secrete HCl acid

Actions: Bind to H2 receptors on parietal cells and antagonise the action of Histamine (thus reducing secretion of acid)

By blocking H2 receptors on parietal cells, they block both histamine that is released by mast cells, and histamine released via action of ACh and gastrin on mast cells in the gastric mucosa.

This results in decrease in basal and food-stimulated acid secretion by 60-90%

Promotes healing of duodenal ulcers

Question 28

Omeprazole, Lansoprazole, Esomeprazole: uses and cellular mechanisms

Answer 28

Proton pump inhibitors to decrease gastric acid secretion

Used for: Peptic Ulcers, GORD, **As part of H pylori treatment, and Zollinger-Ellison syndrome (gastrin-secreting tumour of the pancreas that stimulates acid secretion by stomach parietal cells)

PPIs irreversibly bind parietal cell’s H+/K+ ATPase pump and inhibit the last stage in acid secretion - as it is directly responsible for excreting H+ atoms into the lumen.
New pumps must be produced.
Thus, reduces acid secretion even in the presence of stimuli

• PPIs are not active in a neutral pH environment
• A step-down approach is taken to GORD management. Initially a 4-8 week course is given, with subsequent tapering of dose till a minimum which still reaps therapeutic benefit
• Association between PPIs and increased bone fractures

Question 29

Omeprazole, Lansoprazole, Esomeprazole: uses and cellular mechanisms

Answer 29

Proton pump inhibitors to decrease gastric acid secretion

Used for: Peptic Ulcers, GORD, **As part of H pylori treatment, and Zollinger-Ellison syndrome (gastrin-secreting tumour of the pancreas that stimulates acid secretion by stomach parietal cells)

PPIs irreversibly bind parietal cell’s H+/K+ ATPase pump and inhibit the last stage in acid secretion - as it is directly responsible for excreting H+ atoms into the lumen.
New pumps must be produced.
Thus, reduces acid secretion even in the presence of stimuli

• PPIs are not active in a neutral pH environment
• A step-down approach is taken to GORD management. Initially a 4-8 week course is given, with subsequent tapering of dose till a minimum which still reaps therapeutic benefit
• Association between PPIs and increased bone fractures

Question 30

Magnesium Hydroxide, Aluminium Hydroxide, and Sodium Bicardium: uses and cellular mechanism

Answer 30

Antacids - for relief of symptoms of excessive gastric acid secretion - including gastric ulcer symptoms

Antacids are an alkaline solution which directly neutralises the acid, increasing pH to >4

Also inhbit pepsin activity, as its action ceases at a pH of 5

Reduces gastrin secretion

Slow H pylori proliferation and provides some relief to afflicted gastric mucosal linings

• Most efficient when ingested with food
• Magnesium salt derivatives are more effective than aluminium salt derivatives
• Sodium bicarbonate acts rapidly to increase gastric acid secretions, but stimulates gastrin so a secondary increase in acid secretion may occur. Because bicarbonate sodium is absorbed in the intestine, alkalosis may occur with high doses. Thus, sodium bicarbonate should not be given long term.
• Aluminium hydroxide also absorbs pepsin

Question 31

Amoxycillin: uses and cellular mechanism

Answer 31

H pylori eradication and peptic ulcers

Beta Lactam Bacteriocidal agent

Interferes with the synthesis of the peptidoglycan cell wall of bacteria. They inhibit the transpeptidation enzyme that cross links the peptide chains attached to the backbone of the peptidoglycan.

Also deactivates an inhibitor of autolytic enzymes in the cell wall, leading to lysis of bacteria

Question 32

Amoxycillin: uses and cellular mechanism

Answer 32

H pylori eradication and peptic ulcers

Beta Lactam Abx
Inhibit the transpeptidation enzyme that cross links the peptide chains attached to the backbone of the peptidoglycan

Interferes with the synthesis of the peptidoglycan cell wall of bacteria.

Question 33

Tetracycline, Oxytetracycline, Doxycycline: uses and cellular mechanism

Answer 33

Broad Spectrum Polyketide Abx. Used for H pylori eradication and peptic ulcers

Following active transport into bacterial cells, tetracyclines inhibit protein synthesis via the 30S ribosomal subunit.

Question 34

Metronidazole: uses and cellular mechanism

Answer 34

Used in H pylori eradication and CROHN’S DISEASE most commonly an adjunct to conventional therapies

In H Pylori eradication: Metronidazole interferes with the bacterial DNA helix, inhibiting nucleic acid synthesis

Crohn’s: Metronidazole has direct anti-inflammatory effects, and also affects neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.

