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PHAR 300 > L4: Pharmacokinetics 1 > Flashcards

L4: Pharmacokinetics 1 Flashcards

1
Q

What can affect the magnitude of a drug effect?

A 
Pharmacodynamics
Pharmacokinetics
Genetics
Diseases
Prior exposure to drugs
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2
Q

What does the graph look like if the drug is taken orally?
X axis: time after dose
Y: Plasma level of drug

A
  1. Increase in plasma concentration as the drug is being absorbed. (Pretty steep upward slope)
  2. Steep decline as the drug is being distributed to various tissues
  3. Slower decline as it is being eliminated
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3
Q

What does the graph look like if the drug is injected intravenously?
X axis: time after dose
Y: Plasma level of drug

A
  1. Drug in plasma is initially at 100% because absorption is bypassed.
  2. The initial decrease in plasma drug concentration is because the drug is being distributed to other tissues.
  3. Slower decrease caused by elimination.
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4
Q

What is the apparent volume distribution? Why do we use it?

A

AVD = Amount of drug in body (mg) / Concentration of drug in plasma (mg/L)= X/Cp

We use AVD because we cannot measure the actual volume in which drug molecules are distributed within the body.

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5
Q

What does it mean if you have a low AVD?

A

Large concentration of drug in the plasma (large Cp), gives an apparent low AVD. Means that most of the drug is bound to plasma proteins.

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6
Q

What does it mean to have a high AVD?

A

Low concentration of drug in the plasma (low Cp), gives apparent large AVD. Means that most of the drug is distributed in the tissues (larger volume).

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7
Q

What causes AVD variations?

A
  1. Properties of drug
  2. Protein binding
  3. Tissue binding
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8
Q

How can you determine the loading dose of a drug?

A
  1. Know the apparent volume distribution of a drug.

2. Know the concentration of the drug in the plasma required for an effect.

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9
Q

What is a loading dose?

A

The amount of drug to administer.

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10
Q

What does it mean if the AVD is bigger than the total possible body volume?

A

It means that mot of the drug is found in the tissues and very little drug is left in the circulation (very small Cp so AVD will be very large).

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11
Q

What is the main way to eliminate a drug?

A

Metabolism.

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12
Q

What does metabolism do to drugs?

A
  1. Alteration of the chemical structure of the drug by an enzyme. The change generally involves the conversion of a non-polar lipid soluble compound to a more polar water soluble compound that can be readily excreted in the urine.
  2. Conversion of drug to less active or inactive metabolite.
  3. Sometimes converts inactive pro-drug to active form
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13
Q

As a drug is being metabolized, what happens to the concentration of parent drug and metabolites in the blood?

A

As its being metabolized, the parent concentration in the blood will decrease, and the metabolite concentration will increase.

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14
Q

Why would a drug be administered as a prodrug (inactive/less active form)?

A

To promote absorption and to overcome potential destruction by stomach acidity.

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15
Q

Where does metabolism occur?

A
  1. The liver (mainly)
  2. Skin
  3. Intestine
  4. Kidneys
  5. Lungs
  6. Brain
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16
Q

What does it mean for the liver to have a “large functional reserve”?

A

Even with considerable damage, the liver can still function bc of its ability to regenerate new hepatocytes.

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17
Q

What is a consequence of a damaged liver (Ex: Cirrhosis)?

A

Compromised drug metabolism. Can be fatal.

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18
Q

What is the pathway of blood in the liver?

A
  1. Portal vein carries blood from the intestine to the liver.
  2. Hepatic artery carries oxygenated blood from heart to liver.
  3. Blood from the portal vein and hepatic artery mixes to form sinusoids.
  4. Hepatocytes are in proximity with the sinusoids allowing exchange between them.
  5. Drugs move from the sinusoids to the hepatocytes in order to be metabolized.
  6. Blood flows from the sinusoids to the hepatic venule and back to the systemic circulation.
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19
Q

What is a sinusoid?

A

A small blood vessel lined with one cell on the surface with considerable spaces between the sinusoidal cells.

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20
Q

What are the 2 phases of drug metabolism?

A

Phase 1: oxidation/reduction/hydrolysis

Phase 2: Conjugation

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21
Q

What happens in Phase 1 of metabolism (oxidation/reduction/hydrolysis)? What enzymes catalyze the reaction?

