the Science of Medicines Flashcards
Why do we need to study the solubility of drugs?
there are changes in pH within the GI tract, so changes in ionisation and solubility and drugs could precipitate
Henderson-Hasselbalch equation for a weak acid
log [A-] / [HA] = pH - pKa
When is [A-] greater than [HA]?
when pH is greater than pKa
When is [HA] greater than [A-]?
when pH is less than pKa
Henderson-Hasselbalch equation for a weak base
log [B] / [BH+] = pH - pKa
When is [B] greater than [BH+]?
when pH is greater than pKa
When is [BH+] greater than [B]?
when pH is less than pKa
What is the solubility of a weak acid like in low pH?
you decrease pH by adding H+, so there will be an increased proportion of HA, which is unionised, so low solubility
What is the solubility like of a weak acid at high pH?
you increase pH by removing H+, so higher proportion of ionised form, which is highly soluble
Weak acid as salt equilibrium equation
Na+ A- + H2O <=> NaOH + HA
What is S0?
the saturation solubility of the undissociated species HA
What is Cs?
the ‘total saturation solubility’ of the weak acidic drug –> interpreted as the initial concentration of salt added to solution
What does Cs equal?
Cs = S0 + [A-]
What information do you need to predict the solubility of a weakly acidic drug?
- pH of the solution
- the pKa
- the solubility of the free (unionised) form of the drug (S0)
What is the solubility equation for a weakly acidic drug?
log (Cs-S0) / S0 = pH - pKa
When pH = pKa, what is the Cs of a weakly acidic drug?
Cs = 2 x S0
The solubility of a weakly acidic drug increase by about …. for each pH unit above the pKa
10x
The solubility of a weakly acidic drug approaches S0 as….
pH decreases below the pKa
The solubility of a weakly acidic drug equal 2 x S0 when…
the pH equals the pKa
When is a weakly basic drug more soluble?
when pH is decreased by adding H+, so there is an increased proportion of BH+, so higher solubility
When is a weakly basic drug less soluble?
when pH is increased by removing H+, so there is a smaller proportion of BH+ and higher of B, so lower solubility
Equation for weak bases forming salts
BH+ Cl- + H2O <=> B + H+ Cl- + H2O
What is Cs equal to for a weakly basic drug?
Cs = S0 + [BH+]
When pH = pKa, what is the Cs of a weakly basic drug?
2 x S0
The solubility of a weakly basic drug increases by about … for each unit of pH below the pKa
10x
The solubility of a weakly basic drug approaches S0 as…
the pH increases above the pKa
The solubility of a weakly basic drug equals 2 x S0 when…
pH = pKa
What happens to the pH of a solution when the salt of a weak acid is used instead of the free form?
the pH increases
What happens to the solubility to the salt of a weak acid instead of the free form?
solubility increases
When may the precipitation of the salt of a weak acid occur?
when pH is the solution is lowered
What happens to the pH of the solution of the salt of a weak base instead of the free form?
the pH of the solution decreases
What happens to the solubility of the salt of a weak base instead of the free form?
solubility increase
When may precipitation occur with the salt of a weakly basic drug?
if pH is increased
BCS class 1
high solubility and permeability, use simple solid oral dosage form
BCS class 2
low solubility, high permeability, need techniques to increase surface area OR use solvents or surfactants
BCS class 3
high solubility, low permeability, need to include permeability enhances
BCS class 4
low solubility and permeability, combine 2 and 3
What happens to a weak base in the GI tract?
it will have a high dissolution rate in the stomach, but this falls as the pH of the GI tract rises
What happens to a weak acid in the GI tract?
it will have minimal dissolution in the stomach as pH is so low, but it increases down the gut with pH
How does the salt of a weak acid increase the pH of the diffusion layer?
- Na+ + Cl- + H2O Na+ + OH- + HA
- Cl- reacts with water, forming -OH, increasing pH
How does the salt of a weak base decrease the pH of the diffusion layer?
- BH+ + Cl- + H2O = H2O + B + H+ + Cl-
- BH+ can donate a proton to water through H30+, which forms H2O and H+, increasing pH
What is the major advantage of using the salt form of a drug?
results in a controlled pH of the diffusion layer no matter where in the GI tract it is
When does precipitation of a drug occur?
when the pH of solution is adjusted to a value that produces mostly unionised molecules exceeding solubility
How can the solubility of non-polar compounds in water be improved?
adding water-miscible solvents in which the compound IS soluble
define co-solvent
vehicles used with water to increase the solubility of a drug
What is the purpose of cosolvents? (3)
- get aqueous systems where the drug is more soluble
- formulate higher concentrations of the drug
- improve stability of the formulation
What are the 3 factors a cosolvent needs?
- to be an organic compound
- miscible with water
- better solvent than water for the drug
How do cosolvents works?
- they decrease the hydrogen bond density of the aqueous system
- reduce the cohesive interactions of water
- reduce the polarity of the solution
How does solubility increase with increasing cosolvent concentration?
exponentially
define interfacial area
the total area of contact between two liquids in a liquid-liquid operation –> large one will prevent dissolving
How do inclusion compounds work?
by incorporating the non-polar portion of one molecule into the non-polar part of another molecule that is water soluble –> you reduce the non-polar water interfacial area by inserting the solute into the complexing agent
What is the most commonly used inclusion compouns?
cyclodextrins
What is a cyclodextrin?
an enzymatically modified starch, and their units form a cylindrical ring
What is the structure of a cyclodextrin?
the outer surface of the ring is hydrophobic and the internal surface of the cavity is non-polar
define surface tension
adhesive forces between the liquid phase of one substance and either a solid, liquid or gas phase of another surface at the interface
How do surfactants work?
they reduce the surface tension at an interface without needing large concentrations of them
To be a surfactant, what properties are needed?
