Pharmacokinetics

Question 1

Distinguish between pharmacokinetics and pharmacodynamics.

Answer 1

Pharmacodynamics = What the drug does to the body
Pharmacokinetics = What the body does to the drug

Question 2

Identify the steps in the time course of drug distribution.

Answer 2

LIBERATION = the release of the drug from it’s dosage form

ABSORPTION = the movement of drug from the site of administration to the blood circulation

DISTRIBUTION = process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues)

METABOLISM = chemical conversion or transformation of drugs into compounds which are easier to eliminate

EXCRETION = elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.

Question 3

List the major routes of drug administration, plus their benefits and drawbacks.

Answer 3

ORAL
Pros: Convenient
Cons: First-pass effect (reduced systemic availability of the drug as a result of significant metabolism), many variables and barriers.

SUBLINGUAL
Pros: No first-pass effect
Cons: Inconvenient, small dose limit, taste

INHALATION (gets drugs to lungs)
Pros: Fast, rapid delivery to blood
Cons: Requires special properites of drug (e.g. atomised, vapourised)

TOPICAL
Pros: Convenient, localised
Cons: Only local

TRANSDERMAL
Pros: Prolonged release
Cons: Skin very effective barrier

INTRAMUSCULAR
Pros: Rapid for aqueous, slow for oil
personnel
Cons: Painful, requires trained

INTRAVENEOUS
Pros: Direct, total dose (no first-pass effect), rapid, if short half life of elimination of a drug then possible to continuously infuse it instead (otherwise would only have an effect for v short time)
Cons: Requires professional, infection
risk, rapid response

Question 4

Which route of administration is most commonly used ?

Answer 4

Oral

Question 5

Define bioavailability. What is the relative bioavailability of oral vs IV ?

Answer 5

Fraction of unchanged drug that reaches the systemic circulation

IV injection gives 100% bioavailability
Oral intake much lower bioavailability due to being vulnerable to enzymes, acidic environments, liver metabolism before reaching systemic circulation.

Question 6

How may we calculate percent bioavailability of an oral drug ?

Answer 6

% Bioavailability oral drug = (Area under curve for oral drug / Area under curve for intravenous drug) x 100
in graph showing bioavailabilities of IV and oral injections.

Question 7

Identify the ways through which small molecules cross cell membranes. How is this concept of crossing cell membranes relevant to pharmacology ?

Answer 7

1) Diffusing directly through the lipid
- Lipid solubility highly important (need to be lipophilic and ideally unionised)

2) Diffusing through aqueous pores
- More likely important for diffusion of gases

3) Transmembrane carrier protein
- e.g. solute carriers

4) Pinocytosis
- Mostly macromolecules, not drugs

This is relevant because it applies to oral drugs getting into plasma but also
drugs already in plasma trying to get to target tissues.

Question 8

Relate the general chemical properties of a drug to its subsequent absorption and distribution throughout the body.

Answer 8

1. Hydrophilic vs Lipophilic
   - Hydrophilic drugs are soluble in aqueous, polar media such as blood plasma, cytosol and interstitial fluid (hence require transmembrane proteins to enter cells)
   - Lipophilic drugs are soluble in fats and non-polar solutions such as interior of the lipid bilayer and fat (hence can diffuse easily)
2. Ionisation state
   -Affects drug absorption
   -Many drugs are weak acids or bases (e.g. local anaesthetics weak bases)
   -Ionised:unionised ratio depends on pH
   -Ionised drugs have low lipid solubility
   -Depending on whether weak acid or weak base, more preferentailly or less preferentially absorbed in different parts of GI (since different pH in different compartments of GI, meaning they may be ionised in some and
   unionised in others)

Question 9

Which kinds of drugs barriers to absorption affect ?

Answer 9

Those that are not injected directly to the systemic circulation (e.g. oral drugs)

Question 10

Identify the factors that affect distribution.

Answer 10

• Degree of drug ionisation
• Lipid solubility
• pH of compartments
• Cardiac output and blood flow (Influences how much exposure specific tissues have. e.g. small amounts of drugs distributing to fat tissue at slow rate because low blood supply there. On the other hand drug distribution to kidney much faster)
• Capillary permeability (Eg brain tight permeability)
• Plasma protein binding (Lipophilic drug in plasma tightly bound to proteins)

Question 11

Explain the compartment model.

Answer 11

-Oral drugs start out circulating in a reservoir in the GI system. They then undergo absorption to get to a single, well-stirred compartment (PLASMA + potentially EXTRACELLULAR FLUID, depending on whether drug travels there or just stays in plasma, like warfarin). As soon as drug is in this compartment, it is susceptible to excretion and metabolism.
-This first compartment can be explained as one volume (Vd)
-IV drugs are given directly in this second, well-stirred compartment (and hence vulnerable to excretion and metabolism).
-Some drugs have a second compartment (peripheral compartment)
E.g. biphosphonates in bone (high affinity to calcium). Only way for them to get out again is for them to get back into compartment where they are susceptible to excretion and metabolism

Question 12

Describe the main characteristics of biphosphonate, in the context of pharmadynamics.

