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(D) Pharmacology > Lecture 5: PK > Flashcards

Lecture 5: PK Flashcards

1
Q

What is pharmacokinetics specifically?

A

What happens to a drug’s level in your body.

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2
Q

What two properties determine a drug’s concentration in the body?

A

Drug regimen
ADME

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3
Q

Describe a PK curve for a generic drug X

A

The Cmax, or the peak, would be achieved quickly by the drug.
The Cmin, or the trough, is the lowest drug concentration in the blood before the next dose.
The entire duration of one dose is the dosing interval/frequency.
The curve would increase sharply to Cmax, then slowly decrease to Cmin.

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4
Q

What kind of relationship is PD and what kind of relationship is PK?

A

PD can be described as a concentration-effect relationship.
PK can be described as a dose-time-concentration relationship.

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5
Q

What is the definition of a therapeutic window?

A

A therapeutic window is the interval between the MINIMUM effective dosage and the MINIMUM toxic dosage. The sweet spot between is the therapeutic window, aka where it has an actual effect but doesn’t cause toxicity.

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6
Q

Name at least 5 examples of “Narrow Therapeutic Window” drugs.

A

Warfarin, Levothyroxine, Digoxin, Cyclosporine, Tacrolimus, Theophylline, Carbamazepine, Phenytoin

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7
Q

What are the enteral routes of drug administration?

A

Oral (PO)
Rectal
NG (nasogastric)
PEG

SubL (SL, sometimes enteral)
Buccal (sometimes enteral)

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8
Q

Define bioavailability.

A

Bioavailability, commonly abbreviated as F.
Fraction of drug that reaches systemic circulation.
AKA even if you eat 100mg of a drug, maybe only 80mg actually gets to your bloodstream to do stuff. 80% is the bioavailability of that drug if taken orally.

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9
Q

How do we measure bioavailability?

A

We use the Area Under the Curve (AUC).

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10
Q

How do we determine an AUC?

A

We use the drug’s IV bioavailability, which is usually 100%.
We then measure how much of the drug ends up in the bloodstream with the same dosage given a different way, such as PO.
If the AUC IV for a drug is 100mgh/L and the AUC PO for a drug is 75mgh/L, then F (bioavailability) is 75/100, or 75%.

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11
Q

What can reduce bioavailability?

A

Incomplete absorption
First-pass effect (Only enteral drugs, which is usually just PO/NGT/PEG)

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12
Q

What are the properties of a drug that is well absorbed?

A

Small, lipophilic, and uncharged.

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13
Q

What are the 3 passive modes of movement for a drug?

A

Paracellular transport
Facilitated diffusion
Diffusion

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14
Q

What kind of capillary cares the most about whether a drug has the properties to be well-absorbed and where are these capillaries found?

A

Continuous capillaries, found in the CNS, Skin, and Lungs.

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15
Q

What are the 3 types of capillaries and where do I find them?

A

Continuous, found in CNS (BBB), skin, and lungs.
Fenestrated, found in the kidneys and small intestine.
Sinusoidal, found in the liver, lymph nodes, and bone marrow.

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16
Q

What are the two types of active transporters in our bodies?

A

Influx and Efflux transporters.

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17
Q

Why are efflux transporters important?

A

They keep xenobiotics (drugs/foreign bodies) out of certain areas, i.e. the brain.

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18
Q

What example was used for the efflux transporter and where did we find it? Why was it significant?

A

p-glycoprotein (p-gp)
It keeps drugs IN THE INTESTINE
It keeps drugs OUT OF THE BRAIN

It minimizes drug side effects. The example in class was benadryl (1st gen antihistamine) vs allegra (2nd gen antihistamine + p-gp substrate).

Allegra is effluxed out of the CNS, cause so many pgp transporters kicking it out, so NO drowsiness.

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19
Q

What are the 4 additional considerations in regards to tablet/capsules?

A
  1. Dissolution of the drug from tablet/capsule. (i.e. XR vs SR vs IR)
  2. Stability of drug (survival vs acids, enzymes, etc)
  3. Rate of gastric emptying (most absorption is in our small intestine, so the longer it takes to get there, slower the absorption)
  4. Intestinal motility and drug interactions (pH, SA, permeability, efflux-transporters, binding to intestinal wall, etc.)
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20
Q

What is the effect of food on gastric emptying and therefore drug absorption?

A

Slows gastric emptying, therefore slowing absorption of drugs by increasing how long it takes to get to the small intestine.

