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Pharmacology Year 2 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What do a. Pharmacodynamics b. Pharmacokinetics mean?

A

a. Pharmacodynamics = what a drug does to the body

b. Pharmacokinetics= what a body does to a drug

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2
Q

What is an issue pharmacokinetics brings?

A

Makes it difficult to work out what conc of a drug will make it to the target organ without it being toxic or too low for the desired therapeutic response.

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3
Q

What is an issue pharmacodynamics brings?

A

Different ethnic groups have individual responses to drugs, they have different therapeutic windows.

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4
Q

What effects do the physiochemical (concentrations) properties of a drug have on pharmacodynamics?

A

The physiochemical properties of a drug will effect the affinity, efficacy and potency.

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5
Q

What effect do the physiochemical properties (concentrations) of a drug have on pharmacokinetics?

A

Absorption, Distribution, Metabolism, and Excretion (ADME)

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6
Q

What are the 4 key principles of Pharmacokinetics and what do they regulate?

A

> ADME = Absorption, Distribution, Metabolism, Excretion

> Together they regulate the conc of the drug at the intended target site.

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7
Q

What interactions will occur no matter how selective a drug may be or how high the conc is?

A

Off target effects will always occur due to low affinity interactions with other proteins.

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8
Q

If a drug such as a tablet is ingested, how is it absorbed and distributed through the body in 4 steps?

A
  1. Move into the stomach
  2. Passed onto small intestine quickly
    >Most absorption occurs here
  3. Crosses plasma membrane of cells lining intestine t leave gut into blood vessels.
  4. Bulk flow (drug in plasma) carries the drug around the cardiovascular system towards target.
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9
Q

How does the size of the drug effect the diffusion through plasma membrane and why?

A

> Large molecules diffuse slower across plasma membranes.
As the diffusion coefficient (diffusion rate) = 1/Sqrt (molecular weight), so the larger the molecular weight the slower the rate of diffusion.

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10
Q

Does physiochemical properties of drugs effect the transport or absorption of the drug more?

A

The absorption

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11
Q

What are the 5 factors which effect absorption of a drug?

A
  1. Site/ method of administration
  2. Molecular weight
  3. Lipid solubility
  4. pH and ionization of the drug
  5. Carrier mediated transport
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12
Q

What are the 4 main mechanisms for how drug diffuse in and out of membranes?

A
  1. Diffuse through lipid-bilayer
    2.Diffuse through aqueous pore (ion channels)
  2. Diffusion through carriers
  3. Through bulk flow using Pinocytosis and Transcytosis.
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13
Q

What is Pinocytosis and transcytosis, what is an example of them being used?

A

> Pinocytosis is when the membrane evaginates trapping extracellular fluid and molecules contained, these then enter the cell.

> Transcytosis, pinocytic vesicles inside the cell move across it and fuse through the other side, releasing the contents at the other of the cell

> Can be sued to transport large proteins, e.g. insulin or antibodies across the blood brain barrier

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14
Q

What 2 physiochemical properties of a drug effect how they diffuse through the lipid bi-layer and why?

A
  1. The lipid solubility (the charge)
    >The more lipophilic (lipid soluble/ uncharged) the drug is, the more easily it enters the plasma membrane.
  2. The molecular weight of the drug
    >Inversely related to the diffusivity (rate of diffusion)
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15
Q

Are non-polar (uncharged) molecules lipid soluble

A

Yes they dissolve freely in lipids.

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16
Q

What coefficient determines lipid solubility of a drug and what does it mean?

A

The partition coefficient (how readily a molecule dissolves into water compared to an oil).

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17
Q

What are 3 effects of having non-polar (uncharged) drugs that can dissolve freely across the lipi-bilayer on absorption?

A
  1. An increased rate of absorption from the gut.
  2. Increased penetration into the brain
    >Highly lipophilic drugs will enter fats which act as a reservoir across the blood brain barrier
  3. Increased renal elimination as will enter the kidney directly through the bi-layer
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18
Q

What is the Henderson–Hasselbalch equation and what does it show?

