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Pharmacology. > 5. Pharmacokinetics > Flashcards

5. Pharmacokinetics Flashcards

1
Q

What is drug absorption?

A

Movement of a drug from its site of administration to plasma. Not all drugs need absorbed e.g. bronchodilators or topical

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2
Q

What is first pass metabolism?

A

Oral drug is metabolised by the liver via the portal system prior to reaching the systemic circulation.

The other methods of administration can avoid this

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3
Q

What drugs have high first pass metabolism?

A

Morphine
Midazolam
Lidocaine
Aspirin
GTN

GLAMM

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4
Q

What is bioavailability?

A

The fraction of the administered drug that reaches the systemic circulation intact and so is available to act at the site of action. 100% for IV

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5
Q

How do we calculate bioavailability (BA)?

A

Plot a plasma concentration (y) against time (x) graph, for both IV and other drug to be calculated.

Then calculate the area under the curve.

BA (F) = AUC (PO) / AUC (IV)

F = fraction

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6
Q

What is absolute bioavailability (BA)?

A

Absolute BA = comparison with IV of the same drug. This is the most common description of BA

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7
Q

What is relative bioavailability (BA)?

A

Relative BA = for drugs that can’t be given IV, so comparison made between different formulations e.g. capsule vs. Tablet

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8
Q

What is volume of distribution and how is it calculated?

A

It is the theoretical compartment size a drug would need to occupy in order to give the measured plasma concentration.

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9
Q

How do we calculate concentration or volume?

A

Concentration = dose / volume

Volume = dose / concentration

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10
Q

In terms of distribution of drugs, what is the rough Vd of the following and why?

Small, non polar?
Small polar?
Large polar?

A

Small non, pass through all compartments and so have a Vd equivalent to TBW = around 40L.

Small polar = pass to plasma and ICF so Vd around 14L

Large polar stay in the plasma so Vd around 5L

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11
Q

Why are volumes of distribution often much higher than TBW and what factors effect this?

What drugs do this?

A

There are several other compartment in the body that substances can move to.

Fat e.g. propofol
Bone e.g. bisphosphonates
Thyroid sequestration e.g. iodine
Tissue binding e.g. digoxin
Protein binding e.g. phenytoin or NSAIDs

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12
Q

How do we calculate a drugs loading dose?

A

VD x target concentration

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13
Q

What are the two main protein that bind to drugs in the plasma?

What are the features of this system in terms of: binding, saturation and equilibrium?

A

Albumin = weak base so binds acidic
Alpha - 1 - acid - glycoprotein (ACG) = weak acid so binds to basic drugs.

All binds weak, so undergo competitive displacement
System is saturatable so can get increased free drug levels with low proteins.
Equilibrium reached between bound and free drug

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14
Q

What is the risk with drugs that are over 90% protein bound and what are examples of these drugs?

A

They have a small therapeutic window as small changes in binding can cause toxicity.

E.g. phenytoin and ibuprofen.

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15
Q

What is the role of metabolism?

A

It is bio transformation that transforms hydrophobic molecules into more polar hydrophilic ones to allow them to be excreted via bile or urine.

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16
Q

Do all drugs go through all phases of metabolism?

What are the different routes they can take?

A

No.

Can do phase 1 then 2 then excretion.
Some do phase 1 then excretion.
Some go straight to phase 2 and are then excreted.
Some are excreted unchanged.

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17
Q

Does drug metabolism turn active molecules to inactive?

A

No some do the opposite.

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18
Q

What is the function of phase 1 of metabolism?

What kind of metabolites does this produce?

A

To add or uncover functional groups (OH, SH or NH) to molecules to prepare them for phase 2/excretion. Uses the cytochrome system.

Usually created intermediate metabolites that can be highly reactive or toxic.

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19
Q

What are the three phase 1 metabolic reactions?

A

Oxidation
Reduction
Hydrolysis

20
Q

What is oxidation in phase 1 metabolism?

Some example drugs?

A

Most common phase 1 reaction
Loss of electrons or gain of O (H removal)

Paracetamol and benzo’s

21
Q

What is reduction in phase 1 metabolism?

Some examples?

A

2nd most common phase 1 reaction
Gain of electrons, so usually loss of oxygen or H added.
CYP mediated

Halothane undergoes this to toxic metabolites, especially if liver is hypoxic.

22
Q

What is hydrolysis in phase 1 metabolism?

Are all CYP mediated?

Examples?

A

Splitting into two molecules by adding water.
One = -OH and second = -H

Some non CYP

Hoffman degradation

23
Q

What is phase 2 metabolism?

A

The synthetic phase, involving conjugation with another molecule.
Uses transferases

24
Q

What are the different phase 2 metabolism reactions?

A

Glucuronidation
Sulphation
Acetylation
Methylation
Glutathione conjugation

25
Q

What is phase 2 glucuronidation?

What drugs is this important for?

A

Most common reaction - adds most MW to molecules
Conjugates with glucuronic acid via UDP glucuronyl transferase

Important for morphine (activates) and propofol (inactivates)

26
Q

What is phase 2 sulphation?

A

Adds sulphur to amine via sulphotransferase
Adds second highest MW

27
Q

What is phase 2 acetylation?

Is this done at a standardised speed?

A

Transfer an acetylene group to primary amine via N acetyltransferase, with acetyl COA as the carrier group.