Answer 12

• Phosphonate groups have a high affinity for calcium
• Quickly distributed to the skeleton
• Oral alendronate – Daily/weekly
• IV zoledronate – Yearly (binds more substantially)

Question 13

Discuss the effects of protein binding upon the distribution and availability of drugs within the body.

Answer 13

• A drug must be free to distribute widely or bind to its receptor (otherwise may not have its effect)
• BUT many drugs bind to plasma proteins (such Albumin, α-1 acid glycoprotein, Lipoproteins, Globulins) so fraction of unbound drug can be as low as 1%
• Competition for binding sites on plasma proteins can cause big increases in free drug concentrations

-For instance, 98% of warfarin bound to albumin. BUT, Aspirin has high affinity for albumin so in presence of aspirin, some warfarin is dislodged due to competition and the amount of unbound warfarin undergoes relatively large increases

Question 14

Explain the general concept of pharmacokinetic compartments.

Answer 14

-Body water is distributed in to four main compartments (intracellular water, interstitial water, transcellular water, and plasma water)
-Specialist compartments also exist (e.g. fat, bone)
-These compartments may differ in pH,
-The degree of distribution between these compartments depends on tissue- and drug- dependent factors (including perfusion)
-Side-effects of some drugs can be minimised by limiting their distribution via the route of administration
-Only unbound (free) drug molecules can cross from one compartment to the other
(binding occurs within compartments)

Question 15

Relate the general chemical properties of a Pilocarpine and Bethanechol to their subsequent absorption and distribution throughout the body.

Answer 15

Both non-selective muscarinic agonists

BETHANECHOL

• Quaternary ammonium
• Poorly absorbed and distributed
• If given orally, action will limit itself to where it can get (which is limited given how poorly absorbed it is, so mainly used just for bladder and gastrointestinal hypotonia)

PILOCARPINE

• Tertiary amine
• Better absorbed and distributed because slightly less charged
• As a result, more systemic effects if given orally (including for glaucoma to decrease IOP, for xerostomia following head/neck radiotherapy, and to constrict pupils = miosis)

Question 16

Describe the function and phases of drug metabolism.

Answer 16

“Aim” is to produce metabolites that can be excreted

PHASE 1
• Generally oxidation, reduction or hydrolysis – Introduce/reveal a reactive chemical group
– “Functionalisation”
• Products often more reactive (If accumulate phase I compounds, likely to see some toxicity arising)

PHASE 2:
• Synthetic, conjugative reactions
• Hydrophilic, inactive compounds usually generated (detoxifying phase), which can be secreted out of body much more easily

Some will undergo phase 1, some will only undergo phase 2. In general, not necessarily phase 1 then phase II

Drugs that take the conjugate —> intestines route are vulnerable to deconjugation. Bacterial environment in GI tract can reverse phase II process (deconjugation) and cause re-uptake (liberates the drug)
Drugs that undergo this process have a long half life

Question 17

Where does drug metabolism take place ?

Answer 17

In liver

Question 18

Describe the features of and identify the main group(s) of enzymes in the metabolism of drugs.

Answer 18

CYTOCHROME P450 ENZYMES
-Phase 1 enzymes
-Mixed function monooxygenases
-Found throughout the body, extensively in the liver
-57 human genes coding for CYP P450 enzymes
-Functions:
• Biosynthesis of steroids, fatty acids and bile acids
• Metabolism of endogenous and exogenous substrates
-Genetic variability in metabolic enzymes occurs, and expression of metabolic enzymes can be induced and/or inhibited
-Competition for metabolic enzymes occurs and metabolic pathways can be saturated (e.g. paracetamol)

Question 19

Describe the metabolism of paracetamol.

Answer 19

• Sulphate and Glucoronide conjugates undergo phase II metabolism of paracetamol, without phase I
• Small part of paracetamol undergoes phase I metabolism. This results in the production of toxic metabolite (reactive) due to action of cytochtome p450 in phase I metabolism.
• Normally in body, glutathione at normal levels conjugate with reactive metabolite, detoxify it and allow its conjugation and easy excretion from body
• If increase amount of paracetamol taken, larger accumulation of drug that undergoes phase I metabolism. Start to saturate how much sulphate conjugation and glucaronate conjugation you can do
• Size of part of paracetamol undergoing phase I metabolism increases and so does demand on glutathione and eventually deplete glutathione levels and end up with reactive metabolite of paracetamol then combining with hepatocellular proteins and structures within liver, so end up with hepatocellular necrosis and other injuries associated with toxicity of paracetamol.
• Acetylcysteins to restore glutathione levels back to normal, to detoxify metabolite and limit amount of damage caused

Question 20

Identify factors which affect bioavailability of warfarin and statins respectively.

