ADME Flashcards
What do drugs that are poorly absorbed tend to have?
More than 5 H-bond donors
More than 10 H-bond acceptors
Their molecular weight less than 500
Their calculated log P less than 5
What must a drug be in order to be absorbed?
Solubilized
What is solubilization?
Something it is moving from being a solid to being a solvated molecule.
What factor affects solubilization?
The hydrophilicity of the drug determines whether it is solubilized.
If the drug is ionized or not
Explain how hydrophilicity affects solubilization?
Drugs that are hydrophilic are more likely to dissolve in polar mediums, for example water.
Hydrophobic drugs are less soluble in water.
How does ionization affect solubilization?
If the drug becomes ionized, it accumulates charge and charge promotes solvation by water. Charge could come from an amine or carboxylic acid.
The protonation of these functional groups depends on the pH of the medium.
If a solution is made more acidic, amines are likely to be protonated and gain charge. Whereas, carboxylic acids are going to lose charge.
Explain flat drugs?
Flat drugs tend to stack up against each other
Flat drugs tend to be less soluble than drugs that have got a non-planar structure.
What is Thermodynamic solubility?
How soluble a drug is, if you leave it in solution and allow it to come to equilibrium
What is Kinetic solubility?
how quickly a drug dissolves in solution.
Explain Pinocytosis?
The cell membrane invaginates and forms a vesicle, that traps the drug inside the cell. So the membrane folds in upon itself and captures the drug, allowing the drug to be incorporated into the cell that way.
Explain Paracellular?
The drug moves between cells.
Some cells have a very tight junction between them, others have less tight junctions.
Paracellular is between different cells.
Explain Liquid diffusion?
Drugs moves across a cell membrane directly, they diffuse across the lipid.
The membrane is hydrophobic so drug must have certain hydrophobic nature
Explain Aquaporin?
Aquaporin takes up water, so some drugs may take that channel
But drugs must be quite small, as the channel is quite small.
Explain carrier?
They are primarily proteins.
This can be an active or passive process.
What is paracellular diffusion?
Diffusion, between cells.
What is passive diffusion through the lipid?
A drug moving passively through the bilayer
What does Fick’s law do?
Describes the flux of drugs across the membrane; how many drug molecules (or moles of drugs) are moving across the membrane, by unit time.
What is the equation for flux across membrane?
(C1 – C2) X Area X Permeability/ thickness
Explain factors affecting flux across the membrane?
If the concentration gradient is large, there’s going to be a larger flux of drugs across the membrane
If the concentration gradient is small, there’s going to be a smaller flux of drugs across the membrane.
The larger the area, the greater the total flux across the membrane, due to more opportunity for the drug to get across.
If the membrane is very thick, it will reduce the total flux across the membrane.
What is permeability?
The ability of the drug to move across the membrane.
What factors affect permeability?
The solubility of the drug in the lipid itself – how well the drug is solvated by the lipid.
If the drug molecule is charged (ionization depends upon pH), it is less likely to be permeable in a lipid environment.
Lipophilicity promotes permeability.
Charge demotes permeability.
The mobility of the drug in the lipid – how well the drug can diffuse in the lipid bilayer itself.
Molecular mass of the drug – Large drugs tend to be less permeable in bilayers.
Explain how lipophilicity affects permeability?
Drugs which are lipophilic have a high membrane permeability; they are more permeable across the lipid bilayer.
Where do drugs that have a high lipid solubility usually stay?
Drugs that have a high lipid solubility tend to accumulate more in the bilayer. Because the drugs with a high lipid solubility is more readily dissolved in the lipid bilayer, so it accumulates there.
So it tend to be in the lipid bilayer than in the aqueous compartments on either side of it.
Explain how absorption is controlled by both polarity and lipophilicity?
Drugs need to be soluble, in order to be absorbed.
Polar drugs are more soluble
Drugs need to be permeable in order to be absorbed as well.
Lipophilic drugs are more permeable
If you increase polarity too much, you decrease lipophilicity; there is a conflict between the two. So a comprise needs to be made.
What is the equation for Maximum absorption dose?
