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ESA 1 - ICPP > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What does pharmacokinetics mean? What are the 4 main steps?

A

“What the body does to drugs”

  1. Absorption
  2. Distribution
  3. Metabolism
  4. Elimination
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2
Q

What are the 2 main routes of drug delivery into the body?

A
  1. Enteral delivery: drug enters body via highly vascularised surface area of GI tract and then onto rest of body tissues through CVS.
    - oral
    - sub-lingual
    - rectal
  2. Parenteral delivery: all drug delivery routes that aren’t via the GI.
    - subcutaneous
    - transdermal
    - intravenous
    - intramuscular
    - inhalation/intranasal
    - intrathecal
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3
Q

What are the advantages/disadvantages of the oral route of drug administration?

A

Advantages:

  • Convenient - preferred by patient
  • Safest

Disadvantages:

  • Unpredictable absorption (e.g. degradation by stomach acids and enzymes)
  • Slow absorption
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4
Q

What are the advantages/disadvantages of the intravenous route of drug administration?

A

Advantages:

  • can have immediate effects - useful in emergency situations
  • dosage titration permissible

Disadvantages:

  • can be painful
  • strict aseptic technique required
  • unsuitable for oily substances
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5
Q

What are the advantages/disadvantages of the inhaled route of drug administration?

A

Advantages:

  • lower risk of side effects (localised effects to target lungs)
  • rapid absorption due to large surface area of respiratory endothelium

Disadvantages:

  • most addictive route (drug can enter brain quickly)
  • P may have difficulty regulating dose
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6
Q

Why does absorption of drugs taken orally usually not occur in the stomach?

A
  • If taken in tablet/capsular form, disintegration largely occurs in the stomach.
  • But little absorption takes place in the stomach because:
    • thick gastric mucous layer that protects it from self-digestion can also act to preclude significant absorption.
    • relatively small surface area (1m2)
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7
Q

Where does absorption of drugs taken orally usually occur?

A
  • In the small intestine (drug is mixed with chyme).
  1. Large surface area (30-35m): due plicae circulares (circular infoldings) of the jejenum, epithelial villi and microvilli.
  2. Dynamic churning of chyme to maximise digestion and maximise absorption of nutrient - enhances presentation of drug molecules to epithelial surface area.
  3. Long transit time through small intestine: typically 3-5hrs (may range 1h-10hrs).
  4. Weakly acidic pH (6-7) determines ratio of drug molecule in ionised and unionised state - unionised form diffuses better.
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8
Q

What are the 4 major mechanisms by which drug molecules move from the gut lumen into the vascular system?

A
  • Passive diffusion
  • Facilitated diffusion
  • Active transport
  • Pinocytosis
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9
Q

Which type of drug moves from the gut lumen to the vasculature via passive diffusion?

A

Drugs that:

  • have a small molecular weight (<500 daltons)
  • are not strongly ionic (ionised form is lipid insoluble, unionised form is lipid soluble)
  • are lipophilic
  • Lipophilic drugs (e.g. Steroids) can easily move down their concentration gradient, through the sequence of lipid bilayers presented by epithelial cells.
  • Constant carriage of drug molecules away from the gut by the capillary supply of highly vascularised small intestine maintains the steep concentration gradient driving diffusion.
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10
Q

Many drugs in solution are weakly acidic/basic in nature. What does this mean?

A

Become ionised at physiological pH:

  • if they are acidic, they will release a proton (H+) to go from HA to H+ + A-.
  • if they are basic, they will accept a proton (H+) going from B to BH+.
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11
Q

How can we determine how a drug’s pKa affects its ability to passively diffuse out of the lumen?

A

Henderson-Hasselbach equation

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12
Q

How can weak acids/bases cross lipid bilayers by passive diffusion?

A
  • Gaining of a proton for weak acids.

- Loss of a proton for weak bases.

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13
Q

How can drugs with low lipid solubility/nett residual ionic charge cross membranes?