Answer 20

1. WARFARIN
   - Warfarin is metabolised by CYP450s
   - Phenobarbital ↑ expression of CYP450s
   - As a result of Phenobarbital, bioavailability of warfarin and patient’s response to warfarin decreases (rate at which it is metabolised increased)
2. STATINS
   - Simvastatin metabolised by CYP3A4 in the gut wall and liver (high first pass metabolism, only ~5% reaches circulation)
   - Grapefruit juice blocks CYP3A4
   - As a result of grapefruit, bioavailability of statins increases

Question 21

Describe the metabolism of non-depolarising NMJ blockers. Why is it significant that they have different metabolism routes ?

Answer 21

Different routes of metabolism allow for patient- specific choices to be made (– E.g. Genetic variability, disease state, other treatments)

-Vecuronium: liver – eliminated via the urine and bile (Unaffected by plasma cholinesterase polymorphisms but affected by liver/kidney function)
-Atracurium: Spontaneous degradation in plasma (unaffected by liver/kidney function
or plasma cholinesterase status)
-Mivacurium: Plasma cholinesterase (Plasma cholinesterase polymorphism linked with lower affinity to drug so higher effect,
But unaffected by liver/kidney function)

Question 22

What are possible sources of excretion ?

Answer 22

• Breath
• Urine
• Saliva
• Perspiration
• Hair
• Faeces
• Milk
• Bile

Question 23

Which organ is most involved in the elimination of drugs (and their metabolites) ?

Answer 23

Kidneys

Question 24

Are drugs eliminated unchanged, or changed ?

Answer 24

Drugs are eliminated either unchanged or as metabolites

Question 25

Which of hydrophilic or phobic drugs are eliminated easier ?

Answer 25

• Hydrophilic drugs eliminated more readily than lipophilic drugs (except the lungs)

Question 26

Define distribution in the context of pharmacokinetics.

Answer 26

Reversible transfer of a drug from one location to another within the body. Once a drug enters into systemic circulation by absorption or direct administration, it must be distributed into interstitial and intracellular fluids

Question 27

Describe the shape of the graph of plasma concentration vs time for biphosphonates.

Answer 27

1. Sharp up (IV injection) 2. Comes down as drug getting removed to bone 3. Long tail as process of drug slowly leaking from bone back to plasma to allow it to be metabolised in liver removes it slowly from body (i.e. process of distribution)

Question 28

What are the main pros and cons of using plasma concentration as an indicator of what's going on ?

Answer 28

Pro: Very easily samplable Con: Does not provide the full picture (most drugs will not have their effect in plasma but in tissue)

Question 29

Define the therapeutic window.

Answer 29

Window of plasma drug concentration above the minimum effective concentration but below minimum toxic concentration.

Question 30

Do therapeutic windows apply to all drugs ? Explain.

Answer 30

No, for instance chemotherapy (even above minimum effective concentration already damaging cells so also to a certain extent above minimum toxic concentration).

Question 31

With food in the stomach, does it take more or less time for paracetamol to have an effect ?

Answer 31

More time (20-30 minutes more)

Question 32

Which one of onset of action or duration of action may be easier to measure ? Why ?

Answer 32

Onset. Because in the case of duration, some drugs because may be inducing change in genetic profile phenolbarbitone, thereby inducing cytochrome p450. If this happens then elevation of enzymes will last longer than presence of drug in plasma (hence duration depends on which kind of drug it is)

Question 33

Define absorption half life, and describe its use in pharmacokinetics.

Answer 33

The time taken for half of the drug waiting to be absorbed to reach the systemic circulation (How long drug takes to get to body) -May be used to determine Tmax (If change absorption half life, change rate and time it takes to get to Tmax) - Drugs with longer absorption half lives take longer to produce an effect (later onset) but then have a longer duration of action (good for chronic pain) - Drugs with shorter absorption half lives take shorter to produce an effect (earlier onset) but then have shorter duration of action (good for acute pain) - if drug is dependant on reaching certain plasma concentration for effectiveness (e.g. warfarin), want shorter half life - if drug will be effective above a certain minimum concentration (e.g. pain relief and paracetamol), want longer half life -May change properties of liberation of a drug (how quickly it breaks into moieties which can be absorbed) to change absorption (hence some drugs available as normal, delayed release etc.)

Question 34

List factors that can affect pharmacokinetic parameters.

Answer 34

- Age - Sex - Pregnancy - Body weight - Genetic variability - Ethnicity - Other medications - Disease - Diet

Question 35

Define plasma clearance half life, and describe its use in pharmacokinetics.

Answer 35

=Elimination half life Time it takes for the concentration of the drug in the plasma or the total amount in the body to be reduced by 50% -Used to predict: a) How much drug needed to give to get to peak plasma concentration b) What likelihood is of a subsequent dose building upon previous dose

Question 36

What may happen upon giving repeated doses of a drug ?

Answer 36

-If give another dose of drug before first one completely eliminated from body, summation effect (build upon previous dose) -At one point, reach a saturated maximum -Hence, when shorten time between doses, more likely to get into the toxic region

Question 37

Describe plasma drug concentration during IV infusion.

Answer 37

- Plasma concentration increases during infusion until rate of input equals rate of output (steady rate, plateau). - As soon as take infusion off, elimination and metabolism then become the dominant processes (and get decrease of plasma drug concentration)