A

> pKa= pH + log10(Ha/A-)

Ha= weak acid
A- = anion

> Used to calculate the proportion of a drug in dissociated or associated form.

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19
Q

Are most drugs weak acids or weak bases?

A

Weak acids

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20
Q

What happens to weak acids in 1) Aqueous environment 2) Weak acid environment 3) basic environment?

A

1) Weak acid dissociates into free H+ ion and negative anion.

2)Excess of H+ ions forces equilibrium to the left favouring the forming weak acids.

3) As less free H+ present, pushes equilibrium to the right favouring dissociation of weak acids into H+ and anions.

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21
Q

What is the symbol equation for weak acids dissociating into H+ and an anion?

A

HA <-> H+ + A-

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22
Q

What does PKa show?

A

> The pKa of a drug is that point at which the compound is 50% ionized
It is a constsant value for weak acids or weak bases.

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23
Q

What is the PKa value of a) weak acids b) weak bases?

A

a) below 7
b) Above 7

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24
Q

What is an advantage of weak acid drugs in low pH environments?

A

Weak acids are in their unionised form which is useful as can diffuse directly across lipid membranes (as are uncharged).

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25
Q

What is convenient about most drugs being weak acids or bases

A

They both readily form salts, this is easy to put into a tablet or dissolve into a solution to give to a patient.

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26
Q

What is ionic trapping and where are 2 places in the body this occurs and the advantages of it?

A

> When pH is high so favours dissociation of the weak acid so they are charged and cannot cross the lipid membrane so are trapped in that compartment of the body.

1) In blood vessels the pH is neutral so favours dissociation of weak acids so the drug is carried around by bulk flow.

2) In the bladder pH is 8 favouring dissociation of weak acids trapping the drug in bladder to be passed out of the body in urine.

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27
Q

Is Aspirin a weak acid or a weak base and what is its pKa value?

A

> Weak acid
3.5

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28
Q

What happens if we increase the pH, by adding sodium bicarbonate for example, of blood plasma?

A

Causes weakly acidic drugs to be extracted from the CNS and trapped in the plasma due to ionic trapping.

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29
Q

What are the 6 routes for administration of drugs?

A

1) Intravenous route (injected into bulk flow)

2)Intramuscular injection

3)Intrathecal (directly into cerebral spinal fluid)

4)Inhalation administration

5)Oral or rectal

6)Percutaneous (through skin)

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30
Q

What is an advantage and a disadvantage of Intramuscular injections?

A

> The conc of drug achieved in plasma is less reliable, due to amount of fat surrounding the area

> Proteins won’t be digested as avoids digestive system.

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31
Q

What is an advantage and a disadvantage of Intrathecal (spinal) routes of administering?

A

> Rapid access into CNS

> Limited to situations where we want to ensure the drug has a very localized affect in CNS, e.g. used for analgesics during child birth

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32
Q

What is an advantage and a disadvantage of Inhalation administration?

A

> Useful as lungs are well perfused, so drug easily gets into plasma.

> Restricted to drugs localized to lungs and where drug is a gas

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33
Q

What is an advantage and 2 disadvantages of Oral routes of administration?

A

> Is the easiest route

1)Foods will effect gut pH which effects the dissociation or association of the drug

2)Portal blood system may directly take drugs from the gut to the liver where they are metabolised?

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34
Q

If a patient needs to take a tablet but is too scared to take it orally, what other route could they take it?

A

Through the rectal route.

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35
Q

What are 3 advantages and a disadvantage of Percutaneous administration (through skin)?

A

1)Avoids gut metabolism
2)Rate of drug entry can be slow if desired, e.g. nicotine patches.
3)Can be limited to just the skin it is applied to e.g. allergic reaction cream.

> Some of these drugs are limited to just the skin and can’t enter the plasma.

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36
Q

How does carrier mediated transport effect drug absorption in 2 ways?

A

1)Increasing the conc of a drug will increase absorption but also saturation of transporters; once at maximum saturation absorption rate slows.