Question 35

Metformin: Systemic Actions

Answer 35

Oral Hypoglycaemic

Decreases blood glucose by:

1. Suppressing gluconeogenesis by the liver
2. Decreasing intestinal absorption of glucose
3. Improving insulin sensitivity by increasing peripheral glucose uptake and utilisation

Question 36

Metformin: Cellular Mechanism

Answer 36

Incompletely understood

Metformin binds to hepatocyes
Inhibits mitochondrial respiratory chain (Complex I)
Which activates AMP-activated protein kinase (AMPK)
This inhibits Cyclic Anhydrase Monophosphate (cAMP)
Activation of Protein Kinase A (PKA)

Activation of AMPK is required for metformin’s inhibitory effect on the production of glucose by hepatocytes

Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors

Metformin also increases AMPK activity in skeletal muscle, where AMPK is thought to cause GLUT 4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake

Also a proposed effect on gut microbiota

Question 37

Why doesn’t Metformin cause Hypoglycaemic episodes?

Answer 37

Because it doesn’t trigger release of insulin from Pancreatic Beta Cells

Question 38

How do Sulphonylureas work, systemically?

What are the drug names?

Answer 38

Used in Type II Diabetics as an oral hypoglycaemic

Reduce blood glucose levels by enhancing release of insulin from pancreatic beta cells

Gliclazide. Glibenclamide.

Question 39

Sulphonylureas: Cellular Mechanism

Answer 39

Bind to ATP-dependent K+ channels in the beta cell membrane

This inhibits the usual tonic, hyperpolarising efflux of K+

This causes a positive membrane potential to occur across the cell membrane > Depolarisation

The depolarisation opens voltage-gated Ca++ channels

Influx of Ca++ raises intracellular Ca++ concentrations, which leads to increased fusion of insulin granulae with the cell membrane

Thus increasing (pro)insulin release

Question 40

Alpha-Glucosidase Inhibitors: Systemic effect and indications

Answer 40

Oral Hypogycaemic

Lower blood gucose levels by delaying the absorption and digestion of carbohydrates into glucose and monosaccharides.

This reduces the post-prandial glucose load.

Question 41

Alpha-Glucosidase Inhibitors: Cellular Mechanism

Answer 41

Alpha-Glucosidase inhibitors competitively inhibit the actions of alpha-glucosidase enzymes, which are needed to digest carbohydrates.

Alpha-glucosidases hydrolyse oligosaccharides, trisaccharides and disaccharides.

Alpha-Glucosidase inhibitors also block the action of pancreatic alpha-amylase, which breasks down complex starches into oligosaccharides

Question 42

What are Incretins?

Answer 42

Peptide hormones involved in glucose metabolism

• Glucagon-like Peptide-1 (GLP-1)
• Gastric Inhibitory Peptide (GIP)

GLP-1 is secreted by L cells in the ileum and colon
GIP is secreted by K cells in the duodenum

Incretins are released within minutes of eating as they are relseased as soon as food is present in the GIT. Thus, they become active before blood glucose rises.

GLP-1 and GIP are involved in the post-prandial release of insulin from pancreatic beta cells, and act only when food is present in the GIT

They also slow the rate of absorption of nutrient uptake into the bloodstream by slowing gastric emptying. This, in turn, can result in apetite suppression as the stomach has food in it for longer.

The Incretin response to a meal last 2-3 hours, because they are continually secreted whilst nutrients remain in the GIT

Incretins are broken down by DPP4 (dipeptidyl peptidase-4)

Question 43

What is the Incretin Response of Type II Diabetic?

Answer 43

Extremely attenuated

• No GLP-1 response
• Near normal GIP levels

Result = diminished post-prandial insulin response, lack of apropriate appetite suppresion and hyperglycaemia

Question 44

Cellular and systemic actions of Incretin mimetics?

Answer 44

Incretin mimetics incretin analogues that are resistant to degradation by DPP4.

Incretins: GLP-1 and GIP.

They trigger release of insuling from pancreatic beta cells in response to the presence of food in the GIT. Thus, they begin to act only after food has been ingested, but before blood glucose levels rise.

They slow the absorption of nutrients by slowing gastric emptying. This action also has the added benefit of reducing appetite - because the stomach has food in it for longer.

They inhibit the release of glucagon from pancreatic alpha cells - thus inhibiting gluconeogenesis by hepatocytes

Other Actions of Incretin Mimetics:

• Improving Pancreatic Beta cell sensitivity
• Promoting Beta cell proliferation
• Reducing beta cell apoptosis

Question 45

Features of Exendin

Answer 45

Incretin Mimetic

Exendin is 50% homologous to GLP-1

It is a potent acticator of GLP-1R

Resistant to cleavage by DPP4

Thus has longer circulating life than normal incretins

Question 46

Features of Liraglutide

Answer 46

Incretin Mimetic

Maintains normal activity of the GLP-1R

Resistant to cleavage by DPP4

Longer circulating life than noral incretins

Question 47

Side effects / Advantages of Incretin Mimetics?