A
  • Simple chemical rxns that renders the drug biologically inactive (can’t bind its receptor and usually more water soluble).
  • Possible that the compound is transformed to a more active form and may still not be water soluble (ex: prodrug).
  • Cytochrome P450 are the enzymes that catalyze phase 1 rxns.
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22
Q

What happens in Phase 2 of metabolism (Conjugation)? What enzymes catalyze the reaction?

A
  • Coupling the drug molecule to an endogenous substituent group so that the resulting product will have a greater water solubility (This leads to enhanced renal elimination). It will then enter the systemic circulation.
  • Transferases catalyze phase 2 rxns.
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23
Q

Where is cytochrome P450 found?

A

Mainly in the smooth ER of hepatocytes. Also found in GI tract, lungs, skin, kidneys, and the brain.

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24
Q

Why did the number of CYP450 enzymes increase over evolution?

A

Because they are essential for life. Every living organism needs it to metabolize what they consume.

25
Q

What are the CYP450 families and what do they metabolize?

A

1) CYP1, CYP2, CYP3: metabolize drugs and xenobiotics (foreign/exogenous substances).
2) CYP4, CYP5, CYP8: internal metabolism (ex: fatty acids)
3) other CYP’s : metabolize steroid hormones

26
Q

What does CYP450 do in the liver?

A

Drug metabolism.

27
Q

What does CYP450 do in the brain?

A

Breaking down endogenous compounds required for brain function.

28
Q

What are the most important CYP450’s for drug metabolism? How does this relate to their quantities in the liver?

A

CYP3A, CYP2C, and CYP2D6.

Their importance is not proportional to their relative quantities in the liver.

29
Q

What factors influence enzyme function (ex: CYP450’s) in an individual?

A
  1. Polymorphisms: different versions of the enzymes as enzymes are not usually identical.
  2. Internal & external factors: different levels of inflammatory processes, sex, diseases, age.

(Depending on a person’s exposure to certain things, different enzymes may be induced to increase metabolism of certain substances).

30
Q

What’s the role of CYP450 enzymes in the intestinal epithelium and lumen?

A

Metabolize drugs as they go from intestine to portal vein, before they get to the liver where major metabolism takes place.

31
Q

Where is P-glycoprotein found and what does it do?

A

In the wall of the intestine.

It prevents drug from being absorbed, so it ends up in the feces.

32
Q

What is a polymorphic distribution?

A

A trait that has differential expression in greater than 1% of the population.

33
Q

How does a polymorphic distribution of the CYP450 gene affect the individuality of drug effects? Describe the graph.

A

For the population that is >1% and has a lower metabolic capacity, they are not part of the normal distribution, and they are labelled poor metabolizers on the curve (PM). They require a lower drug dose and lower frequency of administration to avoid toxicity.

As part of the normal distribution, there are effective metabolizers (EM) and ultra rapid metabolizers (URM).

URM’s may require a larger dose and higher administration frequency to get an effective response.

34
Q

What are the consequences of genetic polymorphisms of CYP450?

A
  • Altered drug effects
  • Altered sensitivity to stereoselective metabolism
  • Altered sensitivity to interactions
  • Altered production of active metabolites
35
Q

What can vary based on whether the enzyme polymorphism is WT, hetero, or homozygous for the variant?
Give an example.

A

The concentration of the drug that leads to a toxic or therapeutic effect.

Ex: For example in a certain CYP450 enzyme, the WT might metabolize a drug faster than a heterozygote of the enzyme. Therefore, a drug dose that would be therapeutic for someone with the WT enzyme, might be toxic for the heterozygote.

36
Q

What are some environmental factors that can affect CYP450 enzymes and consequently affect the response to a drug?

A
  1. Drug therapy (can block some liver enzymes)
  2. Alcohol (can cause liver damage)
  3. Cigarettes
  4. Nutrition
  5. Fever & infection
  6. Occupational exposure
37
Q

What can cause the impairment of drug eliminations which leads to varied drug response?

A
  1. Kidney disease
  2. Liver disease
  3. Gastrointestinal disease
  4. Cardiovascular or renal function impairment
38
Q

How does age affect variability of drug effects in people? Focus on metabolic affects.

A
  1. Young children can’t metabolize drugs well bc they don’t have all of the drug metabolizing enzymes yet.
  2. There is a tendency for drug metabolism to decrease in seniors (on average). So for seniors, you need to start by giving a small dose and carefully monitor their response to adjust their dosage if needed.
39
Q

What is the induction of drug metabolism enzymes and what causes it? Give an example where enzyme induction is necessary.