- one element must have a high affinity for the solvent (hydrophilic or polar head, non-ionic or ionic)
- one element must have a minimal affinity for the solvent (lipophilic or nonpolar chain)
What must the polar region on a surfactant be able to do?
- have an affinity for water
- must be capable of pulling long-chain hydrocarbons into water
- must be polar enough to hold the nonpolar region of the surfactant in solution
How are surfactants classified?
by the charge carried by polar part: anionic, cationic, zwitterionic, non-ionic
define critical micelle concentration
the concentration of monomer (surfactant) at which micelles form
define aggregation number
the number of monomers that aggregate to form a micelle
At the critical micelle concentration, which physical properties of surfactants change?
- osmotic pressure
- turbidity
- electrical conductance
- surface tension
What factors of surfactants may increase the critical micelle concentration?
decrease the carbon chain length, increase the polarity of the head
What factors of surfactants may decrease the critical micelle concentration?
temperature, pH, a second surfactant, addition of electrolytes, longer carbon chain length
What are the 4 critical values for micelles?
- critical micelle concentration
- Kraft point (critical micelle temperature)
- cloud point
- critical micelle pH
define the Kraft point
the temperature at which the solubility becomes equal to the critical micelle concentration
What happens when temperature is less than the Kraft point?
the critical micelle concentration is greater than the solubility, so micelles can’t form
What happens when temperature is greater than the critical micelle concentration?
the surfactant forms micelles
What happens to micelles at the cloud point?
an increase in temperature leads to dehydration of POE chains, decreased water solubility and the formation of very large micelles making the solution cloudy
What happens at the critical micelle pH?
if the ionised form of a compound is surface active and the unionised form is surface inactive (or has a lower CMC than the ionised form) then a change in pH can induce micellisation
Can the polar part of a surfactant be non-ionic?
yes, for example hydroxyl and ether groups
What do surfactants do?
decrease the surface tension at the interface
What is the downside to non-ionic polar heads?
they are less polar than ionised groups, so we need more ‘units’ to produce an effective polar head
What is polyoxyethylene (POE)?
a chain with 20 or more ether groups linked to the nonpolar part
What does POE-23 lauryl ether mean?
there are 23 monomeric POE groups in this molecule
What are the applications of anionic surfactants?
oil/water emulsifiers
What are the applications of cationic surfactants?
disinfectants, oil/water emulsifers
What are the applications of non-ionic surfactants?
oil/water and water/oil emulsifiers, also have low toxicity unlike cationic and anionic
Can surfactants be used as drugs?
yes
When does micellisation occur?
when micelle concentration exceeds the CMC
define solubilisation
the process by which water-insoluble or partly soluble substances are brought into aqueous solution by incorporation into micelles
What is the solubilisation capacity (k)?
a measure of the ability of a surfactant to solubilise a solute
What is the molar solubilisation capacity (k)?
the number of moles of solute that can be solubilised by 1 mole of micellar surfactant
What are the equations for solubilisation capacity?
k = molar solubility of the solute in the micelle / molar concentration of micellar surfactants
Why is a low CMC for surfactant drugs preferred?
low CMC means that the surfactant can form micelles at a lower concentration, so when micelles are formed they can solubilise hydrophobic drugs
How can we increase the solubilisation capacity of a low polarity solute?
- increase hydrocarbon chain -> larger nonpolar regions will solubilise more solute and decreases CMC
- introduce polar group
- used branched surfactants as they form smaller micelles
What 4 factors need to be considered when selecting a surfactant?
- amount of surfactant that can be placed in water
- ability of it to solubilise the solute
- the chain length -> influences CMC
- finding a balance
What is Lundelius’ rule?
any factor that decrease the solubility of the surfactant promotes surface activity
What does a high HLB surfactant value indicate?
a surfactant with mainly polar or hydrophilic properties
What does a low HLB surfactant value indicate?
surfactant with mainly lipophilic or non-polar properties
How do you calculate the HLB of a mixture of surfactants?
HLB = x HLB(A) + (1-x) HLB(B) where x are fractions of each surfactant
define required HLB
the particular HLB of a surfactant needed to form a stable w/o or o/w emulsion
Why does HLB of an emulsifier vary with temperature?
temperature affects the relative solubilities of the lipophilic and hydrophilic parts
What happens to non-ionic surfactants at higher temperature?
hydrogen bonds are weakened by thermal forces and the emulsifier is less soluble in water
define the Phase Inversion Temperature (PIT)
the T at which an emulsifier changes from being an O/W emulsifier to a W/O emulsifier
If a non-ionic emulsifier is water soluble at low temperature, what kind is it?
it stabilises O/W emulsions
If a non-ionic emulsifier is oil soluble at high temperature, what kind is it?
it stabilises W/O emulsions
define swallowing
the passage of a food bolus from the oral cavity to the stomach
What muscles does swallowing involve?
muscles in the oral cavity, pharynx, larynx and oesophagus
What are the 3 phases of swallowing?
oral, pharyngeal, oesophageal
What are the steps of swallowing?
- stimulated when a food bolus stimulates pressure receptors in the back of the throat and larynx
- signals to the swallowing centre in the brain
- swallowing centres trigger nerve impulses
- this stimulates skeletal muscles in the pharynx and upper oesophagus
- involuntary contraction in the pharyngeal muscles pushes material into the oesophagus
What are the 2 types of movement in the stomach?
churning, peristalsis
When food is mixed, what are the stomach contents referred to as?
chyme
What does peristalsis in the stomach cause?
opening of the pyloric sphincter
What does the rate of gastric emptying depend on?
viscosity of chyme
How does movement in the stomach affect drugs?
churning is involved in dissolution and gastric emptying rate influences drug absorption
What happens to a drug if there is delayed gastric emptying?
the drug stays in the stomach and affect its stability as it is in acid for longer
What are the two types of movement in the small intestine?
segmentation (causes mixing) and peristalsis
What is peristalsis in the small intestine coordinated by?
the enteric nervous system
define segmentation
when non-adjacent segments of the small intestine alternately contract and relax, moving the food forwards then backwards
What are the steps of peristalsis in the small intestine?