2)Competitive inhibition occurs, as endogenous transporter molecules compete with the drug for the transporters.

37
Q

What does Metformin do and what does it treat?

A

> Enters liver cells and increases activity of an enzyme metabolizing glucose.

> Treats Type II diabetes

38
Q

What gene codes for the transporter Metformin uses to enter liver cells?

A

OCT1

39
Q

What happens if there is a loss of function mutation with the OCT1 gene for Type II diabetes patients when given Metformin?

A

Blood glucose conc doesn’t drop as much as transporters are less efficient at transporting metformin into liver cells.

40
Q

What are the 4 major body compartments and which are aqueous (water compartments)?

A

1)Extracellular fluids
>Aqueous

2)Intracellular fluids
>Aqueous

3)Transcellular fluids
>Aqueous

4)Fat

41
Q

What is distribution of a drug based on?

A

Permeability and lipid solubility

42
Q

What is the largest compartment in our body?

A

Intracellular fluid

43
Q

What is the volume of distribution (Vd) of a drug?

A

A measure of the volume of fluid that would be required to hold the amount of drug in the body (The volume of distribution describes the volume needed to dissolve that dose to give that concentration in the plasma )

44
Q

What is the formula for volume of distribution (Vd) of a drug?

A

Vd=Dose/cp

cp = conc of drug in plasma

45
Q

How is volume of distribution expressed?

A

As a ratio of the dose administered of a drug to the concentration in the plasma.

46
Q

What is the relationship between volume of distribution of the drug and the cp (conc in plasma) and why?

A

> Inverse relationship between Vd and cp (conc in plasma)

> If the conc in the plasma is high, the volume of distribution will be low as if the conc in plasma Is high it indicates the drug is trapped effectivly in plasma

47
Q

Describe the volume distribution of a) Heparin b) Ethanol c) Propranolol.

A

a) Is large molecule so has small volume of distribution, gets trapped within plasma and is efficiently bound up by plasma proteins

b) High Vd as readily distributes across many compartments as is very lipophilic so crosses many barriers.

c) high volume of distribution; shows it can make its way into many compartments

48
Q

Why can many drugs not pass the blood brain barrier?

A

Endothelial cells lining blood vessels in CNS form tight junctions impermeable to water soluble molecules

49
Q

What are 2 ways to cross the blood brain barrier?

A

1)Lipid soluble molecules (eg. Ethanol & caffeine) cross BBB easily,

2)Larger drugs can only get across if there’s a carrier like aspirin.

50
Q

Why can Meningitis be treated with penicillin despite it not being able to cross the BBB normally?

A

Tight junctions between Endothelial cells can become leaky during inflammation (due to immune response) allowing them to be permeable to antibiotics like penicillin.

51
Q

What effect does the presence of Albumin (most common plasma protein) have on acidic drugs?

A

It is a highly charged protein meaning weak acids efficiently bind (non-specific binding), so the drug is not free to diffuse across membranes or to interact with receptor targets.

52
Q

What is an effect of a drug that binds to many plasma proteins

A

High Protein binding drugs can lead to unexpected large increases in concentration of drug as when they dissociate and the protein binding sites become saturated, the conc of the drug will suddenly increase in plasma.

53
Q

What is the relationship of the concentration of drug bound to albumin and the free flowing drug when the concentration of that drug increases?

A

> When we increase conc of drug we see a linear increase in conc of bound drug to albumin, until a point when all albumin is saturated this starts to plateau

> The conc of free drug starts linear but as more albumin becomes saturated the conc of free drug increases drastically.

54
Q

What effect does a)high body fat b)Low body fat have on volume of distribution of a drug?

A

a)In a large amount of body fat, the drug will be distributed into body fat as well as cells, these act as a reservoir for the drug, this decreases the conc of drug in plasma membranes of other cells and is trapped in body fat (not eliminated stays in body for longer)

b)If animal has low body fat, drug goes straight into plasma membrane of cells, so concentrations of lipophilic drug like anaesthetic or alcohol in cells is higher, the drug will be eliminated rapidly as isn’t stored in fats.

