Pharmacokinetics

Question 1

What is First Pass Metabolism?

Answer 1

Drugs getting metabolised in the liver before reaching systemic circulation.

Drugs also partially broken down in GI tract- food, bacteria, enzymes e.g. iron binds with calcium

Question 2

What is the Cmax?

Answer 2

Maximum concentration of drug in the body.

Question 3

What is the Tmax?

Answer 3

The time at which the maximum concentration (Cmax) occurred.

Question 4

What is the Half life (T1/2)?

Answer 4

The time it takes to get from maximum concentration (Cmax) to half of the maximum concentration (C1/2).

• Dependant on the rate of metabolism and renal excretion of the drug
• Usually on or below the minimum effective concentration

Half life Allows prediction of the timing of subsequent drug doses.

Question 5

What is the Area under the curve?

Answer 5

The total exposure to a drug the body reserves.

Question 6

What is the Volume of distribution (VD)?

Answer 6

How much drug needs to be in the body, to get a certain amount in the plasma. Total amount in the body/Total amount in the plasma.

Question 7

What is the MEC?

Answer 7

Minimum effective concentration. At this number there should be an onset of threaputic action.

Question 8

What is the difference between phase 1 and phase 2 metabolism?

Answer 8

Phase 1 is in the liver, before reaching systemic circulation. Phase 1, mostly activates or in activates the drug. Changes the chemical structure through oxidation, hydrolysis, or hydroxylation.
Phase 2 is the changing of the drug to be water soluble; ready for excretion.

Question 9

What is First Order of Kinetics?

Answer 9

The more of the drug in the plasma, the faster it gets excreted in the kidneys. Half-life remains the same through out.

Threaptuic drug doses maintain this.

Question 10

What is a Metabolite?

Answer 10

The product of a drug being metabolised.

Question 11

What is Zero Order of Kinetics?

Answer 11

In some situations, there is a limited amount of enzyme to metabolise the drug. The enzyme gets used up. If more drug is added to the body at this point, there is no more enzyme available to process the added drug. This means that the rate of excretion won’t change. Creates a bottle neck process, and the rate of excretion becomes independent of the amount of drug in the plasma. Half-life not a constant value, dependent on current concentration of the drug. Drug with Zero order kinetics are more easily overdosed.

Question 12

Different ways of drug absorption?

Answer 12

• Simple diffusion:
  Molecules move along a high – low concentration gradient
• Filtration:
  Small drug molecules filter through aqueous pores
• Carrier mediated diffusion (facilitated):
  passive process- uses a carrier molecule
  along a concentration gradient
• Active transport (facilitated):
  active process that uses energy and carrier molecule
  against a concentration gradient

Question 13

Difference between acidic and alkaline drugs?

Answer 13

Oral Drug Absorption

• Acidity or alkalinity of a drug/environment affects absorption “like best absorbed in like”
• Acidic drugs absorbed well in acidic environment of stomach
• Alkaline drugs absorbed in alkaline environment of duodenum
• Drugs predominantly absorbed across a concentration gradient- high concentration to low concentration

Question 14

Drugs taken with or without food?

Answer 14

• pH of stomach very acid so acidic drugs absorbed OK with meals
• Alkaline drugs may take longer to be absorbed if taken with food e.g. paracetamol, morphine
• Acid labile drugs – partly inactivated by food –must be given on an empty stomach e.g. alendronate, flucloxacillin
• Gastric irritant drugs should be given with food unless acid labile.

Question 15

Define Bioavailability?

Answer 15

Absorption measured as a % of the administered dose that reaches the systemic circulation = Bioavailability (Oral availability).

Bioavaliability is 100% of IV drugs as it is administrated directly into the systemic circulation.

Question 16

What is MTC?

Answer 16

Minimum toxic concentration.

Question 17

Define Onset of action?

Answer 17

Time taken until the drug reaches minimum effective plasma concentration.

Question 18

Lipophilic Vs Hydrophilic?

Answer 18

• Hydrophilic (water soluble) drugs soluble in plasma, but hard to cross membranes
• Lipophilic (fat soluble) drugs cross membranes but can get “trapped” in fat compartments.

Distrbution and Absorption

Question 19

Why is VD important?

Answer 19

• Fluid overload – water soluble drugs get diluted – less effect
• Dehydration- water soluble drugs more concentrated – risk of toxicity
• Less muscle mass- need smaller dose of water soluble drug e.g. digoxin
• More fat tissue - need a higher dose of lipid soluble drugs but effect takes longer to wear off

Question 20

Define protein binding?

Answer 20

Drugs form bonds with various proteins in the body.