Genetic polymorphisms give fast and slow acetylators.

Adds third highest amount of MW

28
Q

What is phase 2 methylation?

A

N or O methyltransferases e.g. catecholamines.

29
Q

What does glutathione conjugation achieve?

A

Detoxification to allow excretion or hydrolysis.

30
Q

How is paracetamol metabolised?

A

40% methylation and 40% glucuronidation to non toxic.

Small amount metabolised by CYP to NAPQI which causes necrosis.

This is avoided via glutathione conjugation and renal excretion.

NAC is a glutathione precursor.

31
Q

What is the hepatic extraction ratio?

How do we calculate it?

How is it related to first order kinetics?

A

It is the fraction of blood extracted during one pass through the liver.

Hepatic extraction ratio = concentration in blood entering (Ci) - concentration in blood out (Co) / Co

It is the rate limiting factor in first order kinetics.

32
Q

How do we calculate hepatic clearance?

A

Hepatic clearance = hepatic blood flow x HER

33
Q

What HER values signify high and low clearance and what does this mean?

What drugs are examples of each?

A

HER over 0.7 = rapid clearance, meaning the rate is mainly dependent on blood flow e.g. propofol, fentanyl and lidocaine.

HER under 0.3 = low clearance, meaning this is dependent on liver enzyme ps and not flow e.g. warfarin and phenytoin.

34
Q

What are the different sites of metabolism?

What happens in some of these areas?

A

Liver - contains CYP and esterases, gets high CO.

Gut: enterohepatic recycling when gut enzymes revert previously liver metabolised drugs and reabsorbs e.g. morphine.

Renal

Lungs

Blood: RBC esterases and some CYP.

35
Q

What is a prodrug and example?

A

Has no intrinsic activity until undergoes hepatic metabolism e.g. prednisone to prednisolone and codeine.

36
Q

What are the different categories of factors that can affect metabolism?

What are these with examples?

A

Intrinsic:
Age: old = reduced enzymes and flow = reduced phase 1 and more phase 2. Young = underdeveloped enzymes and crcl.
Sex: men = faster phase 2. Women slower paracetamol.
Enterohepatic circulation: reduced transit = increased recycling.
Polymorphisms: acetylators and esterases etc.
Disease: liver, kidney etc.
Obesity: increased phase 2 and difficult dosing.
Pregnancy: progesterone is and enzyme inducer. Decreased esterases.

Extrinsic:
Enzyme induction/inhibition.
Diet.
Drugs: antibiotics etc.

37
Q

What are the main routes of excretion?

What happens/effects each?

A

Kidney = main. Blood flow and pressure.
Biliary: preferentially for large molecules, effected by gut transit and cholestasis
Pulmonary: affected by blood flow
Salivary: unionised and lipid soluble. Gives bad taste, usually swallowed and recirculated.
Mammary: passive
Skin and mucous membranes: e.g. alcohol (red face) and rifampicin (coloured tears).

38
Q

What are the three main steps in renal excretion of drugs?

What happens at each step?

What is the net flow equation?

A
  1. Glomerular filtration: large pores allows drugs under 7000 Da to freely move in PCT. Negatively charged are repelled by negatively charged GBM.
  2. Tubular reabsorption: mostly passive reabsorption of lipophillic, non ionised in the PCT.
  3. Active tubular secretion: transported against concentration gradient to be excreted in urine

Renal clearance = GF + ATS - TR.

39
Q

What is clearance?

How would we calculate total clearance?

A

Volume of plasma completely cleared of a drug per unit of time.

Total clearance = hepatic clearance + renal clearance + biliary clearance + other cl

40
Q

What is the clearance equation for a one compartment model?

Elimination equation?

A

CL = Vd x Ke (= elimination rate constant)

Ke = time taken for concentration to fall to 1/eth (36.7 %) of the starting number. E = eulers number (2.716…..)

Elimination = concentration x clearance

41
Q

What is the time constant in a 1 compartment model?

A

Time taken for complete plasma clearance if the initial rate of clearance continued.

It is the inverse of Ke (1/ke)

42
Q

What is the elimination half life?

What is left after the first 5 half lives?

After how many half lives is elimination complete?

A

Time taken for plasma concentration to fall by 50%

50% after 1, 25% after 2, 12.5% after 3 etc.

5 half lives = 3.125% left or 97% eliminated.

Said to be complete after 4.5 half lives

43
Q

What is the equation for half life?

A

T 1/2 = 0.693 x (Vd/cl)

44
Q

How does first order kinetics relate to elimination in terms of rate and clearance?

A

First order kinetics has a constant proportion/fraction of drug eliminated per unit of time. The rate is not constant but proportional to drug concentration. As plasma concentration drops, the rate of elimination also drops.

Cl = rate of elimination/concentration

Clearance is constant, so half life is constant.

45
Q

How does zero order kinetics relate to elimination?

Some drug examples?

A

Everything saturated, so a constant rate of elimination e.g. 20mg/h

Clearance rate is variable.

Warfarin, alcohol, aspirin and thio.

46
Q

What is steady state concentration?

When is it achieved?

A

Repeated doses lead to a balance between absorption and elimination.

Usually takes 5 half lives, if dose is given every half life.

Pharmacology. (22 decks)

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