Pharmacokinetics and Drug Metabolism

Question 1

State the five stages of the journey of a drug through the body.

Answer 1

Administration - i.e. drug enters body

Journey through body (ADME):

• Absorption
• Distribution
• Metabolism
• Excretion

Removal - i.e. then the drug is removed from the body

Question 2

What are the different routes of drug administration?

Answer 2

• Dermal
• Intramuscular - deep into muscle
• Subcutaneous - into subcutaneous tissue = layer between skin and muscle (connective tissue layer)
• Intraperitoneal - into peritoneal cavity
• Intravenous
• Inhalation
• Ingestion

Question 3

What is the difference between systemic and local drug administration?

Answer 3

Systemic = affects the entire organism

• So for a systemic effect, it needs to enter the systemic circulation in order to reach its target site and have an effect
• Examples:
  
  • aspirin - taken orally
  • nicotinic patch - need to enter bloodstream to act on brain

Local = restricted to one area of the organsim

• So for a local effect, the drug is administered at the site of action (doesn’t need to enter systemic circulation and you don’t want it too either)
• Examples:
  
  • antacids - taken orall

Question 4

What is the difference between enteral and parenteral administration?

Answer 4

Enteral = via the GI tract

• Doesn’t have to start from mouth, drug can be administered into any part of the GI tract, e.g. directly into stomach

Parenteral = not via the GI tract

Question 5

What are the advantages of intravenous administration?

Answer 5

It gives rapid systemic exposure and a high bioavailability

Question 6

State the two ways in which drug molecules move around the body.

Answer 6

Bulk Flow Transfer – in the bloodstream it will move in bulk to the tissues

Diffusion Transfer – molecule by molecule over short distances

Question 7

Which two environments do drugs have to traverse?

Question 8

What is important to consider about the oral route of administration of drugs?

Answer 8

The drug has to cross lipid barriers (GI tract epithelium and capillary endothelium) in order to enter into the systemic circulation and be able to reach its target tissue

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Question 9

State four methods by which drugs can cross lipid membrane barriers.

Answer 9

• Diffusion through the lipid membrane
  
  • If appropriately lipophilic)
• Diffusion through aqueous pores
  
  • Less common because drugs have to be <0.5mm
• Carrier-mediated transport
  
  • i.e. Binds to carrier protein → conformational change of carrier protein → drug transported onto other side of membrane
• Pinocytosis
  
  • i.e. Endocytosis of small particles suspended in ECF

NOTE: drugs diffuse down their electrochemical gradient

Question 10

Finish the sentence: most drugs are either …… or ……

Answer 10

Weak acids or weak bases

Question 11

Which factors affect the ratio of ionized to non-ionized drug?

Answer 11

pKa of the drug pH of the environment

Question 12

What is K_a and pK_a?

Answer 12

K_a = acid dissociation constant

• This is essentially a measure of how much (i.e. what percentage of) a weak acid dissociates
• Higher K_a = more dissociation = stronger acid
• pK_a = -log₁₀[K_a] → therefore lower pK_a = stronger acid
• Therefore weak bases have a higher pK_a than weak acids (stronger base = weaker acid)

Question 13

What is the pH partition hypothesis?

Answer 13

Weak acid equilibrium (e.g. aspirin HA):

• HA ⇌ H⁺ + A^-
• pK_a = 3.5 → lower pK_a = higher K_a
• Higher Ka means more dissociation (i.e. proton loss)

Weak base equilibrium (e.g. morphine B):

• B + H⁺ ⇌ BH⁺
• pK_a = 8 → higher pK_a = lower K_a
• Lower K_a means less dissociation (i.e. less proton loss → proton gain)

Question 14

What equation can be used to determine the ratio of non-ionised : ionised drug in an environment with a certain pH?

Answer 14

NOTE:

• 10^{[pKa - pH]} is the ratio (non-ionised ÷ ionised)
• A value of 100 means:
  
  • 100 non-ionised molecules : 1 ionised molecule
  • Value > 1 means you have more non-ionised
• A value of 0.01 means (1 ÷ 0.01 = 100)
  
  • 1 non-ionised molecule : 100 ionised molecules
  • Value < 1 means you have more ionised
• When pK_a = pH the ratio is 1:1 because 10⁰ = 1

IMPORTANT:

• pK_a of drug DOES NOT change
• pH of different body compartments DO change

Question 15

Describe and explain the difference in the ratio of non-ionised : ionised aspirin in the stomach and the small intestine. How does this affect the absorption of aspirin?

