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Pharmacology > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

what is pharmacokinetics?

A

what the body does to a drug:
- dose and frequency of administration must be within therapeutic window

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2
Q

what do drug effects depend on?

A
  1. pharmacodynamics
  2. pharmacokinetics (ADME): absorption, distribution, metabolism, excretion
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3
Q

what is pharmacodynamics?

A

mechanism of action and effects on cellular functions (protein targets)
- physicochemical properties of the drug affect affinity, efficacy and potency

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4
Q

how is a drug distributed in the body?

A

by bulk flow transfer through the bloodstream
- drug is carried in the plasma
- physicochemical properties of the drug does not impact bulk flow

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5
Q

what does the absorption of a drug depend on?

A

the physicochemical properties of that drug:
- properties of drug impacts on how the drug enters plasma in the first place
- movement of drugs between compartments involves penetration of lipid diffusion barriers
- this determines where and for how long a drug is present in the body after administration

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6
Q

what 2 factors affect drug absorption?

A
  1. size of drug: diffusion coefficient (1/sqrt(molecular weight))
    - large molecules will have greater difficulty crossing plasma membrane
    - the larger the molecular weight, the slower the diffusion
  2. polarity
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7
Q

what are the 4 main mechanisms in which drugs can cross plasma membranes?

A
  1. diffusion through lipid: if drug is charged, it will be repelled
  2. diffusion through aqueous ion channel
    - only small drugs fit through
  3. carriers: allows large molecules to pass
    - highly specific
  4. pinocytosis: bulk uptake where membrane invaginates and traps molecules in ECF
    - transcytosis: internalised vesicle releases drug into cell
    - useful for large proteins e.g. insulin
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8
Q

what is the partition coefficient?

A
  • determines the lipid solubility of a drug: how readily a molecule dissolves in water vs oil
  • the more a molecule is soluble in lipids, the more easily it can enter the plasma membrane
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9
Q

what is the diffusion coefficient?

A
  • determines diffusivity of a drug
  • inversely related to the molecular weight of the molecule
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10
Q

how does the lipid solubility of a drug determine its passing through the plasma membrane?

A
  • non-polar molecules dissolve freely in lipids and can pass through membrane freely compared ton polar
  • the more lipophilic the drug, the more it readily diffuses into tissues
  • the more lipid soluble a drug is, the increased rate of absorption from gut, increased penetration into brain and tissues, increased renal eliminaton
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11
Q

how does pH and ionisation determine drug absorption into the plasma?

A

weak acids can dissociate into free H+ ion and an anion in aqueous solution:
- in acid environment, there is excess H+, so equilibrium favours associated form of weak acid
- in base environment, there is less H+, so equilibrium favours dissociated form of weak acid

ONLY UNCHARGED MOLECULES CAN CROSS LIPID

At low pH (acid), weak acids are un-ionised

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12
Q

How does pH affect steady-state distribution of drugs?

A
  • basic environments favour dissociation of acids, so weak acids become trapped in these compartments e.g. renal tubules
  • urinary acidification opposes excretion of weak acid
  • ionic trapping: increasing plasma pH causes weak acid drugs to be extracted from CNS and get trapped in plasma
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13
Q

what are the different ways in which drugs can be administered to the body?

A
  1. intravenous injection
  2. intramuscular injection
  3. intrathecal injection
  4. inhalation administration
  5. percutaneous route
  6. oral
  7. rectal
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14
Q

what is intravenous injection?

A
  • drug directly enters plasma for bulk flow (best way to administer drug)
  • used in emergency for fast drug uptake e.g. during seizures
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15
Q

what is intramuscular injection?

A
  • drug injected into muscles
  • conc of drug in plasma is less reliable depending on site of injection and fat in the area
  • avoids entering digestive system
  • used for drugs that are protein in nature e.g. insulin, monoclonal antibodies
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16
Q

what is intrathecal injection?

A
  • direct lumbar puncture into CSF to access CNS
  • needs a clinically trained person to administer
  • limited situation where drug needs localised effect in CNS e.g. epidural in pregancy
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17
Q

what is inhalation administration of a drug?