A

Facilitated diffusion: passive process driven by the electrochemical concentration gradient.

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14
Q

Which proteins enable facilitated diffusion to occur across membranes?

A
  • Solute Carrier (SLC) proteins: Organic Anion Transporters (OATs) andOrganic Cation Transporters (OCTs). At least 350 genes coding for OATs and OCTs.
  • Expressed throughout all body tissues. Pharmacokinetically important (for both drug absorption and elimination) when expressed in GI, hepatic and renal epithelial.
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15
Q

What is the role of active transport in drug absorption?

A
  • Primary active transport mainly concerned with carriage of drugs out of cells or specific body compartments by efflux - important in limiting drug uptake and can affect drug bioavailability.
  • Secondary active transport involves use of pre-existing electrochemical gradients across the cell membrane by the SLCs.
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16
Q

What is the role of endo-/exo-cytosis is drug absorption?

A
  • Transport of very large molecules (e.g. Insulin, VitB12) across the blood-brain barrier.
  • Involves the cell membrane invaginating to non-specifically capture molecules present at the cell surface.
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17
Q

Which physiochemical factors affect drug absorption in the gut?

A
  • Drug lipophilicity/pKa
  • Density of SLC expression in GI
  • GI length/SA (e.g. Small in children)
  • Blood flow: increased post-meal, reduced by shock/anxiety or exercise
  • GI motility: slow post-meal, rapid with severe diarrhoea
  • Presence of food: can reduce or increase uptake dependent on drug
  • Drug destruction by gut and/or bacterial enzymes
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18
Q

What is first pass metabolism of drugs, and what is its effect?

A
  • The metabolism of drugs by enzymes, mainly in the liver (hepatic 1st pass) but also in the gut.
  • Metabolism mediated by the cytochrome P450s (phase I) and conjugating (phase II) enzymes.
  • Reduces availability of drug reaching systemic circulation - affects therapeutic potential.
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19
Q

What is bioavailability?

A

The relative amount of drug that reaches the greater systemic circulation (i.e. Once the drug molecules have gone through their first passage of the hepatic circulation).

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

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20
Q

By clinical definition, what is the denominator of the bioavailability fraction?

A
  • Total amount of drug administered by the IV route.

- In this case, bioavailability = 1 when the IV route is used.

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21
Q

What does the bioavailability fraction mainly depend on?

A
  • Administration route used.
  • Oral route and subsequent enteral passage normally involves more barriers to systemic uptake than intramuscular or subcutaneous route.
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22
Q

After being absorbed, how are drugs distributed to tissues?

A
  • Fist distributed rapidly around the body over large distances (up to 10s of cm) by bulk flow via the arterial system.
  • Then travel out of capillaries into surrounding interstitial fluid and tissues by diffusion.
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23
Q

What is the overall rate of drug delivery to a given tissue bed dependent on?

A
  • The density of the capillary supply.
  • So drugs will first reach well vascularised organs like the kidneys, heart and lungs, more rapidly than the skin, bone or adipose tissue.
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24
Q

At the level of capillaries, what is the diffusion process determined by?

A
  • The ‘micro-leakiness’ of the capillaries themselves.
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25
Q

Give examples of capillary beds which facilitate the distribution of drugs to the tissues.

A
  • In some capillary beds (e.g. Intestinal, endocrine, pancreatic, kidney), the capillary endothelial cells can be fenestrated by 60-80nm pores.
  • In others (e.g. Liver, bone marrow, lymph, spleen), the endothelial cells are separated by slit junctions or large intercellular gaps to allow large movements of molecular material.
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26
Q

Give example of capillary beds that do not facilitate the movement of drugs to tissues.