Answer 15

HA ⇌ H+ + A- (where HA is aspirin in its non-ionised form)

pKa of aspirin = 3.5

Stomach:

• Stomach pH = 3 (acidic)
• More protons in stomach so [H+] increases
• Therefore, equilibrium shifts to the left forming more HA (non-ionised form)
• 10^{[pKa - pH]} = 3.16 (> 1 so more non-ionised)
• Therefore, in the stomach, aspirin mainly exists in the unionized state and is rapidly absorbed (non-ionised molecues can easily cross lipid bilayers and enter into bloodstream via the stomach)

Small intestine:

• Small intestine is a basic environment
• Small intestine pK_a > aspirin pK_a
• Bases are proton acceptors so the [H+] will decrease
• Therefore, equilibrium shifts to the right forming more H+ and A- (ionised form)
• 10^{[pKa - pH]} = <1 because 10^-n (so more ionised)
• Therefore, aspirin in the small intestine is mainly in the ionised formand hence absorption is slower

Question 16

How can you increase the excretion of aspirin in the urine?

Answer 16

HA ⇌ H⁺ + A^- (where HA is aspirin in its non-ionised form)

Aspirin pK_a = 3.5 (weak acid)

• Urine pH = 8 (weak base)
• Bases are proton acceptors so the [H+] will decrease
• Therefore, equilibrium shifts to the right forming more H+ and A- (ionised form)
• 10^{[pKa - pH]} = 0.00003 (NI : I = 1 : 30000)

To increase renal excretion:

• Increase the pH (e.g. by treatment with IV sodium carbonate)
  
  • You get an even bigger equilibrium shift to the right forming more ionised aspirin
  • 10^{[pKa - pH]} decreases even more so the proportion of ionised aspirin increases even more
• You want the most of the aspirin to be ionised once in the urine so that it cannot cross lipid bilayers and move back into the kidney tubule cells and be reabsoprbed back into the blood

Question 17

What is ion trapping?

Answer 17

If the pH of the environment is too far above the drug’s pKa, the drug may become ‘ion-trapped’ as it is mainly in ionised form and thus isn’t passively diffused much.

Example:

• Normally blood pH = 7.4
• 10^{[pKa - pH]} = <1
• Therfore, aspirin in the systemic circulation will mainly exist in an ionised form
• As it is ionised it will not be able to move into the tissues and hence is ‘trapped’

Question 18

State four factors affecting drug distribution.

Answer 18

• Regional blood flow
• Extracellular binding (plasma-protein binding)
• Capillary permeability
• Localisation in tissues

Question 19

Explain how regional blood flow affects drug distribution.

Answer 19

Highly metabolically active tissues have denser capillary networks

• This means that they receive a greater proportion of the cardiac output
• Assuming that the drug is evenly distributed within the systemic circulation, this means that these tissues would also receive a greater proportion of the drug

Question 20

In which state can plasma proteins bind to drugs? Ionised or non-ionised?

Answer 20

Both in the ionised and unionised form

• 50-80% of acidic drugs tend to be found in the systemic circulation bound to plasma proteins
• Plasma-protein bound drugs can’t get into the blood because most capillaries are continuous
• This means they have water-filled gap junctions between the endothelial cells, which the plasma proteins cannot get through (too large)
• So dose needs to be adjusted taking into account plasma protein binding

Question 21

State three types of capillary architecture. Explain how this affects drug distribution.

Answer 21

It is important to bear in mind that different tissues (e.g. CNS, kidneys, placenta) have different capillary structures

Continuous

• Very small drugs (not common) can diffuse through the water-filled gap junctions
  
  • No option for this in BBB due to tight junctions between endothelial cells
• Otherwise, need some other transport mechanism to transport them across the endothelial membrane (e.g. carrier mediated transport, pinocytosis)

Fenestrated

Discontinuous

• Fenestrated and discontinous capillaries have bigger gaps (big enough to allow some proteins to pass through)
• Therefore, it would be easier for drugs to pass through these gaps and get into tissues

NOTE: Capillary permeability is not really relevant for lipid soluble drugs as they could just passively diffuse out by crossing the lipid membranes of the endothelial cells

Question 22

Give a broad example of localization of a drug in tissue.