A
  • restricted to drugs which must be localised in the lung, or if the drug is a gas
  • lungs have blood perfusion, so the drug can later enter the plasma
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18
Q

what is the percutaneous route of drug administration?

A
  • drug enters skin
  • nature of skin means that the rate that the drug enters plasma is variable and slow, but controlled
  • slow delivery of drugs is desirable as drug is constantly supplied over long period
  • avoids gut metabolism
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19
Q

what is the oral route of drug administration?

A
  • easiest way for adults to take medicine
  • swallow tablet and drug enters gut
  • pH of gut dissolves drug and is absorbed in small intestine
  • must consider what food is in the gut and how it will interact with the drug
  • portal blood connects to liver, which could metabolise the drug and lead to its excretion
20
Q

what is the rectal route of drug administration?

A
  • drug applied through anus
  • minimises problems with vomiting causing decrease in drug conc
  • avoids portal system and liver metabolism
21
Q

what is bioavailability?

A

fraction of ingested dose that gains access to circulation
- only 1% of ingested dose makes it to the plasma

22
Q

how does carrier-mediated transport affect drug absorption?

A
  • absorption into body shows saturation: as drug conc increases, there is no change in plasma conc over time due to limited no. transporters working at a specific rate
  • once max is reached, body cannot uptake anymore drug
23
Q

what is metformin?

A

a drug which acts on enzyme in liver cells involved in glucose homeostasis and insulin:
- treats type 2 diabetes
- gains access to liver cells via OCT1

24
Q

how do genetic variants of OCT1 transporter cause different responses to metformin?

A

gene for OCT1 naturally has polymorphism variant between different populations
- this means metformin has different effectiveness for different patients
- metformin on variant patients will be less effective in glucose homeostasis

25
Q

what are the major body fluid compartments?

A
  1. extracellular fluids:
    - plasma = 4.5%, interstitial fluid = 16%, lymph = 1-2%
  2. intracellular fluids = 30-40%
  3. transcellular fluids e.g. CSF = 2.5%
  4. fat = 20%
26
Q

what determines the distribution of a drug?

A

based on the drug’s permeability and lipid solubility:
- conc depends on the physicochemical properties of drug, how it crosses barriers and whether the drug binds to proteins in different compartments

27
Q

what is Volume of Distribution (Vd)?

A

Vd is a measure of the volume of fluid that would be required to hold the amount of drug in the body as measured in the plasma
- shows us where drugs are and how efficiently they are distributed

Vd = dose/cp
- cp is the conc in plasma after equilibrated in its Vd but before significant elimination
- inverse relationship between Vd and cp
- if cp is high, Vd is low

28
Q

how is drug distribution the CNS limited?

A

Blood-brain barrier:
- endothelial cells in CNS form tight junctions which are impermeable to water-soluble molecules
- lipid-soluble molecules (ethanol) can cross BBB easily

tight junctions become leaky during inflammation -> treat meningitis with penicillin

29
Q

how does drugs binding to plasma proteins affect drug distribution?

A
  • drugs that bind to albumin are no longer free to diffuse across membranes and interact with receptor targets
  • high protein binding leads to large increases in conc of drug as protein binding sites become saturated
  • drugs compete for binding to albumin, causing displacement of one another and impacting conc of drug in plasma and free-drug conc
  • lots of albumin binding shows linear relationship, but at saturation a plateau is caused
30
Q

what determines whether drugs partition into body fat?

A

based upon how lipophilic the drug is (partition coefficient):
- if body fat % is low, this will cause increased drug conc in plasma and increased drug effects in cells as drug only has to pass through plasma membrane. also drug can be eliminated rapidly
- if body fat % is high, adipose tissues act as reservoir for the drug and decrease conc of drug in plasma. drug is trapped in body fat and is more difficult to be eliminated

31
Q

how are drugs metabolised in the body?

A

2 biochemical reactions:
Phase 1: catabolic
- produces more reactive compounds to provide active ingredient for phase 2

phase 2: anabolic
- conjugation to produce larger, inactive product
- leads to inactivation of drug via change in molecular structure and inhibits it from reacting with receptor

32
Q

what enzymes does the liver produce to metabolise drugs?