- contraction of circular muscles behind food mass
- contraction of longitudinal muscles ahead of food mass
- contraction of circular muscle again forces food mass forward
What does the enteric nervous system control?
intestinal and colonic motility
What are the 2 main branches of neurones in the ENS?
Auerbach’s (myenteric) plexus and Meissner’s (submuscosal) plexus
What is the ENS influenced by?
neurotransmitters and autonomic input
How does the sympathetic NS affect the ENS?
inhibits the ENS -> decreases peristalsis, blood flow, secretion and absorption
How does the parasympathetic NS affect the ENS?
stimulates ENS -> increases peristalsis, blood flow, secretion and absorption
Which hormones increase activity of the ENS?
gastrin, motilin, serotonin, insulin, cholecystokinin
Which hormones decrease the activity of the ENS?
secretin and glucagon
How does intestinal motility affect drug absorption?
- transit time -> influences absorption
- distribution -> contractions in GI tract increase SA of drug
- migrating mobility complex -> involved in regulating drug absorption
define migrating motility complex
a recurring motility pattern that is regulated by electrical activity
When does migrating motility complex occur?
between feeding
What is the function of the migrating motility complex?
used to get rid of undigested food -> cleansing mechanism
How can the migrating motility complex affect drug administration?
if people take drug with an empty stomach, then it helps it pass through the body quickly and be absorbed quicker
What are the 2 types of motility in the large intestine?
haustral shuttling and mass movement
How does haustral shuttling work?
done by localised contraction and relaxation of haustra (bands) and occurs all the time
What is mass movement?
coordinated contraction of the intestine that moves the contents of the colon towards the rectum
Where does mass movement occur?
ascending and transverse colon
What is mass movement triggered by?
the gastrocolic reflex that signals to your body that you need to defaecate
What causes constipation?
weak mass movement, increased transit time, too much water absorbed into the body
What causes diarrhoea?
hyperactive mass movement, decreased transit time, too little water absorbed into the body
define vomiting
forcible expulsion of gastric contents through the mouth
Where are signals relayed for vomiting to?
the vomiting centre in the brainstem
What are the steps of vomiting?
- increase salivation to protect teeth
- relaxation of the lower oesophagael sphincter to allow contents to move up
- contraction of diaphragm and abdominal muscles to increase pressure in stomach
- opening of the uppoer oesophageal sphincter
mouth and oesophagus role in motility
chewing, swallowing, peristalsis
stomach role in motility
churning, peristalsis, gastric emptying
small intestine role in motility
segmental contractions, peristalsis
large intestine role in motility
haustral shuttling, mass movement, defaecation
sphincters role in motility
regulation of movement
define digestion
the sequence by which food is broken down and chemically converted so that it can be absorbed by the cells of an organism
What are the 2 types of digestion?
mechanical and chemical
What are the 4 sites of digestion?
- mouth
- stomach
- small intestine
- large intestine
What are the secretions from the salivary glands?
amylase, ligual lipase, mucus
Which type of cell secretes amylase in the salivary glands/
serous cells
What happens to amylase in the stomach?
it is inactivated due to low pH
Which cell is ligual lipase secreted from?
serous cells
What does ligual lipase do?
breaks down lipids and is NOT degraded in the stomach
Why are mucous cells in salivary glands important?
they secrete mucus to lubricate food and protect the mouth from stomach acid
What are the 4 types of cells that secrete substances in the stomach?
- parietal cells
- chief cells
- mucous cells
- G cells
What do parietal cells do?
they secrete HCl and release pepsinogen, which is cleaved to pepsin
What do chief cells do?
secrete pepsinogen also, which is cleaved to pepsin to digest proteins
What do mucous cells do?
secrete mucous for lubrication and protection of food from acid
What do G cells do?
produce gastrin
What is gastrin?
a hormone involved in regulating the release of HCl
What are the 4 main secretions from the stomach?
pepsinogen, HCl, gastrin, mucus
What is gastric acid production stimulated by?
histamine, gastrin, acetylcholine
What cells does gastric acid production involve?
parietal cells, G cells, enterochromaffin cells
What does the gallbladder do?
collects bile from the liver and concentrates it -> bile then passes through bile duct into small intestine
What does the pancreas secrete?
- bicarbonate (neutralise stomach acid)
- lipase
- amylase
- RNAase and DNAase
- trypsinogen, chymotrypsinogen
How is the digestive process initiated and controlled?
- stretch receptors in the stomach trigger secretion of digestive enzymes and juices
- the stomach releases gastrin, which causes proudction of gastric acid
- intestines release secretin and cholecystokinin to stimulate the secretion of pancreatic juice and bile
How is the small intestine adapted for absorption?
cells have projections called villi, which contain microvilli, giving a large SA
What is the route of absorption for sugar and amino acids?
absorbed directly into the bloodstream
How is absorption of fats different?
they are absorbed into the lymph lacteal system
What are the 2 main mechanisms of absorption?
active transport and facilitated diffusion
Where are proteins digested and by which enzymes?
- stomach -> pepsin
- pancreas -> trypsin and chymotrypsin
- intestinal brush border -> peptidases
How are proteins absorbed?
by active transport into the gut cells, then by diffusion into the bloodstream
Where are carbohydrates digested and by which enzymes?
- mouth -> salivary amylase
- small intestine -> pancreatic amylase
- enzymes in the intestinal brush border
Where does carbohydrate digestion stop?
in the stomach as the stomach acid denatures amylase
How are carbohydrates absorbed?
by facilitated diffusion and active transport
Where is fat digested and by which substances/enzymes?