55
Q

What three factors control the concentration of drug in the body?

A

1) Amount entering the body

2) Distribution throughout the body (absorption)

3) Metabolism of drug.

56
Q

Where does metabolism of drugs occur in our body?

A

Liver

57
Q

What 2 biochemical reactions occur during metabolism of drugs in the liver and what do they produce?

A

1) Phase 1, Catabolic reactions
>Provides active ingredient for phase 2
>Can be a more reactive product.

2) Phase 2, synthetic (anabolic) reactions
>Involves conjugation to produce inactive product.

58
Q

What are microsomal enzymes and what are they used for?

A

> Enzymes which are associated with intracellular organelles.

> Used for metabolising drugs in the liver.

59
Q

What are 3 examples of microsomal enzymes used for metabolism of drugs in the liver, and which is most common?

A

1) Cytochrome P450
>Most common

2) Alcohol dehydrogenase

3) MAO (monoamine oxidases)
>Metabolise amine nuerotrasmitters.

60
Q

What are 3 examples of microsomal enzymes used for metabolism of drugs in the liver, and which is most common?

A

1) Cytochrome P450
>Most common

2) Alcohol dehydrogenase

3) MAO (monoamine oxidases)
>Metabolise amine neurotransmitters.

61
Q

What must a drug do to be able to be metabolised?

A

Cross the plasma membrane either by being lipid soluble or using a specific transporter.

62
Q

What are pro-drugs?

A

Drugs which only activate after phase 1 of metabolism.

63
Q

Why is taking too much paracetamol in a short time dangerous?

A

Paracetamol produces a toxic compound (NAPQI) after phase 1, most phase 1 reactions are so reactive that they are short lived.

64
Q

How can a drug act on an enzyme and what is the effect?

A

> Via enzyme induction, where a drug leads to increased transcription of an enzyme involved in another drugs metabolism.

> This will metabolise more of this drug, as well as other types of drugs as one enzyme metabolises many types of drugs.

65
Q

How can a drug act on an enzyme and what is the effect?

A

> Via enzyme induction, where a drug leads to increased transcription of an enzyme involved in another drugs metabolism.

> This will metabolise more of this drug, as well as other types of drugs as one enzyme metabolises many types of drugs.

66
Q

What are 4 exit routes for drugs in the body, and which is most common?

A

1) Metabolism in liver and excreted in urine by Kidneys.
>Most common

2) Conjugation with bile, then excreted out of gut as faeces.
>Doesn’t always require metabolism of drug

3) Through breastmilk and sweat

4) Drugs administered through lungs can be expelled via exhaled air.

67
Q

What occurs in the 2 phases of metabolism for Aspirin?

A

1) Phase 1
>Cytochrome enzyme carries out hydroxylation reaction
>Makes the lipophilic compound into water soluble compound for excretion.

2)Phase 2
>Conjugation occurs with glucuronide molecule (large molecule made in liver) changing aspirin’s structure.
>This binds to plasma and transferred by bulk flow to kidneys where it is actively excreted in urine.

68
Q

What is the most common enzyme used in the liver for drug metabolism?

A

Cytochrome P450 enzymes

69
Q

How many isoforms are there of Cytochrome P450 enzymes and how many are involved in drug metabolism in the liver?

A

74 isoforms, 3 used for metabolism of drugs in the liver.

70
Q

What should not be consumed while taking Wolfrin (blood thinners) and why?

A

Grape fruit juice, as it inhibits cytochrome P450 enzymes so leads to too high wolfrin concentrations as less is being metabolised.

71
Q

All the drugs: Acetaminophen, aspirin and ibuprofen are anti-inflammatory drugs but all have different enzymes which metabolise them. What does this show?

A

This shows it is the chemical nature of the drug which determines which cytochrome P450 metabolizes it, not its pharmaceutical properties.

72
Q

What would an inducer of P450 enzymes cause?