A

Induction is the increased synthesis of drug metabolizing enzymes to increase the speed of metabolism. Caused by high exposure to drugs. It is a protection mechanism.
Ex: High alcohol or nicotine intake would be lethal without enzyme induction.

40
Q

What happens when enzymes for drug breakdown are inhibited?

A

It can lead to a rapid overdose of a drug because it cannot be broken down.

41
Q

What does a CYP3A4 inducer and inhibitor do?

A

Inducer: increases the clearance of a drug and decreases blood level concentration of a drug.
Inhibitor: reduces clearance and increase blood level concentration of a drug.

42
Q

What catalyzes phase 2 rxns and what do they do?

Give examples.

A

Transferases catalyze phase 2 reactions by transferring a conjugate onto the metabolite from phase 1 to render it water soluble for excretion. It also renders the metabolite inactive.
Ex: Glutathione, Glucaronic acid

43
Q

What is excretion and where does it predominantly take place?

A

Removal of the drug from the body.

Takes place in the nephrons of the kidney.

44
Q

What are the 3 functions of the kidney? Explain them.

A
  1. Filtration: blood flowing through bowmans capsule. Fluids and solutes enter tubule system.
  2. Secretion: Things are leaving the systemic circulation and going into the tubules in the nephron.
  3. Reabsorption: The body re-absorbs what it needs from what’s in the nephron. This is essential because the body needs a lot of what is filtered at the glomerulus. Most fluid is re-absorbed along with other components.
45
Q

Where does filtration happen and what state does the drug have to be in to be filtered?

A

Bowmans capsule.

The drug has to be free (not bound to abumin). If it isn’t then it will come around again in the next pass.

46
Q

Can lipid soluble drugs be filtered at the glomerulus?

A

Yes. if they are small enough. However, lipid soluble drugs are reabsorbed by the body from the proximal convoluted tubule (to be metabolized by liver), therefore they will not be excreted.

47
Q

What are ways to eliminate drugs not including urine?

A
  1. Feces
  2. Exhalation
  3. Sweat
  4. Saliva
48
Q

What is drug clearance?

A

A quantity that describes excretion. It is the quantity of blood cleared of a drug in a given amount of time.

49
Q

What’s the formula for renal drug clearance?

A

Renal drug clearance = Filtration + secretion - Reabsorption

50
Q

What is the total body clearance?

A

The sum of the individual organ clearances.

51
Q

What value do you obtain when you extrapolate the elimination phase to time 0?

A

You get C0: the hypothetical drug concentration predicted if the distribution had been achieved instantly.

52
Q

What is a half life and what can you use to calculate it?

A

The time taken to get rid of half of the drug in the body.

The straight line of elimination allows us to calculate the half life.

53
Q

How many half lives does it take to completely eliminate drugs from the body?

A

4

extremely toxic drugs may have 5 half lives bc after 4 half lives 6% of the drug still remains

54
Q

Why is knowing the half life of a drug important?

A

It tells you how often you need to take the drug for therapeutic affects. Tells us how long the patient will be in danger in case of overdose.

55
Q

Does half life change with dose of drug administered?

A

NO. It’s always the same for a given drug.

56
Q

What is the difference between first order and zero order kinetics for drug elimination?

A

1st order kinetics: a constant fraction of drug is eliminated per unit time. (logarithmic decrease due to half lives). Enzymes are not saturated.

Zero order kinetics: constant amount of drug eliminated per unit time. (linear excretion). Takes longer to excrete. Could occur after overdose of first order kinetic drug when enzymes get saturated so it switches to zero order excretion.

57
Q

What is a dosing schedule? What is a sign of a good dosing schedule? How is this achieved?

A

A dosing schedule is the schedule to administer drugs to benefit the patient.

A good dosing schedule is when the drug concentration reaches a steady state in the therapeutic window. This is usually done by administering drugs at multiples of half lives to achieve the steady state within the therapeutic window.

58
Q

When is the steady state achieved?

A

After 4 half lives the drug reaches a steady state. It is independent of dosage. The drug will just plateau at different concentrations depending on the dose.

59
Q

What is a loading dose? When can it be used?

A

it is a much higher initial dose, you then add smaller doses regularly at half lives to reach a steady state.

it is to be used in emergency situations.

PHAR 300 (20 decks)

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