- small intestine -> secretions from liver, pancreas and gallbladder to emulsify
- gallbladder and pancreas -> lipase and bile
How are lipids absorbed?
- lipids are broken down into fatty acids
- fatty acids absorbed into epithelial cells of small intestine
- they are coated with cholesterol, phospholipids and protein to form chylomicron
- chylomicron is water soluble and can enter the lacteal system
- transported to bloodstream
What does an enteric coating do?
prevents degradation of drugs in the stomach by protecting them from gastric acid -> allows them to be release in the small intestine
What is an enteric coating made from?
a gastric resistant polymer which is insoluble at low pH
Anatomically, how many lobes does the liver have? What are they called?
4 = left, right, caudate, quadrate
define diaphragmatic surface
the upper surface of the liver that sits underneath the diaphragm
define visceral surface
the lower surface of the liver that faces the abdominal organs and gallbladder
How is bile removed from the liver?
the bile duct feeds into the gallbladder, which joins the pancreatic duct and empties into duodenum of small intestine
What are Kupffer cells?
immune cells in the liver
What are the 3 blood vessels connected to the liver?
hepatic artery (oxygenated blood from heart), hepatic portal vein (little oxygen from GI tract), hepatic vein
What are the 6 main functions of the liver?
- endocrine function
- exocrine function
- clotting
- cholesterol metabolism
- organic and drug metabolism
- secretion of plasma proteins
What is the exocrine function of the liver?
secretes bile salts and HCO3-
What do hepatocytes secrete?
bile, cholesterol, phospholipids
What is bile made up of?
bile salts
What are bile salts important for?
solubilising fats
What is bilirubin?
byproduct of breakdown of red blood cells
What do epithelial cells secrete?
bicarbonate
What happens to bile during a meal?
the body must prepare to digest fats, to the gallbladder contracts and releases bile into the duodenum via the sphincter of Oddi
What is contraction of the gallbladder stimulated by?
cholecysotkinin which is triggered by fatty acids
define enterohepatic circulation
when the liver extracts bile salts from the blood and secretes them back into the bile to prevent having to synthesise them constantly
Where are small amounts of bile lost to?
faecas and urine
What are new bile salts synthesised from?
cholesterol
What happens to bile salts during a meal?
- bile salts are absorbed into the small intestine by Na+ coupled transporters
- most is then returned to the liver through the hepatic portal vein via enterohepatic circulation
What does dietary fibre do to cholesterol?
it conceals the bile in the small intestine to prevent it returning to the liver and it is removed from the body with the cholesterol it contains
What are the functions of cholesterol?
- membrane synthesis
- bile synthesis
- precursor for steroid hormones
Where and how is cholesterol synthesised in the body?
in the liver by HMG-CoA
How are cholesterol levels maintained in a normal range?
increasing dietary cholesterol or suppressing HMG-CoA
What do saturated fatty acids do?
increase plasma cholesterol
What do poly/monounsaturated fatty acids do?
decrease plasma cholesterol
How does cholesterol circulate in the body?
in lipoprotein complexes
What do low density lipoproteins do (LDLs)?
deliver cholesterol to cells
What do high density lipoproteins (HDLs) do?
remove cholesterol from plasma and deliver it to the liver
What is atherosclerotic disease caused by?
deposition of cholesterol in the artery walls, increasing risk of heart attack
What increases HDL?
smoking
What increases HDL?
weight loss, oestrogen (until menopause)
What are gallstones caused by?
cholesterol crystallising out of bile salts in the gallbladder
What do gallstones cause?
- they block the gallbladder and bile duct
- prevents fat digestion and causes fat build up in the gut -> diarrhoea
- decrease in absorption of fat-soluble vitamins, clotting issues and calcium deficiency
What are the endocrine functions of the liver?
- synthesis of hormones and peptides
- synthesis of plasma proteins
- synthesis of clotting factors
How is the liver important in clotting?
- bile absorbs fats, which absorb vitamin K
- vitamin K is needed for prothrombin production
- this is a precursor for thrombin
What is hepatitis caused by?
viruses or excessive alcohol intake
What is liver cirrhosis caused by?
drugs, alcohol, viruses
In liver function blood tests, what do raised levels of liver enzymes indicate?
liver damage -> most of the enzymes should be in hepatocytes, but are detected in blood
Which compounds are used in liver function tests?
- alanine transaminase (ALT)
- aspartate aminotransferase (AST)
- alkaline phosphatase (ALP)
- gamma-glutamyltransferase (GGT)
- bilirubin
- albumin
What does any raised hepatocyte enzyme indicate?
liver cell damage
What does an AST:ALT ration above 2:1 indicate?
alcoholic liver disease
What do raised levels of ALP indicate?
bone disease
What do raised levels of GGT indicate?
alcohol excess
What do raised levels of ALP and GGT indicate?
obstruction of the bile duct
define elimination
the removal of a substance or termination of its biological action
In which two ways does elimination of substances in the body occur?
- metabolism
- excretion
define anabolism
the build-up of compounds
define catabolism
breakdown of compounds
Which organs are responsible for removal of substances?
- liver
- kidneys
- lungs
What are the aims of the phase I and phase II reactions in the liver?
to decrease lipid solubility and enhance renal elimination
How do molecules reach the liver?
through the hepatic artery and portal vein
What are the steps of enterohepatic circulation?
- compounds from the liver are secreted into the bile
- most are then reabsorbed in the small intestine
- circulated back to the liver
What do liver enzymes do to lipophilic molecules?
metabolise them to form polar products so they can be excreted in the urine
What are the two stages of liver metabolism?