Answer 22

Lipophilic drugs tend to localise in fatty tissues e.g. brain and testes

• Fat (adipose tissue) isn’t usually highly perfused
  
  • 15% body weight but 2% blood supply
• Drugs that are very lipophilic tend to localise in adipose tissue
  
  • 75% partitioned in fat at equilibrium
  • Essentially once the drug diffuses from the blood into the adipose tissue, becuase it is so lipid soluble, it tends to stay there
  • It will slowly leak back into the plasma
    
    • A small proportion will diffuse across the lipid membranes into back into the blood
    • But most will stay within the adipocytes

Question 23

What are the two main routes of drug excretion?

Answer 23

Kidneys

• Ultimately responsible for the elimination of most drugs

Liver

Question 24

What are some other routes of drug excretion?

Answer 24

• Lungs (expiration)
• Skin (sweat)
• GI secretions (incl. saliva)
• Milk (breastmilk)
• Genital secretions

Question 25

Describe drug excretion in the kidneys.

Answer 25

Ultrafiltration - glomerulus

20% of the plasma is filtered by the glomerulus during ultrafiltration

• This only applies to low molecular weight drugs
• Plasma-protein bound drugs will NOT be squeezed out (too large to fit through the gaps)

Active Secretion - PCT

• Acidic/basic drugs are actively secreted into the urine - as not all was excreted during ultrafiltration
• This is dependent on whether the relevant transporters are available
• But the kidney has has so many different transporter to transport the range of substances it encounters
• Therefore, there should be a transport protein which fits the drug (i.e. allows its transport)

NOTE:

• Some of the acidic/basic drug molecules need to be in the ionised form - these need to be actively secreted
• Lipid soluble molecules don’t undergo active secretion - they just passively diffuse through lipid membranes

Passive reabsorption - DCT/collecting duct

Lipid soluble (non-ionised) drugs can diffuse through the lipid membranes of the DCT/collecting duct cells and be reabsorbed back into the blood

Question 26

What types of molecule tend to get excreted via the biliary route (i.e. by the liver)?

Answer 26

Usually large molecular weight drug conjugates are concentrated in bile

• Some drugs form conjugates with large molecules as part of their metabolism process in the liver
  
  • Most commonly form conjugates with glucuronic acid → glucuronides
• This is done to make them more polar
  
  • Polar molecules are easier to excrete
  • This is because they stay in the bile/urine and don’t cross lipid membranes and be reabsorbed back into body tissues
• These drugs are usually actively secreted into the bile, which then enters the GI tract
  
  • There are active secretion systems for bile acids and glucuronides
• The drug is then excreted through the faeces

Question 27

What is a potential problem with biliary excretion of drugs?

Answer 27

Enterohepatic cycling

• The drug conjugate is excreted into the liver via bile
• However, gut bacteria cause breakdown of the drug conjugate to release the free drug
• The free drug can then be reabsorbed back into the portal circulation → taken to liver → excreted again in bile
• This leads to drug persistence

Question 28

Define bioavailability.

Answer 28

The proportion of the administered drug that is available within thebody to exert its pharmacological effect

Question 29

Define apparent volume of distribution.

Answer 29

The volume in which a drug appears to be distributed – an indicator of pattern of distribution

Question 30

Define biological half-life.

Answer 30

The time taken for the concentration of a drug (in blood/plasma) to fall to half its original value

Question 31

Define clearance.

Answer 31

The volume of plasma cleared of a drug per unit time

Question 32

Define First-Order kinetics.

Answer 32

When the rate of drug excretion is proportional to the concentration of drug remaining within the body Log of drug concentration is proportional to time

Question 33

State the equation for half-life in first-order kinetics reactions.

Answer 33

T1/2 = Vd x log(2)/Cl Vd = volume of distribution Cl = clearance

Question 34

Define Zero-Order kinetics.

Answer 34

A constant amount of drug is removed from the body per unit time

Question 35

What does zero-order kinetics suggest about the enzymes involved?

Answer 35

It suggests that the enzymes are saturated Once the enzymes are saturated, the rate of removal of a drug peaks and remains constant NOTE: most drugs follow first-order kinetics

Question 36

Give an example of a drug which is a weakacid and one that is a weak base. What will happen to them at physiological pH?

Answer 36

Aspirin = weak acid

• At physiological pH (7.4), aspirin will be more likely to donate protons

Morphine = weak base

• At physiological pH (7.4), morphine will be more likely to accept protons