A

microsomal enzymes:
- cytochrome P450, alcohol dehydrogenase, MAO

33
Q

what are prodrugs??

A

drugs which only become active after being metabolised:
- metabolism can alter/prolong pharmacological drug actions

34
Q

what is enzyme induction?

A

some drugs can alter the effect of other drugs:
- drug leads to increase in transcription of enzymes involved in metabolism and rids the body of other drugs
- this can cause complications as the drug may cause the body to metabolise itself

35
Q

what are the 3 ways in which drugs can be metabolised?

A
  1. drugs administered via oral route may enter portal system and liver
    - some drugs are absorbed into bile which then re-enters gut to be excreted via faeces
    - other drugs re-equilibrate into plasma, enter kidney and are excreted via urine
  2. drugs can be eliminated via breast milk and sweat glands
  3. drugs administered to lungs may be expelled through expired air, not the metabolism
36
Q

how is aspirin eliminated?

A
  1. phase 1: hydroxylation of acetyl group by cytochrome P450
    - produces salicylic acid as intermediate compound, which is more reactive and toxic
  2. phase 2: salicylic acid is conjugated to form glucuronide, causing aspirin structure to change
    - aspirin can no longer bind to protein target
  3. glucuronide re-equilibrates with plasma, enters kidneys and is excreted via urine
37
Q

how many genes have been identified that code for cytochrome P450?

A

57 genes
- there are multiple spliced variants which form 74 different isoforms of the enzyme

first 3 P450 enzymes are involved in drug metabolism and are found in liver

38
Q

what determines the action of P450 drugs?

A

different isoforms of P450 react with different drugs based on the chemical structure of the drug
- not determined by the pharmacological effect of the drug

39
Q

how do inducers of P450 increase drug metabolism?

A
  • lowers plasma conc of drug sufficiently so that it will no longer achieve its therapeutic conc
  • occurs at level of transcription so more metabolic enzymes are produced
40
Q

how are drugs eliminated from the body?

A
  • mainly from liver, through plasma, into kidney and filtered out with urine
  • lipophilic drugs are not well eliminated from kidneys as they easily pass out of kidney, so conjugation in phase 2 is crucial to faciliate excretion
41
Q

what are the 3 ways of drug excretion?

A
  1. renal
  2. GI tract: when drug is conjugated with bile, so leaves via faeces
  3. lung
42
Q

what are the 3 methods of renal excretion?

A
  1. glomerular filtration:
    - works for conjugated drugs or drugs with molecular weight < 20kDa
    - if drug is bound to protein, MW will be to high so cannot be excreted this way
  2. tubular secretion
    - most common method for weak acids and bases that are conjugated
    - uses OCT and OAT transporters for active secretion
  3. passive diffusion through tubular epithelia: used by lipophilic drugs but is inefficient
43
Q

how do chemical properties of drugs affect renal secretion?

A

e.g. penicillin is cleared from blood on single transit vs diazepam (lipophilic) is cleared slowly as it produces active metabolites

if drug is lipophilic, excretion via kidney takes longer

44
Q

what is time course clearance of drugs?

A

follows a mono-exponential decay, determined by rate of metabolism and excretion

rate constant of elimination = the fall rate of the curve
- half-life of drug is constant and independent of the conc of drug achieved in the plasma

dosing regime does not alter the time it takes to reach steady-state, but no. doses needed does vary

45
Q

what does a disproportionate increase in steady-state plasma conc cause?

A

clinical side-effects and toxicity

46
Q

what is the difference between normal kinetics and saturation kinetics?

A

normal kinetics: steady-state of drug level must be proportional to size of dose

saturating kinetics: metabolism of drug/transporters cause saturation
- at higher drug concs, steady-state fails
- there is a dramatic increase in rate of drug accumulation in plasma
- rate of drug conc increases linearly with dose of drug as elimination systems become overwhelmed

Pharmacology (10 decks)

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