Phase I and Phase II
What happens in phase I to molecules?
catabolic reactions and introduction of a functional group which adds as a ‘tag’ to provide a point of conjugation for phase II
What are the main mechanisms of catabolism in phase I?
oxidation, reduction, hydrolysis
Which enzymes carry out the phase I reaction?
liver microsomal enzymes from the cytochrome P450 family (CYP enzymes)
What type of molecule does liver metabolism deal with? Why?
mainly applicable to lipid soluble molecules as polar molecules can be excreted at least partly unchanged
How does cytochrome P450 enzymes differ?
they have different..
1. amino acid sequences
2. substrate specificity
3. susceptibility to inducers and inhibitors
define polymorphic form (enzymes)
an enzyme that exist in multiple different forms within the same species
What determines your cytochrome P450 enzymes?
different alleles in your genes -> different amino acid sequences
What does an individuals cytochrome P450 enzymes affect?
the rate of activity of the enzymes, therefore creates differences in side effects and drug response
What happens in phase II?
anabolism and involves the addition of a subtituent group to inactive the compound
What are examples of substituent groups added?
glucuronyl, sulphate, methyl, acetyl
What happens to the product after phase II?
several hydrophilic products are secreted into the bile and delivered to the small intestine where the conjugation and the drug is reabsorbed
What different processes do different enantiomers undergo?
- different pharmacological effects on receptors
- they are metabolised differently
What are the steps of pre-systemic first-pass metabolism?
- food and drugs are absorbed into small intestine and pass into the blood
- the blood is carried to the liver by the hepatic portal vein
- so hepatic microsomal enzymes can metabolise food or drugs before entering systemic circulation
For drugs administered by IV, is a higher or lower dose needed?
lower –> as there is no initial metabolism as drug goes straight into systemic circulation
For patients with less GI motility, is a higher or lower dose needed?
high dose as less absorption of drug into bloodstream
For patients with decreased liver function, is a higher or lower dose needed?
lower as there is less metabolism of the drug and metabolites may be toxic
define prodrug
a drug that is inactive when administered and is only activated when it is metabolised
define single nucleotide polymorphism
a DNA sequence variation with a different single nucleotide at a particular locus
What are the effects of SNPs on CYP450 enzymes?
the different nucleotide sequence may change the amino acid sequence
What do different polymorphic forms of enzymes lead to?
different rates of enzymatic activity and metabolism
fast metaboliser and active drug
higher dose needed
fast metaboliser and prodrug
lower dose needed as increased risk of toxic effect as fast activation
slow metabolisers and active drug
lower dose needed as metabolised slower -> may be toxic
slow metabolisers and prodrug
higher dose needed as prodrug will not be active for long
How are CYP450 profiles of patients roughly determined?
start patients on a low dose of the drug and take blood samples to find the amount of active drug in the blood and increase from there
Do CYP450 inducers make drugs work faster or slower?
faster as they increase the activity of the enzymes so drug is broken down and cleared quicker
What are 3 inducers of CYP450 enzymes?
brussel sprouts, smoking, St John’s Wort
What is an inhibitor of CYP450 enzymes?
grapefruit juice
How do co-administered drugs affect each other?
many drugs can compete as substrates for CYP450 enzymes so affect the metabolism of each other
What do CYP450 enzyme inducers do?
increased the activity of the enzymes, so increase rate of metabolism
What are the drawbacks of enzyme inducers?
- a single co-administered drug may be metabolised too quick reducing its effect
- toxic metabolites will increase
What 3 main factors affect CYP450 enzymes?
genetic polymorphisms, diet and co-administered drugs
What are the 5 main functions of the kidneys?
- regulation of water, salts, acidity
- removal of metabolic waste
- removal of foreign chemicals e.g. drugs
- gluconeogenesis
- production of hormones and enzymes
Name 2 enzymes the kidneys produce
erythropoietin (controls RBC production and renin (controls blood pressure and Na+ balance)
What are the 4 regions of the kidney?
- capsule -> boundary separating it
- cortex -> outer region where nephrons sit
- medulla -> inner region
- pelvis -> feeds into the ureter
What happens in the Bowman’s capsule?
blood is filtered
What happens in the loop of Henle?
main site of water reabsorption
What are the 3 stages of nephron function and filtering by the kidneys?
- glomerular function
- tubular function
- tubular reabsorption
define tubular secretion
the process by which the kidneys move substances from the blood into the tubules
define tubular rebabsorption
the process by which the kidneys remove water and solutes from the filtrate and return them to the bloodstream
How does the structure of the glomerulus allow for much filtration to happen?
the vessel is ‘bunched up’, so blood spends a long time within the vessel inside the Bowman’s capsule
How are cells in the glomerulus adapted?
the endothelial cells have tiny pores, so are leaky
define podocyte
specialised cells on the outside of the glomerular capillary with many small projections to create sieve like structure
define glomerular filtration rate
the volume of fluid filtered from the glomeruli to the Bowman’s capsule per unit of time
How is the GFR regulated?
by the body adjusting the blood pressure on either side of the glomerulus
How is the glomerular filtration rate reduced?
constrict the afferent arteriole or dilate the efferent arteriole to reduce pressure
How is the glomerular filtration rate increased?
dilate the afferent arteriole or constrict the efferent arteriole to increase the pressure -> increases the excretion of water and salt
Where is Na+ (salt) reabsorbed?
- proximal convoluted tubule
- loop of Henle
- the collecting duct
Which regions does salt go through to be reabsorbed into the blood?
tubule fluid -> tubule cell -> interstitial space -> blood
How does reabsorption of Na+ from the tubule fluid to tubule cells occur (proximal convoluted tubule)?
via cotransporters and counter-transporters
define cotransporter
a membrane protein that moves two different molecules or ions across a cell membrane at the same time in the same direction
define counter-transporter
a membrane protein that moves two or more molecules in opposite directions across a cell membrane
What is the main counter-transporter found at this stage?
Na+ pumped into cell, H+ pumped out
How does rebabsorption of Na+ from the tubule cells to interstitial space occur (proximal convoluted tubule)?
active transport by Na+/K+ ATPase
What is Na+/K+ ATPase?