Answer 47

Advantages:

1. DO NOT CAUSE HYPOGLYCAEMIA
   - Incretin effect on insulin only occurs in the presence of hyperglycaemia (i.e. after ingestion of food)
2. Can cause weight loss because they slow gastric emptying - reduced appetite

Side Effects:

1. Anorexia
2. Nausea
3. Vomiting
4. Long term effects are unknown

Question 48

What are important factors associated with DPP4 inhibition?

Answer 48

Specificity in inhibition of DPP4 is crucial

GLP-1 and GIP are the only known substrates for DPP4

Inhibiting DPP8 or DPP9 causes renal or skin toxicity

Question 49

Cellular and Systemic Actions of Incretin Enhancers

Answer 49

Incretin Enhancers increase the concentration of circulating incretins by inhibiting DPP4 (dipeptidyl peptidase 4), which normally breaks down incretins.

They are highly specific for DPP4. GIP and GLP1 are the only known substrates for DPP4
INhibition of DPP8 or DPP9 causes renal or skin toxicity

Incretin Enhancers effectively restore:

• GLP-1 circulating volume
• The postprandial response of GLP-1 to that of a non-diabetic
• Low levels of fasting incretins
• Low fasting blood glucose levels
• Beta cell mass is preserved

Long half-life allows 1 d dosage
2 hours post-dose, they show almost complete inhibition of DPP4
24 hours post-dose, there is 85% inhibition of DPP4

Potential side-effect? DPP4 may be associated with tumour suppression. Thus, suppresion of DPP4 could lead to increased risk of certain cancers

Question 50

Describe administration and composition of Insulin Preparations and the general indications for use of insulin

Answer 50

Insulin is used in some forms of diabetes

• Type I Diabetics depend on exogenous insulin to survive, because it is no longer produced internally
• Some Type II Diabetics will require Insulin if other medications fail to control their blood glucose
• Insulin is the only safe hypoglycaemic medication for use in pregnancy

Insulin is administered: Parenterally, IV or IM

• IV used in ketoacidosis emergencies
• Intraperitoneal insulin used in diabetics with ESKD treated by ambulatory peritoneal dialysis

Human insulin made from recombinant DNA technology is now the standard

Or, chemically altered pork insulin - has 1 aa different to human insulin (thus fewer allergic reactions than bovine insulin)

Previously, bovine insulin had been used - was 3 aa different to human insulin. Associated with higher rates of allergic reaction

Question 51

How does Ultra Short Acting Insulin work?

Answer 51

Ultra-short insulin preparations -aka bolus injections. Lispro Aspart, Novorapid

• AA substitutions make it easier for the insulin molecules to dissociate into the subcutaneous tissues upon injection
• This speeds up absorption and onset of action (15 mins)
• This allows the formation of an insulin profile that is closer to normal postprandial insulin release patterns

As such, ultra-short acting insulin offers better control of postprandial hyperglycaemia

It also carries less risk of hypoglycaemia in between meals, because the preparation is shorter acting

However, as the patient recieves the bolus of insulin at a time, they MUST eat after injecting

Better for weight management. Good for people who don’t mind having to inject multiple times per day.

Question 52

How does Very Long Acting Insulin work?

Answer 52

Very long Acting Insulin - Basal Insulin. Insulin Glargine

• A change of AA composition reduces the insulin’s solubility in the subcutaneous tissue
• The insulin is soluble in an acidic pH (in the vial) but is insolbule at a neutral pH (in the subcutaneous tissue)
• Thus, after injection, the insulin forms an insoluble crystal which is absorbed very slowly
• This produces the long, flat absorption profile

Because it produces a ‘basal’ level of insulin, it is often associated with more weight gain, because there is more risk of hypoglycaemia occuring in between meals - need to consume more to ‘feed’ the insulin

Question 53

How does Intermediate Acting Insulin Work?

Answer 53

Intermediate Acting Insulin - Insulin Detemir

• Composed of an insulin-fatty acid complex
• The fatty acid causes the insulin to complex with albumin when it is injected into the subcutaneous tissue/plasma
• Insulin slowly dissociates from the albumin and diffuses from the extracellular environment into the circulation, to act

Absorption profile is in between that of very long acting insulin and ultra short acting insulin

Question 54

Describe the Insulin Delivery Systems

Answer 54

Insulin Pens:

• contain a cartridge of insulin
• simple injection - no need to draw up
• Allows multiple daily injection schemes to be much easier - allows more flexible self management

Syringes:

• free syringes and subsidised test strips through NDSS Australia

Insulin Pumps:

• Attached to patient’s clothing, injects via an infusion set attached to the skin
• Infuses ultra short acting insulin at variable rates which can be programmed, into the subcutaneous tissues
• can be programmed to provide basal insulin infusion rates throughout the day
• can also provide pre-prandial doses

Question 55

Cellular Mechanism of Oestrogen-only contraceptive pills

Answer 55

Hormonal Contraceptive

Oestrogen in the blood creates a negative feedback on gonadotrpoin releasing hormone (GnRH) which leads to inhibition of FSH and LH release from the anterior pituitary

This inhibits follicular maturation (primarily selection of a dominant follicle and its subsequent development into a graafian follicle). Inhibition of this development means that there is no estradiol being produced by the follicle, which in turn prevents the normal mid-cycle LH surge that normally triggers ovulation.