A

An increase in drug metabolism/ lowering plasma concentrations of the drug

73
Q

Why is phase 2 of metabolising drugs important for their excretion?

A

> Lipophilic drugs will not be well eliminated from kidneys as they pass out easily, conjugation in phase 2 is very important as it allows for their excretion into urine.

> Hydroxylation reactions change the lipophilic drugs into hydrophilic (water soluble) molecules that can pass out in urine.

74
Q

What are the 5 ways drugs are excreted and how do they work?

A

1) Glomerular filtration
>For small drugs

2) Active tubular secretion
>Most common, uses transport proteins to actively secrete drugs.

3) Passive diffusion
>Some lipophilic drugs do this but is inefficient.

4) Gi excretion
>Bound by bile acids and excreted as faeces.

5) Lung excretion
>Excreted by exhale of air.

75
Q

What is an advantage of the more alkaline pH of urine?

A

The higher pH of urine has ion trapping effect as weak acid drugs enter their dissociated (unionised) form so cannot diffuse directly through the lipid bi-layer, particularly effective in trapping weak acids and increasing their excretion

76
Q

How can kidney disease affect drug clearance?

A

Increased build up of concentration of drugs, leading to drug toxicity.

77
Q

Why does diazepam have a long 48 hour effect?

A

After it is metabolised, the metabolite formed is lipophilic and cleared slowly.

78
Q

Is Penicillin cleared from the body quickly, and why is it not what we would expect?

A

Penicillin is cleared quickly, despite it being a large molecule.

79
Q

What are 2 effects of a drug being lipophilic?

A

1) Lipophilic drugs are easy to administer as can diffuse across easily via passive diffusion.

2) but they won’t stay in kidney so is slow to excrete.

80
Q

What does Kel stand for?

A

Rate constant of elimination ( the fraction of drug eliminated per unit of time).

81
Q

What does T1/2 mean?

A

The half-life of a drug.

82
Q

Does the half life (T1/2) of a drug change when the concentration of the drug in plasma changes?

A

No, the half-life of a drug is constant and independent of the concentration achieved in the plasma.

83
Q

What does it mean when a drug is at steady state?

A

At steady state the rate of infusion of drug is counterbalanced by rate of metabolism and excretion, so plasma conc stays stable during infusion (on a graph it is where the conc curve plateaus)

84
Q

Does the Dosing regime (conc of drug per injection) effect the time taken to reach a steady state?

A

> No, the dosing regime DOES NOT alter time it takes to reach steady state BUT it will effect number of doses needed DOES vary

>

85
Q

What would a concentration curve look like for a drug with a a) High dosing regime b) Low dosing regime, link this to steady state.

A

a) On a graph with a lower dosing regime there will be more peaks and trophs as more injections are needed but a steady state will be reached in the same time as a higher dosing regime.

b) but in the same time a steady state will be reached with a higher dosing regime but with less injections (less peaks and trophs).

86
Q

What does it mean when a drug follows first order kinetics and why is it useful?

A

> The drugs monoexponentially decay, so the steady state level of the drug is proportional to the size of the dose.

> This is useful as it is easy to predict the needed concentration to keep the drug in a safe and desired therapeutic window.

87
Q

What is saturation kinetics and why does it occur?

A

> The steady state level of a drug is not proportional to the size of its dose. So at higher dosing regimes instead of seeing steady state attainment (like with first order kinetics), there is sudden dramatic increase in rate of drug accumulation in plasma

> Occurs due to fully saturating the proteins needed to metabolise the drug, so metabolization decreases so steady state cannot be reached.

88
Q

What is an example of saturation kinetics?

A

When having alcohol, moderate drinking the alcohol dehydrogenase can keep up, however this enzyme needs a cofactor which is limited in amount, if we increase alcohol consumption too much the enzyme can’t keep up with metabolism, blood levels of alcohol increase dramatically and is toxic.

89
Q

What issue does saturation kinetics bring?

A

Disproportionate increase in steady-state plasma concentration can lead to clinical side effects

Pharmacology Year 2 (8 decks)

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