Na+/K+-ATPase pumps three sodium ions out of the cell into interstitial space and two potassium ions into cell -> Na K pump
How are K+ ions returned to interstitial space (proximal convoluted tubule)?
active transport into cell creates K+ concentration gradient, so they diffuse through K+ channels back into interstitial space
How is Na+ moved from the tubule fluid into tubule cells in the ascending loop of Henle?
using a cotransporter, Na-K-Cl transporter (NKCC)
How does Na-K-Cl transporter work?
Na+ is pumped into tubule cells through contransport with Cl- and K+
How is K+ returned to the tubule fluid?
eventually K+ has a high concentration in the cell and diffuses back into tubule fluid -> this keeps the transporter moving
How does Na+ move from tubule cells to interstitial fluid in the ascending loop of Henle?
Na+/K+ ATPase
How does Na+ move from the tubule fluid into the tubule cells in the collecting ducts?
diffusion
How does Na+ move from the tubule cells to the interstitial space in the collecting ducts?
Na+K+ ATPase moves Na+ into interstitial space and K+ back into cells
What is the hormone that controls rebabsorption of Na+?
aldosterone
What type of hormone is aldosterone?
a steroid hormone
How does aldosterone work?
it changes the number of ion channels and Na+K+ ATPase transporters to change how much salt is moved across
How long does aldosterone take to work?
hours as it is a steroid hormone
Where does water reabsorption occur?
DESCENDING loop of Henle and the collecting ducts
How does water move into the interstitial space in the descending loop of Henle?
- the descending loop is permeable to water, so it can freely move into the interstitial space
- reabsorbtion of salt occurs at the ascending loop, so creates a hypertonic solution (high salt concentration) in the interstitial fluid surrounding the loop of Henle
- this causes water to diffuse out of the descending loop of Henle by osmosis
How does countercurrent flow work in the loop of Henle?
- blood flow around the loop of Henle is counter to flow through the loop of Henle
- the freshly filtered blood (low in salt) goes next to ascending LOH first, encouraging salt reabsorption
- the salt-rich blood circulates around descending loop
- so water is reabsorbed into the blood
- maintains concentration gradient
How is water absorbed into the collecting ducts?
diffusion through aquaporins as the interstitial space will be full of salt from Na+ reabsorption
Which hormone controls water re-absorption?
vasopressin
What type of hormone is vasopressin?
a protein that acts on g protein-coupled receptord
How does vasopressin work?
causes vesicles with aquaporins to fuse with plasma membrane of tubule cells, increasing water reabsorption
Why is the action of vasopressin much quicker than aldosterone?
vasopressin has aquaporins already made in vesicles, aldosterone involves making more transporters
What are the 3 functions of the nephron?
glomerular filtration, tubular secretion, tubular rebabsorption
What is the equation for ‘amount excreted’ from the kidneys?
amount excreted = (amount filtered + amount secreted) - amount reabsorbed
How do the kidneys regulate body pH?
the kidneys regulate HCO3- levels, therefore regulate pH
Equation for carbonic acid
CO2+ H2O -> H2CO3 -> HCO3- + H+
How do the kidneys make sure net gain/loss of carbonate is 0?
- carbonate is freely filtered into tubules from the blood
- carbonic acid made in tubule cells breaks down into H+ and HCO3-
- the H+ is transported to the tubules, where it combines with filtered HCO3- to form carbonic acid and break down into CO2 and H2O
- the HCO3- from the tubule cells is reabsorbed into blood
- HCO3- reabsorbed into the blood replaces that filtered, so NO net loss or gain
Which 2 ways do the kidneys increase HCO3- levels?
H+ secretion and glutamine metabolism
How does H+ secretion increase HCO3- levels?
- carbonic acid in tubule cells breaks down into H+ and HCO3-
- H+ moves into tubule and combines with filtered phosphate instead of carbonate and is excreted
- HCO3- is transporter into bloodstream
- increased of HCO3-
How does glutamine metabolism increase HCO3- levels?
- the amino acid glutamin enters tubule cells either from the blood or filtrate
- it is metabolised to NH4+ and HCO3-
- ammonia is secreted into the tubules to be excreted
- HCO3- is transported into the body
- net gain of HCO3-
define acidosis
when the body gains hydrogen ions and pH decreases becoming more acidic
define alkalosis
when the body loses hydrogen ions and pH increases becoming more alkali
How does the body respond to acidosis?
- lots of H+ is secreted into the tubules as there is too much in the body
- H+ ions react with filtered HCO3- and H2PO4- to cause reabsorption
- glutamine metabolism is increased to generate more HCO3- to react with H+
How does the body response to alkalosis?
- less H+ entering the tubules
- H+ secretion into tubules cannot keep up with filtered HCO3-
- so excess HCO3- will be excreted to lose carbonate, allowing H+ to increase and lower the body’s pH
- glutamine metabolism is decreased to reduce HCO3- generation so there are more H+ ions around
How does urine play a role in drug excretion?
- in alkaline urine, acidic drugs will be ionised
- in acidic urine, alkaline drugs will be ionised
- ionised drugs are less likely to be reabsorbed, so more is excreted
How is aspirin poisoning treated?
- patient is given an IV infusion of sodium bicarbonate, increasing pH of the urine
- the active metabolite salicylic acid becomes ionised, reducing its rebabsorption
- aspirin is excreted quicker, lowering the plasma concentration
define bioavailability
a measure of the amount of drug that reaches its site of action AND the rate at which it gets there
define pharmacokinetics
what the body does to the drug
define pharmacodynamics
what the drug does to the body
define extravascular administration
not injecting into the blood e.g. tablet
What two steps does a drug need to achieve after administration to get into the systemic circulation?
- release
- absorption
define release
the drug dissolving at the administration site
define absorption
the drug crossing the biomembrane to reach the blood
What are the 2 steps of dissolution of a solid crystal in a liquid?