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21
Q

What two ways do IM/SQ/ID injections enter the systemic circulation?

A
  1. Diffusion via capillary membranes
  2. Carrying via lymph system
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22
Q

What should I be concerned about if a drug is getting carried via the lymph system?

A

Enzymatic breakdown & lymph is slow

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23
Q

What kind of molecules typically travel in lymph?

A

Large molecules such as proteins.

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24
Q

Why is diffusion via capillary membranes more preferred?

A

Forgiving of polarity and charge, not forgiving of size.
Faster than lymph.

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25
Q

What can affect the speed of absorption for an injection?

A

Site of injection, local bloodflow/temperature, and rubbing.

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26
Q

What is the first-pass effect and why is it important?

A

Enteral drugs experience this because they go through the liver PRIOR to entering systemic circulation.
The liver is a major site of metabolism, so enteral drugs must survive the first-pass effect to enter systemic circulation.

All of the drugs that enter the liver are via the hepatic portal vein.

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27
Q

What are extra hazards for enteral drugs besides the first-pass effect?

A

Not getting absorbed by the gut wall (excretion into feces)
Breakdown (metabolism) by the gut wall
Excretion into bile by the liver (post metabolism)

Note: This is in order, i.e. excretion into feces would happen prior to metabolism. See slide 28 for visual

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28
Q

What is extravascular space?

A

It is the different body tissues of our body. It occurs AFTER a drug enters systemic circulation.

29
Q

What properties does distribution depend on?

A

How well a drug diffuses across different membranes.
What a drug likes to bind to (aka albumin, protein, membrane, bone tissue, etc)

30
Q

What kind of affinities do drugs have? Name 2 examples.

A

Protein-bound drugs, which often bind to albumin in the bloodstream, preventing it from having an effect.

Bone mineral affinity, such as with bisphosphonates, which are used to treat osteoporosis.

31
Q

What is Vd (or volume of distribution)?

A

Volume of distribution is used to determine whether a drug goes into tissue or stays in the bloodstream.

Vd = Total amount of drug in BODY/Plasma concentration of a drug

32
Q

What does high Vd imply? low Vd?

A

High Vd implies the top number is big and the bottom number is small. This means the total amount of drug in the BODY is high, making there be little to no drug in the bloodstream. (example: Chloroquine has a Vd of 15,000L)

Low Vd implies the reverse, so the drug is staying in the bloodstream. (Example: warfarin binds to albumin, making its Vd 8L)

33
Q

What kind of drugs would have a high Vd?

A

Drugs that can diffuse easily or be absorbed easily. This means the drug is most likely small, uncharged, and lipophilic, aka fat-soluble). It does not stay in the blood.

34
Q

What is a metabolite?

A

When a parent drug is metabolized/biotransformed.

Metabolites are different chemical forms that are more readily excreted from the body.

They come as both active and inactive.
Example: Morphine has both active and inactive metabolites.

35
Q

What is a prodrug?

A

A drug with an INACTIVE parent form but ACTIVE metabolite.
Example: Plavix/Clopidogrel

36
Q

What are the two phases of metabolism?

A

Phase 1 - Oxidation, Reduction, Hydrolysis
Phase 2 - Conjugation (with glucoronide, sulfate, glutathione), acetylation, methylation

37
Q

What is the goal of metabolism?

A

Making drugs MORE polar and MORE hydrophilic (water-soluble)

38
Q

What is it called when a drug leaves the body prior to metabolism?

A

Excretion, aka via the kidneys through urine.
(hydrophillic through urine, lipids through liver)

39
Q

What phases of metabolism do drugs go through?

A

They can go through either phase, or they can go through both sequentially.

40
Q

What are the 5 most common CYP enzymes? Whats the most common?

A

3A4 (nearly 50%)
2D6
2C9 (warfarin)
2C19
1A2 (warfarin)

41
Q

Define elimination.

A

Irreversible loss of a drug (from original form)

42
Q

What are the two ways we eliminate drugs?

A

Metabolism and Excretion

43
Q

What is hepatic clearance?

A

It is the rate of metabolism, since metabolism is dependent on your liver.

44
Q

What is excretion? Most common type?

A

Renal clearance is the most common, and what we refer to clinically.

Excretion can be done via other liquid forms, such as breastmilk, bile, sweat, etc…)

45
Q

What do we refer to clinically when we say clearance?

A

Renal clearance!

46
Q

Name the two substances we use to estimate GFR.

A

Serum Creatinine and Serum Cystatin

47
Q

Define the key difference in creatinine and cystatin for GFR estimation purposes.