Thus, oestrogens work by preventing ovulation

Ostrogens tend to be associated with increased bleeding toward the end of the cycle. This may be preventable with icnreased dosages, but icnreasing oestrogen dose is associated with side-effects and risk factors

• increased nausea and breast tenderness
• increased risk of thromboembolic event (frin increased risk of DVT)

Question 56

Cobined pill: oestrogen + progestogen Mechanism of Action

Answer 56

Progestogen (synthetic version of progesterone which is stronger) and Oestrogen in the blood creates a negative feedback on gonadotrpoin releasing hormone (GnRH) which leads to inhibition of FSH and LH release from the anterior pituitary

This inhibits follicular maturation (primarily selection of a dominant follicle and its subsequent development into a graafian follicle). Inhibition of this development means that there is no estradiol being produced by the follicle, which in turn prevents the normal mid-cycle LH surge that normally triggers ovulation.

Thus, COCPs prevent ovulation

Progestogen also causes decreased water content and increased viscosity of the cervical mucous, which inhibits the sperm’s ability to move through the cervix

Question 57

Mini-pill mechanism of action

Answer 57

The mini-pill is a very low-dose progestogen only pill

Often used by breastfeeding mothers

Decreased effictiveness

Very low doses of progestogen are successful in preventing ovulation in only ~50% of cycles and thus rely mainly on the progestogen’s effect on the cervical mucous - primarily, causing decreased water content and increased viscosity

This prevents sperm’s ability to swim through the cervix to the upper repoductive tract

Question 58

High-dose progestogen mechanism of action

Benefits and Down-sides

Answer 58

Medroxyprogesterone Depo (Depo-Provera)

Usually given as an IM injection every 12 weeks

High doses of progestogen successfuly inhibits ovulation and maturation of ovarian follicles

Also inhibit the proliferative development of the endometrium - even though risk of fertiliation is negligable, this increases the likelihood that implantation would not be unsuccessful anyway

Has the same effects on cervical mucous - decreased water content and increased viscosity

Progestogen creates negative feedback on gonadotropin releasing hormons (GnRH) which reduces release of FSH and LH from the anterior pituitary gland

Decreased levels of FSH and LH inhibit the selection of a dominant primary ovarian follicle and its subsequent development into a graafian follicle

By preventing this development, progestogen further prevents that follicle’s secretion of estradiol which would normally induce a surge of LH that triggers ovulation

Thus, medroxyprogesterone inhibits ovulation

Benefit: administration only once every 12 weeks
Can be used during breastfeeding
Contains no oestrogen - so no increased risk of DVT, and associated thromboembolic complications (PE, stroke, MI, etc.)
If side-effect - has already been injected. awks.

Question 59

RU486 Mechanism of Action

Answer 59

In the presence of progesterone, mifepristone acts as a competitive (with much greater affinity than progesterone) antagonist of progesterone receptors

Blackage of progesterone receptors directly causes endometrial degeneration

(as well as cervical softening and dilation, release of endogenous prostaglandins and increased myometrial sensitivity to these prostaglandins)

Endometrial breakdown leads to trophoblast detachment, which leads to decreased hCG production

Decreased hCG production leads to decreased Progesterone production by the corpus luteum

Until 9 weeks gestation (when the placenta is creating enough progesterone), pregnancy is dependent on the corpus luteum’s progesterone production

Thus, progesterone production decreases, pregnancy cannot be supported, and abortion ocurs

Most women abort within 6 hours of taking the 2nd pill, with 97.5% success rate

(mifepristone taken initially, and misoprostol taken 48 hours later)

Question 60

What is administered in RU 486

Answer 60

Initially - Mifepristone (200-600mg oral)

48 hours later - Misoprostol (400-800ug)

Question 61

Glitazones Cellular Mechanism & Use

Answer 61

Oral Hypoglycaemic

Glitazones selectively bind to nuclear receptor PPAR-y and to a lesser extent PPAR-alpha

This leads to modulation (increase) in the expression of insulin-sensitive genes involved in the control of glucose + lipid metabolism in muscle and adipose tissue, and in the liver

Systemically, Glitazones:
1. Decrease Insulin Resistance in the liver and peripheral tissues

2. Decrease withdrawal of glucosa from the liver
3. Decrease serum glucose, insulin and glycated haemoglobin