- solvation of the drug at the crystal surface to create a stagnant layer of saturated solution –> called the diffusion layer
- diffusion of the dissolved molecules across the diffusion layer into the bulk solution
Which equations gives the overall rate of dissolution at constant temperature?
Noyes-Whitney equation
Which 3 factors can be used to predict the solubility of a weakly acidic or basic drugs?
pH of solution, pKa, solubility of the unionised form (S0)
What are the 3 methods of membrane transport in the transcellular pathway?
- passive diffusion
- aqueous pore
- facilitated diffusion
- active transport
What is the equation used to calculate flux (diffusion)?
J= C x v x A
What does Fick’s 1st law describe?
rate of passive transport
What are the membrane properties affecting passive transport?
membrane thickness (h) and membrane area (A)
What are the drug properties affecting passive transport?
concentration gradient (C1-C2) and partition coefficient (K)
What are the drug and membrane properties affecting passive transport?
diffusivity (D)
What is used to give a drug’s lipophilicity?
LogP
drug that is 10x more lipid soluble than water soluble…
P=10
LogP=1
drug that is 100x more lipid soluble than water soluble…
P=100
LogP= 2
drug that is 5x more lipid soluble than water soluble…
P= 0.2
LogP= -0.7
What does Lipinski’s rule of 5 predict?
whether a drug will have good oral bioavailability
What are Lipinski’s 5 rules?
- molecular weight is less than 500
- LogP is less than/equal to 5
- no more than 5 hydrogen bond donors
- no more than 10 hydrogen bond acceptors
- all units are multiples of 5
define therapeutic window
the area of concentration of drug on a graph to have the efficacy needed
Why is insulin administered by subcutaneous injection?
pepsin degrades polypeptides in the stomach, do cannot be administered orally
What is the order of the rate of the stomach gradually releasing its contents into the small intestine?
zero order
What is the order of the rate of the stomach gradually releasing its contents into the small intestine if in a fasted state?
first order
What are 8 factors that affect gastric emptying and therefore drug absorption?
- meal volume
- type of meal
- physical state of stomach contents
- chemicals
- drugs
- body position
- disease
- exercise
How does meal volume affect gastric emptying?
the larger the meal, the quicker the INITIAL gastric emptying
How does the type of meal affect gastric emptying?
fatty acids, triglycerides, carbohydrates and amino acids all reduce gastric emptying rate
How does physical state of stomach contents affect gastric emptying?
solutions or suspensions of small particles empty quicker than chunks of material
How do chemicals affect gastric emptying?
- acids reduce emptying rate
- alkalis increase emptying rate at low concentrations and increase it at higher concentrations
How do drugs affect gastric emptying?
drugs including anticholinergics, narcotics, ethanol all reduce emptying rate
How does body position affect gastric emptying?
lying on the left side reduces emptying rate
How does disease affect gastric emptying?
emptying rate is reduced by the presence of ulcers and in some diabetics
How does exercise affect gastric emptying?
vigorous exercise reduces emptying rate
How does gastric emptying time affect drug absorption?
the longer the gastric emptying time, the longer it will take for the drug to appear in the systemic circulation
What is one way membrane permeability can be increased?
using prodrugs
How can using prodrugs increase membrane permeability?
can use a prodrug with high permeability, and after crossing the membrane, there are enzymes which convert the drug into its active form
How may the stomach degrade drugs?
HCl= degrades some, so gastro-resistant coatings are needed
Pepsin= digestive protease destroys polypeptide drugs
How may drugs be degraded in the duodenum?
Trypin, chymotrypsin, elastase, carboxypeptidase A and B degrade many large proteins
How may drugs be degraded in the small intestine?
Cytochrome P450 enzymes
Esterases
Glucuronosyl transferases transfer glucuronic acid to nucleophilic sites on drugs
How may drugs be degraded in the colon?
gut flora can metabolise and inactive drugs
What is the hepatic first pass effect?
- drug passes intestinal membrane into systemic circulation
- drug is transport to liver via hepatic portal vein
- some drug is metabolised
- reduces bioavailability of the drug
What are the 4 processes of transportation of drugs across the GI membrane?
paracellular transport, diffusion, facilitated diffusion, drug transporters
define efflux protein
a cellular protein that can prevent intracellular accumulation of drug by pumping the drug that enters the cell immediately back out
How can P-glycoprotein inhibitors help with cancer treatment?
- P-glycoprotein is an efflux protein that prevents chemotherapeutic drugs entering cancerous cells
- also prevents oral delivery due to presence in intestinal epithelial cells
- co-administration prevents drug efflux
What are the 4 types of absorption rates for oral dosage forms?
- rapid release
- delayed release
- slow release (zero order kinetics)
- slow release (1st order kinetics)
What are the characteristics of delayed absorption on a graph?
delayed and fast absorption have the same Cmax values but different Tmax due to a large lag time
What does the amount of a first order absorption drug absorbed per unit depend on?
concentration of drug at the site of absorption
What are examples of diseases treated by topical delivery to the mouth?
ulcers, fungal infections, periodontal disease
What is different about oral dosage forms and dosage forms that cross membranes in the mouth?
crossing membranes in the mouth allows them to bypass the GI tract, so they avoid hepatic first-pass
define sublingual
under the tongue
define buccal
via the epithelia that line the cheek
What is the name given to the lining of the mouth?
the oral mucosa
What is the structure of the oral mucosa?
- squamous epithlial cells
- layers of basal, intermediate, superficial cells
- lipophilic membrane-coating cells
- lamin propia underneath basement membrane contains blood vessels, so it where drug must reach
How do drugs absorb via the transcellular pathway in the oral epithelia?
- good for small, lipophilic drugs
- occurs by passive diffusion
- depends on epithelial thickness
- rate of absorption is therefore determined by Fick’s 1st law
How do drugs absorb via the paracellular pathway in the oral epithelia?