A

Both are created and excreted by the body at approximately the same rate.
Cystatin is LESS dependent on muscle mass (so less age dependent on muscle mass).

48
Q

What are the two common clinical estimates for GFR?

A

CKD-EPI-cystatin, dependent on age and gender (not race). Gives us eGFR.

Cockcroft-Gault, dependent on age, gender, and weight. Gives us CLcr

49
Q

How is absorption affected in the elderly (around 80yrs/o)?

A

Decreased gastric acid = impaired absorption of some drugs. (iron, levothyroxine, HIV drugs)

Decreased liver function -> decreased first-pass metabolism, which causes increased levels of some drugs and decreased levels of PRODRUGS.

50
Q

How is distribution affected in the elderly?

A

Decreased total body water = lower doses of hydrophilic drugs needed (water-soluble drugs, such as digoxin and ethanol)

Increased body fat = Higher Vd for lipophilic drugs (fat-soluble drugs such as diazepam)

Decreased serum albumin = Higher sensitivity to protein-bound drugs, such as warfarin and phenytoin

51
Q

How is metabolism affected in the elderly?

A

Decreased liver function = increased levels of drugs that require hepatic clearance, such as propranolol, morphine, and some Abx

52
Q

How is excretion affected in the elderly?

A

Decreased renal function = increased levels of drugs that require renal clearance, such as digoxin, lithium, NSAIDs, diuretics, and some Abx

53
Q

What are some of the effects on absorption from a Roux-en-Y gastric bypass?

A

Reduced gastric volume
Increased gastric pH
Delayed gastric emptying
Decreased surface area for absorption
Reduced first-pass metabolism
Shorter intestinal transit time
More distal delivery of pancreatic secretions

54
Q

What are some of the effects on absorption from a laparoscopic sleeve gastrectomy?

A

Reduced gastric volume
Increased gastric pH
Accelerated gastric emptying

55
Q

Describe the PK curve for an IV bolus/push of a medication.

A

It would have an extremely sharp increase to Cmax, and then decreased rapidly over time.

56
Q

Describe the PK curve for a daily oral dosed medication.

A

It would increased in a sinusoidal pattern, hovering between the therapeutic window, going up and down.
See slide 55

57
Q

Describe the PK curve for a single oral dosage of a medication.

A

A moderate increase to Cmax, then a moderate decrease back to 0.

58
Q

Describe the PK curve for a continuous infusion.

A

Steady increase to a plateau, which is the steady state level.

59
Q

What is steady state and what is steady state concentration?

A

Steady state is defined as when the rate of the drug in = rate of the drug out.

Steady state concentration is the actual drug level staying within a certain range.

60
Q

How long does it take to achieve steady state concentration? (Css)

A

3-5 halflives.

61
Q

What is half-life?

A

The time it takes for drug concentration in plasma to decrease by half.

62
Q

What are the two half-lives? Which do we care about?

A

Elimination half life, which is the time it takes for plasma levels of a drug to be halved by elimination (metabolism and/or excretion)

Distribution half life, which is the time it takes for plasma levels of a drug to be halved due to distribution in tissues.

We care more about elimination half-life for drug dosing.

63
Q

If a drug is dosed at long intervals relative to its t1/2, what will the drug levels look like?

A

Long intervals = Large fluctuations between Cmax and Cmin.

See slide 66

64
Q

If a drug is dosed at short intervals relative to its t1/2, what will the drug levels look like?

A

Short intervals = Small fluctuations between Cmax and Cmin.

See slide 66

65
Q

What are the advantages and disadvantages to shorter dosing intervals?

A

Pros:
Less fluctuation, less effect when you miss a dose.

Cons:
Convenience (taking multiple doses a day can be difficult)

66
Q

Define IR, SR, XR.

A

IR = immediate release
SR = sustained release
XR = extended release

67
Q

What are some disadvantages to drugs with very long half-lives?

A

Long washout periods. This can be dangerous if the drug has adverse effects, if you want to switch to a different drug, or if you need to start a different drug that interacts.

Slow to get to steady state.

68
Q

What is a loading dose? Why do we give it and when?

A

Allows us to get to steady state concentration faster. We give a much larger initial dose, which will boost us to the Cmax we want immediately.

69
Q

What is TDM and when do I need it?

A

Therapeutic drug monitoring, done for drugs with narrow therapeutic windows (think warfarin or digoxin)

(D) Pharmacology (18 decks)

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