A
  • In the brain, the capillary structure is continuous and there are no slit junctions.
  • Lipid-soluble drugs readily penetrate into CNS as they can dissolve in the membrane of endothelial cells whereas ionised or polar drugs fail to pass.
  • Some drugs can be actively transported, e.g. A specific large, neutral amino acid transporter carries levodopa into the brain.
27
Q

What are the 4 major factors affecting the ‘push and pull’ for drug movement out of plasma and into tissues?

A
  1. Drug lipophilicity/hydrophilicity
  2. The degree to which the drug binds to plasma protein
  3. The degree to which the drug binds to tissue proteins, e.g. Muscle
  4. The mass or volume of tissue and density of binding sites within that tissue
28
Q

How does drug lipophilicty/hydrophilicity affect drug movement from plasma to tissues?

A
  • The more lipophilic a drug molecule is, the greater it will partition out of blood plasma into surrounding tissues, esp. those with a higher lipid content.
  • If drug has a net negative charge it can still leave the capillaries through endothelial fenestrations. Further penetration of tissues will then depend on the local pH in the tissue interstitial fluid, the pKa of the drug and the presence of SLCs.
29
Q

How does the degree to which a drug binds to plasma protein affect drug movement from plasma to tissues?

A
  • Main plasma protein is albumin - has a number of potential sites for drugs to bind.
  • Binding due to relatively weak electrical polar bonding sufficient for the sites en masse to act as a large reservoir. This reservoir can contribute to determining the concentration of the free unbound drug that is available to exert a pharmacological/therapeutic effect.
  • In plasma, there is an equilibrium between the protein bound and unbound form - independent of its concentration, the proportion or percentage of the drug bound to protein remains the same (e.g. 50% of aspirin is bound to plasma protein).
30
Q

How does the degree to which a drug binds to tissue protein affect the movement of that drug from plasma to tissue?

A
  • Moves the drug from plasma so reduces its plasma concentration. Can affect the amount of free drug available for pharmacological effect.
31
Q

How does the mass or volume of tissue and density of binding sites within that tissue affect the movement of a drug from plasma to tissue?

A
  • This can vary significantly from individual to individual.
  • E.g. Digoxin binds with very high affinity to Na/K ATPase in muscle so would have a reduced plasma concentration in very muscled person.
32
Q

How can the body fluid compartments be modelled?

A
  • Plasma water = plasma water (3 L)
  • Extracellular water = plasma water + interstitial fluid (14 L)
  • Total body water = plasma water + interstitial fluid + intracellular water (42 L)
33
Q

How do drugs move between body fluid compartments?

A
  • From plasma to interstitial fluid to intracellular fluid.

- There are membrane boundaries between each of these compartments, limiting drug mov. (E.g. Insulin cannot cross)

34
Q

What are the effect of increasing penetration by drug into interstitial and intracellular fluid compartments?

A
  • decreased plasma drug concentration

- increased Vd

35
Q

What is the ‘apparent’ volume of distribution?

A
  • Models grouping of main fluid compartments as though all one compartment, i.e. Pretend drug conc is the same throughout the body.
  • Summarises movement out of plasma to interstitial fluid to intracellular compartment. The larger the Vd, the greater the drug movement out of plasma.
  • Value is dependent on push factors.
  • Vd = total amount of drug in body/plasma conc of drug (at time = 0)
36
Q

How is apparent volume of distribution calculated?

A
  • By back extrapolating along the log drug concentration curve until it reaches the y-axis when time = 0.
37
Q

Give examples of factors that can affect apparent volume of distribution.

A
  • Changes in protein binding throughout fluid and tissue compartments. If a disease state affects the level of plasma protein available (e.g. Hypoalbuminaemia) this will change Vd and the concentration of the drug.
  • Drug interactions: if binding sites are taken up by other drugs given in combination, free drug concentration will increase.
  • Marked +/- changes in body weight (e.g. In cancer patients).
  • Paediatrics/neonate/pre-term
  • Pregnancy
38
Q

What is drug elimination?

A

The set of processes whereby a drug is irreversibly removed from the body. Involves metabolic and excretory mechanisms (2nd 1/2 of ADME).