S x Ka x Tsi x Vsi
S = solubility
Ka = rate constant for absorption across the mebrane
Tsi = transit time through the small intestine
Vsi = Volume of small intestine
Explain factors affecting maximum abosorption dose?
The longer the drug is in the small intestine, the greater the chance it has of being absorbed. Increased residence time in the small intestine, promotes drug absorption.
The larger the volume of the small intestine, the larger the amount of drug that can fit in the small intestine, which increases the maximum amount that can be absorbed.
Explain the pH partition hypothesis?
This suggest that if a molecule is not charged ( not ionized), it has a higher chance of moving across the membrane, than molecules that are charged.
Charge is regulated by pH.
What is the pH in the body?
The stomach is acidic and the GI tract is more alkaline.
Explain what happens in an alkaline enivronment?
The carboxylic group has its proton stripped off it. Resulting in a negative charge on the molecule (this is what happens to acids)
For amines, it results in it being uncharged (this is what happens to bases)
Explain what happens in an acidic environment?
The environment protonates the carboxyl group. So the group is not charged as a result (this is what happens to acids)
For amines, it is protonated and it gets a positive charge (this is what happens to bases)
Explain Carrier-mediated transport?
They are usually proteins that sit inside the cell membranes.
They facilitate the movement of drugs from one side of the membrane to the other.
So affects the absorption of the drug.
Can be active or passive
Explain how drug concentration affects carrier mediated transport?
If the drug concentration is high, all the transport proteins can become saturated (full of the drugs).
So as you increase drug concentration, you can saturate transport.
This is non-linear pharmacokinetics.
What are the factors effecting gastrointestinal absorption?
- Surface area
- pH
- Permeability and solubility transit time
- Binding to other material in GI tract
- Gastric emptying
- Efflux pumps in membrane of GI tract
- Metabolism
Explain how surface area affects gastrointestinal absorption?
The stomach has a small surface area.
The small intestine has a large surface area due to having microvilli.
Large amounts of drugs are absorbed from the small intestine
How does pH affects gastrointestinal absorption?
The pH varies along the GI tract.
It is acidic in the stomach and becomes more alkaline as you move down the tract.
Depending on the drug property, the drug can either be protonated or deprotonated and become charged or not.
If they are not charged, they can move down across membranes but if charged they are less likely to move across.
So pH affects charge.
PH can cause drug hydrolysis in the stomach.
Explain how gastric emptying affects gastrointestinal absorption?
Emptying the stomach speeds the passage to the small intestine and therefore favours absorption.
Explain the how pyloric sphincter affects absorption?
The pyloric sphincter opens and closes to control the passage of food and drugs, from the stomach into the small intestine.
If sphincter is closed, it prevents the drug from getting into the small intestine and so prevents the drug from being absorbed.
Explain what happens when you take drugs with a meal and without a meal?
If drug is taken with a meal, it will close the sphincter and delay the drug getting into the small intestine, and therefore delays the absorption.
So taking drugs on an empty stomach, usually increases the rate at which the drug can progress through the small intestine, and speeds up absorption.
What is an advantage of a delay in gastric emptying?
If a drug dissolves quite slowly, a delay would be good. The delay provides more time for dissolution.
Explain how metabolism affects gastrointestinal absorption?
The metabolism of the drug in the GI tract itself.
In the walls of the GI tract, there are enzymes that catalyse the metabolism of certain drugs eg. Cytochrome P450, Monoamine oxidase.
If the drug gets metabolised before it gets absorbed, it means there is less drug available to get absorbed. So the total amount of drug that can get absorbed is reduced.
Explain how grapefruit affects absorption?
Grapefruit juice can inhibits cyp34A. Cyp3A4 metabolises certain drug, so if grapefruit juice is taken, there will be larger amounts of drugs, as cyp3A4 is no longer working properly.
Explain how efflux pumps in membrane of GI tract affects gastrointestinal absorption?
P glycoprotein – prevent absorption of drugs from GI tract. Once drug diffuses across Epithelium layer, it may be able to pump the drug back out, straight into the GI tract. Meaning the drug doesn’t get absorbed into the systemic circulation.
