BLOCK 3 WEEK 4

what is diarrhoea?

change in bowel habit which is more frequent and looser stool than usual

according to WHO 2017 diarrhoea is where there is passage of three or more loose or liquids stools per day.
why is consistency more significant than frequency?

because frequency is relative to the individual. should be if going more regularly than normal for the individual

what is acute diarrhoea?

if it lasts less than 14 days

what is persistent diarrhoea?

if it last more than 14 days but less than 28 days

what is a possible cause of persistent diarrhoea

possible infection

what is chronic diarrhoea?

if it lasts for longer than 28 days

out of acute, persistent and chronic diarrhoea which is a sign of an underlying health condition

chronic

what is pathophysiology ?

the disordered physiological processes associated with disease or injury.

what is the pathophysiology of diarrhoea?

- increased osmotic load
- increased secretion
- inflammation of intestinal lining
- increased intestinal motility

typically how many time a year is normal for children to experience acute diarrhoea?

1-3 episodes

typically how many time a year is normal for adults to experience acute diarrhoea?

1 episode

give some examples of possible causes of acute diarrhoea

- infection
- anxiety
- drugs (side effects or adjusting to new medication)
- parasites
- food poisoning
- dysentery (infection of the small intestine)

a patient has come to you with acute diarrhoea, she wants to know how long it will last for. what should you tell her?

most cases resolve themselves within 72 hours

a patient has come to you with diarrhoea, she wants to know how long it will last for. what is an important question to ask and why?

important to ask if they have recently been abroad as they may have travels diarrhoea which may take longer to resolve.

What is traveller's diarrhoea?

experienced by travelers
has early onset
same symtoms as acute diarrhoea
typically resolved in 7 days

what are the causes of travelers diarrhoea?

salmonella
viruses
e.coli

what are potential causes of chronic diarrhoea?

IBS
inflammatory bowel disease
malabsorption syndromes
metabolic disease
laxative abuse

what are the symptoms of acute diarrhoea?

- loose/ liquid stools
- increased frequency
- abdominal cramping
- flatulence
- abdominal tenderness
- rapid onset

why is it important to ask about dehydration if a patient says they have diarrhoea?

because large amounts of fluid is lost

what are red flag symptoms of diarrhoea in adults ?

- over 72 hours in healthy adults
- over 48 hours in elderly
- over 24 hours in diabetics
- associated with severe vomiting and fever
- blood or mucus in stool
- change in bowel habit if over 40
- severe rectal pain
- weight loss

what is first line of treatment for acute diarrhoea?

oral rehydration therapy

what do oral rehydration therapies often contain?

- sodium and potassium to replace essential ions
- citrate or bicarbonate to correct acidosis
- glucose

What is acidosis?

when there is too much acid in bodily fluids

why must oral rehydration therapies be slightly hypo-osmolar?

prevent possible induction of osmotic diarrhoea?

typically with acute diarrhoea the advice is to let its run its course, what may be treatment if this isn't possible

gut mobility agents

what are gut mobility agents

slow down the passing though the gut

what is a issue with gut mobility agents slowing down passing of things through the gut?

bacteria which may have been causing diarrhoea is being held in body for longer so it could potentially cause more problems

what type of drug is loperamide?

Antidiarrheal agent. its a mu opiod receptor agonist

What is an agonist?

Activates receptor to cause a response

How does loperamide work?

* direct action on opiate receptors in the gut wall.
* reduces propulsive peristalsis so there is increased transit time leading to more reabsorption
* increases tone of anal sphincter which reduce faecal urgency -

why do patients who take loperamide not feel the effects of an opioid

has extensive first pass metabolism so very little reaches systemic circulation

what are other possible treatments for diarrhoea

morphine
diphenoxylate
adsorbents
antibiotics

what is constipation

infrequent or difficult defecation

which groups of people are more likely to suffer constipations

pregnant women
older people

What is pathophysiology of constipation?

- large intestine removes water and salts from the colon
- drys and expels faeces
- in constipation increased water reabsorption leads to harder stools

What causes constipation?

- functional
- induced by particular condition or medicine
- medications
- non-medical factors
- medical conditions

give some examples of non-medical factors which can cause constipation

Non-medical factors which pre-dispose to constipation include
Inadequate fluid intake
Inadequate dietary fibre
Dieting
Changes in lifestyle
Suppressing the urge to defecate

give some examples of medical conditions which can cause constipation

Medical conditions predisposing:
Coeliac disease
Depression
Diabetes
GI obstruction
Irritable bowel syndrome
Parkinson's disease
Hypercalcaemia
Hypokalaemia
Hypothyroidism

what are possible medications can cause constipation?

Antacids containing aluminium and calcium
Antihypertensives - diuretics, calcium channel blockers
Antidepressants - tricyclics and some monoamine oxidase inhibitors
Antimuscarinics - procyclidine, oxybutynin
Antiparkinsonian medicines - levodopa, dopamine agonists, amantadine
Opioid analgesics
Iron

what are the symptoms of constipation

abdominal discomfort
abdominal cramping
bloating
nausea
difficult passing stool
specks of blood due to straining

what are the red flag symptoms of constipation for adults?

- unexplained weight loss
- blood in stools
- rectal bleeding
- family history of colon cancer or IBD
- signs of obstruction
- nausea
- change in habit with no obvious cause in people over age of 40
- tiredness

what is non-pharmacological treatments for constipation?