- good for small, hydrophilic drugs
- involved intracellular lipid molecules (MCGs) from the membrane-coating granules
- also depends on epithelial thickness
What are the 2 main factors affecting drug absorption in the mouth?
saliva and mucus, blood supply to the mouth
How does saliva affect drug absorption via the mouth?
- aids absorption by solubilising drug, but can hinder it by saliva washout
- enzymes in the mouth may break down drugs
How does mucus affect drug absorption via the mouth?
it is a physical AND chemical barrier as it is thick
How does blood supply affect drug absorption via the mouth?
- very good blood flow which is good for absorption
- avoids hepatic first pass metabolism
What are the advantages of buccal and sublingual drug absorption?
- rich blood supply
- avoids hepatic first-pass
- low metabolism
What are the disadvantages of buccal and sublingual drug absorption?
- high MW drugs must be potent
- saliva and mucus can impact absorption
- development costs
give examples of patients who the rectal route of drug administration would be beneficial for
- unconscious patients
- children
- vomiting
- upper GI tract disease
- drugs that are much degraded via oral delivery
What are examples of rectal dosage forms?
tablet, capsules, suppositories, ointments, creams, gels, solution, emulsions, suspension
What is the structure of the rectum?
- makes up last part of the colon
- upper and lower regions
- no villi
- normally empty
- small amount of mucus
- epithelium is one cell thick
What are the two routes of drug absorption in the rectum?
transcellular and paracellular - MOSTLY transcellular
How is the rectal route a possible route for protein delivery?
there is no esterase or peptidase activity
Why must you be cautious on where in the rectum a drug is administered?
- blood vessels may reach systemic circulation in upper region
- superior vein in upper region will empty into hepatic portal vein -> hepatic first pass
- inferior and middle veins go into systemic circulation in lower region, so avoid this
Why is diazepam gel administered rectally?
- it is highly metabolised to desmethyldiazepam in the liver by CYP450 enzymes
- this is an active metabolite
- avoids metabolism and is used to manage seizures in refractory epileptic patients
What are the advantages of rectal administration?
- avoids degradation in GI tract
- avoids hepatic first pass
- potential for extended absorption
- good alternative when oral delivery is not possible
- potential for protein delivery!
define enteral
via the intestine, opposite to parenteral
define parenteral
anything administered other than through the digestive tract e.g injections
define ‘other routes’
delivery directly to a site of action for a localised effect e.g. topical
intradermal injection
into the epidermis
intramuscular injection
into the muscle
intravenous injection
into the vein
subcutaneous injection
into the subcutaneous tissue
intramedullary injection
into the bone marrow
What are the advantages of intravenous drug delivery?
- drug administered to site of action rapidly
- precise dosing
- 100% ‘bioavailability’
What are the disadvantages of intravenous drug delivery?
- needs suitable vein
- professional is required
- higher cost
- potential toxicity as concentration rises very quickly
How are drugs administered by subcutaneous injection?
drug passively diffuses into the capillaries or lymphatics
What are the advantages of subcutaneous delivery?
- slow and sustained
- self-administration is possible
- implants can give long-term delivery
What are the disadvantages of subcutaneous drug delivery?
- small doses must be used
- irritation from repeated injections
What is nasal drug delivery used for?
topical treatment for allergies, congestion and infection
Why is nasal drug delivery better than oral?
- avoids hepatic first pass
- the drug may be sensitive to enzymes
- acid-sensitive drugs
- poor oral absorption if a polar compound
What is the structure of the nasal epithelium?
- microvilli so large SA
- protective layer of mucus and cilia
- a pseudo-stratified epithelium
Why is the olfactory region a good potential target for drug delivery?
it is an area where the blood brain barrier is not present, so the drug can go straight from the olfactory region to the brain
How can drugs enter the brain from the olfactory region?
by paracellular diffusion or axonal transport through the olfactory nerves
What is ocular drug delivery used for?
ONLY for treatment of local conditions as NOT a goof route for systemic delivery
What is used to treat diseases at the BACK of the eye?
intraocular delivery as it is very difficult to reach
What is the main route of drug absorption at the front of the eye?
the corneal route -> either by paracellular or transcellular diffusion
What is the conjunctival route?
when the drug passes through the conjunctiva and sclera, but most of the drug will be lost into the capillary bed and enter systemic circulation
What are the issues associated with drugs delivered to the front of the eye?
- tear ducts allow a good drainage and defence system
- much of drug is lost to nasolacrimal drainage and goes down the back of the throat
Which factors affect drug absorption in vaginal delivery?
pH
When does pH in the vagina change?
- with age
- depending on time in the menstrual cycle
Why does pH change during the menstrual cycle?
thick epithelium before menstruation with lots of glycogen, which is broken down into lactic acid
Why is pH change in the vagina an issue?
the drug may be ionised, so it less likely to be absorbed over the membrane
What are the issues with pulmonary drug delivery?
defence mechanisms clear waste
What is the main issue with transdermal delivery?
the skin is a good barrier
What is the main barrier in the skin?
the stratum corneum
What is the structure of the stratum corneum?
- brick structure made of dead, flattened cells
- the inside of the membrane is protein-coated
- there are lipid rafts between cells making a lipophilic layer
What are factors affecting transdermal drug absorption?
- hydration of the stratum corneum -> patches are occlusive so water builds up
- pH
- age -> babies and elderly have weaker skin
What are two methods in increasing skin permeability for drug absorption?
iontophoresis and microneedles
What is iontophoresis?
a device in which the electrical field increases the permeability of the skin, allowing molecules to be transported across the stratum corneum
How do microneedles work?
they are inserted into the skin to create microchannels in the skin’s outermost layer, the stratum corneum, which allows for the transport of drugs and other substances