Factors affecting absorption from Intramuscular and subcutaneous sites ?
Capillary endothelium is more permeable than GI epithelium. So easier transit to blood or lymphatic system.
Local blood flow is major factor.
Explain unbound drugs?
Only unbound drugs can move between compartments.
What prevents access to the CNS?
Blood-brain barrier restricts access to CNS.
It prevents water-soluble drugs from reaching the CNS.
What limits rate of distribution?
Perfusion and permeability.
Explain Permeability limited drugs?
Membranes present a barrier
These drugs don’t cross the membrane readily so blood flow doesn’t really affect it.
The permeability of the membrane controls It instead.
Explain Perfusion limited drugs?
The membranes don’t present much of a barrier so lipophilic drugs can usually just get through.
Blood flow limits their drug distribution to tissue.
Drug accumulation is favoured in tissues that have a better blood supply.
What are the two classic plasma proteins?
The two classic plasma proteins are:
Serum albumin (mostly binds to acidic drugs)
a-acid glycoprotein (mostly binds to basic drugs).
Explain how protein binding affects distribution?
Binding to a protein can limit its distribution because when it creates a complex with the protein, the drug can no longer bind to its targets receptor.
So can no longer have its pharmacodynamics effect.
Is drug binding to a protein reversible or irreversible?
Reversible
What kind of drug exerts a pharmacodynamic effect?
Unbound drugs as they can move between different compartments and exert a pharmacodynamic effect.
Explain why rate of dissociation is important?
When there is a rapid dissociation, the drug is basically still available. But a slow dissociation or an irreversible dissociation is equivalent to elimination.
Explain one compartment model?
all the tissues in the body behave as one compartment. The drug can diffuse into ‘all’ the tissues at the same rate.
It can easily get into the compartments at the same rate; and drug is eliminated from that one compartment.
Compartments could be plasma, muscle tissues.
What is Metabolism?
It is a chemical change that is catalysed by metabolic processes in the body and it may or may not alter the pharmacological activity of the drug.
What is phase 1 metabolism?
Conversion to more reactive form to allow conjugation
Phase 1 makes the drug more reactive so that in phase two, hydrophilic molecules can be conjugated and make the drug more soluble.
What is phase 2 metabolism?
Conjugation with another biomolecule to increase solubility to allow excretion.
Metabolism: phase 1?
Oxidation and Reduction reactions occur
One of the Cytochrome contains a haem group and Fe2+/3+ which undergoes a redox reaction; this allows the enzymes to catalyse the redox reaction on the drugs.
One isoform cytochrome can oxidize several different drugs and may have overlapping specificities.
Alcohol dehydrogenase and mono-amine oxidase can take part aswell.
What does Carboxylesterase do?
converts an ester into the acid and the alcohol, making it more reactive
What do Dehydrogenases and oxidases do?
Oxides molecules
What do reductases do?
Reduces molecules
Metabolism: Phase 2?
The phase in which a hydrophilic group gets conjugated to the drug molecule to increase its solubility.
Hydrophilic groups includes glucuronic acid, glutathione, sulfate.
What can biotransformation do?
Render a drug more reactive; aids in conjugation
What is excretion?
The irreversible removal of drug from the body
Via: Urine, bile, sweat, exhaled breath, milk
What is Biliary Excretion?
Active excretion from the liver via the bile duct.
What are the processes involved in renal excretion?
Filtration in renal corpuscle
Active secretion in the tubule - Active transport with non-specific transporters. Only non-bound drugs can undergo active transport
Reabsorption in the tubule - lipophilic drugs are easily absorbed across the membrane
What are the advantages of making the drug more polar during metabolism?
Polar drugs are less likely to bind to serum binding proteins, so there’s an increased concentration of the free drug.
Making the drug more polar, by adding hydrophilic groups, also inhibits tubule reabsorption
What is the equation for renal excretion?
Glomerular filtration + Tubular secretion – Tubular reabsorption
The rate at which a drug undergoes renal excretion = the rate at which the drug is filtered + the rate of which the drug is secreted into the kidney tubule - the rate at which the drug is reabsorbed back into the capillaries.