Albumin is the most abundant protein in the plasma. Because of its size, Albumin can not leave the plasma. It is too large to squeeze between the pores of the capillary walls.

Drugs are smaller in size and therefore can pass the capillary walls and enter the system to get to their sites of action, metabolism or excretion.

Binding between albumin and drugs is reversible.

Even though drugs can bind to albumin, there is only a limited amount of drug that can bind to albumin at one time (due to the amount of receptor sites available for the drug on the protein)

The amount of drug bound to albumin at any time is determined by the strength of attraction between the two.

Warfarin = 99% protein biding, so only 1% can leave blood stream to reach action site.

Gentamicin (antibiotic) = 10% protein binding, so 10% can leave blood and reach action site.

Albumin only has few receptors for drugs to bind to. If two drugs are taken at the same time, the compete for the binding sites on the albumin. This results in one drug (drug a), displacing the other(drug b). This means that this is more of drug b available free in the blood and more of it can get through to action site and increase intensity of drug action. This may result in toxicity.

Question 21

Blood brain barrier?

Answer 21

• Blood brain barrier - many molecules can’t cross this barrier. Lipid soluble substances can diffuse across
• In older adults blood brain barrier not as effective – less soluble drugs can cross
• Drugs that cross into CNS – increased risk of seizures in susceptible clients e.g. pethidine, tramadol

Question 22

Liver importance?

Answer 22

Phase 2 metabolism. - Drugs need to be water soluble to be excreted.

• Drug may pass thru liver many times before drug water soluble enough to be inactivated and excreted.
• Two phases of metabolism.
  Phase 1 can inactivate the drug (metabolite might be active still)
  Phase 2 makes the drug metabolite water soluble – conjugation processes
• Liver impairment or decreased perfusion of the liver – less enzyme produced –prolonged drug effect

Question 23

Enzymes Metabolism in relation to INHIBITORS E.g cimetidine, grapefruit juice?

Answer 23

Prolongs action of drugs…….

or inhibits action of prodrugs

Question 24

Enzymes Metabolism in relation to INDUCERS E.g. barbiturates, carbamazepine, coffee,nicotine?

Answer 24

Shortens action of drugs……

or increases effects of prodrugs

Question 25

What are prodrugs?

Answer 25

Prodrugs are not active drugs until they are metabolised in gut or liver
Bio-transformed into the active drug
E.g ACE inhibitor enalapril (inactive)- converted to enalaprit (active)
E.g Codeine- converted to active analgesic by liver

Question 26

What is Polymorphism in drug metabolism?

Answer 26

Individual differences in the enzymatic processes used to metabolize drugs.
Can be inherited or acquired
Gender and racial differences
Drugs may be metabolized at a slower or faster rate or by different pathways
Common at CYP2D6 & CYP2C9- these enzymes metabolize 24% of all drugs

Question 27

What is Enterohepatic recycling?

Answer 27

• Metabolites can be de-conjugated ( converted back) into active drug
• This can occur in liver or GI tract
  Bacteria in GI tract often break down metabolite conjugate so drug reabsorbed back into blood stream
• Enzymes in GI tract also deconjugate metabolites
  1) Drug goes through phase 2 metabolism, gets conjugate and becomes water soluble ready for excretion.
  2) Excreted via bile into intestine.
  3) Enzymes in intestine reverses some metabolite conjugate (deconjugate)
  4) conjugate drug metabolite get excreted, deconjugate get reabsorbed into blood, have further drug actions.

In Oral contraceptive and Antibotics, this does not happen. Most drugs remain deconjugate metabolites and therefore Plasma oestrogen levels too low for effective contraception

Question 28

What does Drugs with fu of 1.0 mean?

Answer 28

Drugs with fu of 1.0 are excreted 100% unchanged in the urine
Drugs with a fu of 0.6 are excreted 60% unchanged in the urine

Question 29

What does Clearance of drugs mean?

Answer 29

Refers to the volume of plasma from which the drug is cleared per unit of time.
E.g 1ml/min of drug cleared from plasma
Usually refers to renal or hepatic clearance
When renal function impaired drug dose needs to be adjusted
Calculate creatinine clearance ( Cockcroft & Gault equation)
Calculate dose adjustment from creatinine clearance and fraction of drug excreted unchanged in urine

Question 30

Define Steady state?

Answer 30

Steady state: Amount of drug absorbed equals amount of drug excreted so steady plasma level of drug in body

Question 31

Define Therapeutic range?

Answer 31

Therapeutic range: The range between minimum effective concentration of a drug and minimum toxic concentration