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PHYS/PHARM > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

How does the pKa of a drug determine it’s absorption in the gut?

A

Because it is the pH at which 50% of drug is ionised so would determine how much (unionised - lipophillic) will pass across membrane

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2
Q

What are the 4 main factors affecting drug entry and removal?

A

Absorption
Distribution
Elimination
Excretion

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3
Q

What’s OI IT IS SIR

give pro/con of each

A

Oral - convenient, may have low bioavailbility
Intravenous - 100% bioavailability and immediate, bolus may cause adverse affects
Intramuscular - easier than IV for pt self administering, painful
Transdermal - bypasses first pass, slow effect
Intranasal - avoids first pass, quick effect but only for potent drugs as limited uptake from small volume of nasal cavity
Subcutaneous - good for slow release drugs, bad for large volume of drugs
Sublingual - bypasses first-pass, limit of drugs that can be taken this way
Inhalation
Rectal - Partially avoids first pass - ideal if drug causes vomiting, not well accepted route by patient

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4
Q

Where are most enteral (oral) drugs absorbed along GI tract?

A

Most in small intestine

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5
Q

Most drugs are weak _______ or _______

A

Acids or bases

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6
Q

Why is stomach not ideal for drug absorption?

A

Low pH isn’t compatible with most drug pKas and also mucous prevents absorption

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7
Q

What is the pH of small intestine normally between?

A

6-7

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8
Q

What are 4 major methods of drug absorption? Give a few drug examples

A

Passive diffusion - valproate
Facilitated diffusion - met formin - OCTs
Active transport - (more relevant for efflux of drug)
Pinocytosis (endocytosis) - large drugs e.g. insulin

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9
Q

What is the most common way for drugs to pass across GI membrane for absorption and what 2 things must the drug be for this to occur?

A

Passive diffusion - lipophilic and small (<500daltons)

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10
Q

What is the driving force for drugs to cross the GI membrane for absorption?

A

The concentration gradient

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11
Q

What happens at physiological pH to a weak acid and weak base?

A

Weak acids release a proton

Weak bases gain a proton

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12
Q

In the example of Valproate - only 10% is in unionised form in small intestine, why is this enough % for absorption?

A

Because small intestinal transit time is long 3-5hours but up to 10 so there is time for absorption even if 10% is unionised at any one time

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13
Q

What is the transit time for the small intestine?

A

3-5 hours but range from 1-10

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14
Q

How do drugs with low lipid solubility and an ionic charge get across intestinal membrane?

A

Using facilitated diffusion/secondary active transport using OCTs and OATs (cation and anion transporters respectively)

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15
Q

Give an example of a drug carried by OCT and OAT

A

OCT - metformin

OAT - methotrexate

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16
Q

What things affect drug absorption? Explain some examples of how these affect drug absorption.

A
  • Uptake in GI
  • Metabolism - First-Pass

Uptake in GI can be affected by: pKa of drug, pH of GI, food eaten, transit time, lipohilic nature of drug, GI length, Density of capillaries and amount of blood flow e.g. post exercise/shock it reduces.

Metabolism can affect drug absorption as drugs may be metabolised into inactive former reducing the therapeutic effects at target tissues

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17
Q

What is first-pass effect and what happens?

A

First stage of metabolism - drugs pass via hepatic portal vein to liver and some of the drug will enter hepatocytes and undergo phase I&II metabolism (CYP450 enzymes and conjugating enzymes)

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18
Q

Briefly describe what happens during phase I and II of drug metabolism and how this helps elimination

A

Phase I - CYP450 enzymes make drug molecules more charged by adding groups

Phase II - conjugating enzymes further increase charge by adding molecules to drug (most common glucoronate)

Aim is to make drug less lipophilic more hydrophilic as this aids elimination at the kidney (many OCTs and OATs and they carry highly charged molecules)

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19
Q

What is bioavailability and what does it determine? What is the equation? What is the bioavailability of IV administration and why?

A

Bioavailability is the fraction of drug given that will reach the systemic circulation. Equation is

Bioavail = amount drug reaching systemic circulation/total amount of drug administered.

Bioavailability of IV route is 1 because there are no absorption or first pass barriers.

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20
Q

Why is it useful to know bioavailability of different drug route administrations?

A

Because you can use it to decide which route of administration is best for therapeutic effect

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21
Q

What two functions of the small intestine help with absorption of drugs?

A

Villi and mixing of chyme (to deliver to large surface area)

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22
Q

What are the two main stages of drug distribution? Explain them

A

Bulk flow - large distances via arteries

Diffusion - smaller distances from capillaries to surrounding interstitium and tissues.

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23
Q

Why do drugs first reach highly vascularised organs? Name the organs (3)

A

Because rate of delivery of drug is dependant on density of capillary bed so drugs will first reach heart, kidneys, lungs.

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24
Q

What characterises of capillaries affect the diffusion through? Give examples of different types.

A

The ‘leakiness’ of capillaries affects diffusion through. E.g. capillaries may be:

Continuous - BBB - hard for drugs to get through

Fenestrated - e.g. intestinal, kidney with pores

Sinusoid - liver/spleen - incomplete basement membrane allows drugs through

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25
Q

What are 4 major factors that affect drug distrubtion?

A

1) Lipophilicity of drug to diffuse through
2) Degree to which drug molecule binds to plasma protein (won’t be distributed) e.g. albumin.
3) Degree to which drug binds to tissue proteins e.g. muscle
4) Mass or volume of tissue and density of binding sites within the tissue

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26
Q

How do plasma proteins act as a drug reservoir to reduce pharmacological effect? Give an example of a drug that binds to plasma proteins.