- diet
- increased fluid intake
- increase exercise

laxatives may be used a pharmacological treatment for constipation. what are the different types of laxatives

- bulk - forming
- stimulant
- osmotic
- faecal softening

how do bulk forming laxatives work?

increase faecal mass through water binding to stimulate peristalsis

can bulk forming laxatives be used long term?

yes can be used for people who were prone to constipation

What are stimulant laxatives?

increase intestinal mobility via muscle contractions

Senna is an example of what type of laxative?

stimulant

should stimulant laxative be used long term?

no avoid pro-longed use

What are the osmotic laxatives?

work within colonic lumen to retain and draw water into intestine by osmosis

arachis oil is a faecal softener. what is a faecal softener?

stimulate peristalsis by increasing faecal mass to lower surface tension and allow water and fats to penetrate

if giving out arachis oil why is important to ask the patient about allergies

cannot be used if have a nut allergy

what is IBS?

Chronic functional disorder characterized by recurrent abdominal pain associated with disordered bowel movements, which may include diarrhea, constipation, or both

how long must symptoms have occurred for to be IBS

6 months

What are antispasmodics?

smooth muscle relaxants

what are possible treatments for IBS

- dietary changes
- exercise
- antispasmodics
- anti-diarrhoeal
- laxatives
- probiotics

a cavity needs to be created for drug molecule to be inserted in. How is this done?

by breaking bonds between solvent

what is disintegration

Breakdown of oral drug form into small particles

why are hydrophilic excipients added to tablets and capsules to aid disintegration

they will attract water leading to lines of fracture in the tablet. these lines of fracture will break down into granules or aggregates

what do granules and aggregates disaggregate into

fine particles

why does decreasing size of particles lead to an increase in dissolution rate

decreasing size leads to an increase in surface area in contact with liquid

What is the Noyes-Whitney equation?

Rate of dissolution = (D*A*(Cs-C))/h

D=diffusion coefficient, A=surface area, S=solubility, C=concentration, h=thickness of dissolution boundary

why is decreasing the size of particles not increase dissolution of hydrophobic particles?

leads to agglomeration

how is agglomeration prevented

adding surfactants or wetting agents

what does solubility depend on?

interaction between molecules in the solid with intermolecular interactions in the solvent

pH in the bulk layer is different from pH in the bulk but:
weak acid solubility \_____________with pH
weak base solubility \____________ with pH

increases
decreases

if the thickness of the diffusion layer increases what happens to rate of dissolution

rate of dissolution will decrease

why is the environment of villi very viscous

presence of peptidoglycan

if diffusion coefficient decreases what happens to rate of diffusion

decreases

what will have a faster dissolution rate amorphous solid or crystal

amorphous solid

what is the intrinsic dissolution rate

rate of mass transfer per area of dissolving surface (mg/mm2/s)

what is the aim of dissolution testing?

determine the rate at which a substance is released from the dosage form and dissolve in particular medium

QC testing is usually done under sink conditions, the medium should be one which the drug is soluble in. what else is important about the medium?

shouldn't contribute to the decomposition of the drug
easy to prepare
inexpensive
(non- organic)

define absorption in relation to drug molecules

movement of the drug from the site of administration into the blood, usually across a membrane

what are the types of parental administration

intravenous
subcutaneous
intramuscular

what is absolute bioavailability?

assessed with reference to an intravenous dose

what is relative bioavailability?

comparisons of the bioavailability between formulation of a drug given either by the same or different routes of administration

if a drug has a bioavailability of 1 what does this mean

drug has complete bioavailability all of it will reach systemic circulation

if a drug has a bioavailability of 0 what does this mean?

no drug has entered systemic circulation or it has been metabolised

why is bioavailability important

drug concentration in blood plasma and site of action needs to be high enough to have a pharmacological response

why may extent of drug which reaches systemic circulation be reduced when taken orally

because of First pass effect

why are biological drugs such as monoclonal antibodies or hormones not administered orally

contain proteins which would be digested by enzymes

what is lipinski's rule of 5

-not more than 5 hydrogen bond donors
-not more that 10 hydrogen bond acceptors
-a molecular weight under 500 g/mol
-a log P value under 5.0

name 4 potential barriers for oral bioavailability

- disintegration time and dissolution rate
- gastric emptying + internal transit
- passive and active movement of drug across membrane
- first pass metabolism

how does bile enhance solubility of drugs

acts as a surfactant and helps dissolve lipophilic compounds

how does bile act as a natural surfactant

- bile acids form micelles
- lipophilic drug prefers to distribute into lipid core of micelle

what affect can transporters have on drug permeability

increase or decrease permeability

if a the lipophilicity of a drug is increased what does it mean for the permeability

the drug will be more permeable

if the size of the drug is increased what affect does it have on permeability?

decrease in the permeability

are highly ionised drugs more or less permeable

highly ionised drugs are less permeable

What is first pass metabolism?

loss of a drug as it passes through the intestine and liver during absorption

what does pre-systemic metabolism mean?

before the drug has reached systemic circulation

how does first pass metabolism affect bioavailability of a drug

extensive first pass metabolism leads to a decrease in the bioavailability of a drug

what is the class of enzymes which are predominantly involved in first pass effect

CYP3A4

what physiological changes occur due to gastric bypass surgery

- reduction in stomach surface area
- change in pH

what is the function of transporter proteins?

translocation of substances across the membrane

What are SLC transporters?

solute carrier transporters

What are ABC transporters?

ATP-binding cassette transporters

how is glucose absorbed in the small intestine?

SGLT-1 and SLC5A1 transporter which are dependent on Na+

why is glucose uptake dependent on Na+

glucose uptake is energised by movement of Na+ ions down their electrochemical gradient into the enterocyte

how many membrane spanning regions does SGLT1/SLC5A1 possess

14