A

Because only free drug molecules can diffuse to target tissue to exert effect, up to 100% of drug can be bound in this way. 50% of aspirin can be bound in this way

27
Q

What is the volumes (L) of:

1) Plasma Water
2) Interstitial Water
3) Extracellular Water (interstitial plus plasma)
4) Intracellular Water
5) Total body Water

A 
3L
11L
14L
28L
42L
28
Q

What is Vd, what does it show?

A

Volume of distribution - indicates drug distribution between model ‘compartments’

29
Q

Many things can affect Vd - name 5 of the 10

A

1) Weight of patient
2) Changes in regional blood flow
3) Protein binding
4) Drug interactions
5) Renal failure
6) Drugs with narrow therapeutic window
7) Pregnancy
8) Age
9) Cancers
10) Anaesthetics - titration essential.

30
Q

What is the general range (L) of Vd

A

10-40L (somewhere in between extracellular and total body water).

31
Q

What can make the Vd appear higher or lower?

A

Higher - if very lipid soluble drug all will move from plasma to tissue = higher value

Lower - if all bound to proteins and can’t get out of plasma will give lower value

32
Q

Why might you see Vd written as just L or L/kg

A

If just L assume 70Kg person. If L/Kg will be a specific weight of person.

33
Q

Which groups may phase I enzymes introduce or unmask on a drug molecule to make it more polar?

A

OH or NH2

34
Q

What is the main conjugating molecule?

A

Glucoronate

35
Q

Why do you want drug molecules to not be lipophilic when they get to kidney for excretion?

A

Because they will just diffuse back into body down conc gradient, so need to be hydrophilic

36
Q

What are the 3 superfamilies of CYP and one common CYP?

A

1, 2, 3,

CYP3A4

37
Q

Are CYP450 enzymes specific or more general?

A

They are generalists so they deal with a wide range of drug molecules.

38
Q

Many factors affect drug metabolism - name a few of 5

A 
Age
Sex
Genetic status
Cardiac Output
Disease
39
Q

What does CYP450 induction and inhibition mean?

A

Induction is enhanced activity so will metabolise a drug quicker, so less therapeutic effect and quicker elimination

Inhibition is reduced activity so will elevate blood plasma levels and may cause toxic side effects

40
Q

Can induction of CYP450 cause adverse drug reactions?

A

Yes if toxic metabolites made

41
Q

What happens to Cabamezepine and why does it need to be monitored in the first few months after prescription?

A

Carbamezepene is metabolised by and induces CYP3A4 - can reduce the effects meaning risk of epilepsy still so need to monitor dose for a while

42
Q

When can metabolism active a drug? Give an example

A

When drug is take in pro-form phase I may activate drug e.g. Aspirin

43
Q

Where is excretion of most drugs carried out?

A

Kidney

44
Q

How can genetics affect drug metabolism?

A

E.g. some caucasians/africans don’t express certain CYP450s

45
Q

___(number of) CYP450 isozymes metabolise _______% of prescription drugs

A

6 90%

46
Q

What are the three main areas of kidney where excretion occurs? Broadly, what happens at each of these?

A

Glomerulus - filtration
Proximal Tubule - secretion
Distal tubule - reabsorption

47
Q

How much of renal blood flow serves glomerulus/proximal tubule

A

20%

80%

48
Q

How do drugs travel through Bowman’s Capsule? What do the capillaries have to allow this?

A

Diffuse as free form (not bound to protein) Bowman’s Capsule capillaries have slits to allow molecules through .

49
Q

How are drugs secreted into the tubular lumen of the proximal tubule?

A

Via OCTs and OATs - secondary active transport

50
Q

Are OATs and OCTs specific or general carriers?

A

General -
A- anions deprotonated weak acids
C - cations - protonated weak bases

51
Q

How are drugs reabsorbed in distal tubule? What does reabsorption of drugs do the the elimination rate?

A

Drugs in lipophilic form will diffuse down their conc gradient back into the blood = reduced elimination rate.

52
Q

How would drugs be in lipophilic form in distal tubule?

A

If drug pKa and distal tubule pH be favourable

53
Q

What affect would it have on the half life of 2 drugs if both used OCTs and taken together?

A

It may increase the half life as both will be competing for OCTs to eliminate. Elimination rate will be lower.

54
Q

Define drug half life

A

The time it takes for blood plasma [drug] to reduce by half that when initially measured.

55
Q

What equation may the exam use for half life (simplified)?

A

0.7 x Vd/CL

56
Q

Is half life dependent on Vd and CL?

A

Yes

57
Q

Define clearance

A

Rate of elimination of a drug from the body (hepatic and renal)

58
Q

Why is knowing clearance important clinically (3)?

A
  • designing dose schedules
  • avoiding ADRs
  • Designing regime of drug taking
59
Q

Whats HRH

A

Heart Renal Hepatic - things that can affect elimination (e..g blood flow to the area of elimination, renal elimination, hepatic metabolism)

60
Q

What is first order kinetics? What does it assume (2) ?

A

That drug elimination/metabolism is proportional to concentration of drug. Assumes plenty of phase I&II enzymes and plenty of OCT OAT transporters

61
Q

What is 0 order kinetics? When does it occur? What can happen?

A

Elimination/metabolism slows (on graph starts to plateau out). Occurs when CYP enzymes/OCTs OATs are at max capacity. Can cause increase [plasma drug] and ADRs/toxicity

62
Q

Is half life easier to predict with zero order or first order kinetics?

A

First order

63
Q

What common drugs give 0 order kinetics

A

Aspirin, fluoxetine, MDMA, alcohol, paracetamol

64
Q

How can polypharmacy lead to non linear kinetics?

A

As CYPs and OCTs OATs become saturated - this increases the chances of drug-drug interactions

PHYS/PHARM (10 decks)

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