39
Q

Why are drugs metabolised?

A
  • Chemically changing drugs to enhance their ionic charge makes their renal elimination or excretion much easier.
  • Is essential for highly lipophilic compounds which will otherwise simply diffuse back down their concentration gradient through the renal cell membranes and back into the plasma.
40
Q

Where are drugs metabolised?

A
  • Largely, but not exclusively, in the liver. As the primary organ receiving blood directly from the gut following absorption, it is well position to carry out homeostatic and protective metabolism on molecules entering the body.
  • But first pass metabolism can also occur in the gut.
41
Q

How does metabolism occur generally?

A

Molecular structure is changed in 2 major ways:

  1. Phase I reactions: oxidation/reduction reactions or hydrolysis. These introduce or unmask more polar groups on the drug molecule, such as -OH or -NH2.
  2. Phase II reactions: addition of a number of molecules that conjugate with the drug. E.g.
    - glycine amino acid
    - glutathione molecule (contains glutamate, cysteine and glycine)
    - glucoronate (most common conjugating molecule, very similar in structure to glucose)
    - methyl, acetyl or sulphate groups can be added to enhance polarity
42
Q

Which enzymes carry out Phase I metabolism?

A
  • Cytochrome P450s: large family of >50 enzymes located on the external face of the ER in hepatocytes.
  • 3 superfamilies: CYP 1, 2 & 3.
  • 6 isoenzymes metabolise about 90% of prescription drugs.
43
Q

Are CYP450s generalist or specialist enzymes?

A
  • Generalists: specific CYP450 types will optimally metabolise different drug molecules but there is considerable overlap - can deal with a wide range of drugs.
  • Means it might take them a long time to metabolise a drug compared to a highly specific enzyme, but primary function is to be versatile. Versatility explains the great variation in elimination half-lives seen for drugs.
  • There is significant variability between individuals in CYP450 type expression.
  • Each CYP450 type also exhibits a wide range of genetic polymorphism - can affect the efficiency with which is removes drugs that it preferentially metabolises.
44
Q

Which factors affect metabolic elimination?

A
  • Wide range of factors inc. sex, age, genetic status, cardiac output, disease state.
  • Individual CYP450 enzymes can be inhibited and induced by both prescription and non-prescription (OTC) drugs.
45
Q

Describe the role of CYP450 inducers.

A
  • > 200 drugs known to act as inducers for specific CYP450 isoenzymes.
  • Act by stimulating increase enzyme transcription, translation or slower degradation.
  • Induction will lead to a more rapid elimination of the drug as there is simply more of the enzyme to metabolise and eliminate it.
  • Dosing of the affected drug may then have to be increased.
46
Q

Why is the dosing of carbamazepine important in terms of metabolism?

A

Carbamazepine (important anti-epileptic) is metabolised by CYP3A4, which it also induces - induces its own metabolism.

47
Q

Describe the role of CYP450 inhibitors.

A
  • Inhibitors of CYP450 can result in elevation of drug plasma levels and a risk of toxic side effects of the therapeutic drug.
  • CYP450 inhibition can occur both via competitive (2 drugs metabolised at same time) and non-competitive (inhibitor binds at separate site) inhibition.
48
Q

After being oxidised in phase I metabolism, what happens to a drug?

A

Either eliminated quickly or go on to be further metabolised by phase II enzymes.
Some drugs can enter directly into phase II depending on if they already possess -OH, -NH2 or COOH groups.

49
Q

Where is drug excretion carried out?

A

Vast majority of excretion is carried out by the kidney, but some drugs can also be excreted via an intestinal route or via the lungs, sweat or other body fluid.

50
Q

What are the 3 parts of renal drug excretion?

A
  1. Glomerular filtration
  2. Proximal tubular secretion
  3. Distal tubular reabsorption
51
Q

What is glomerular filtration?

A
  • Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus.
  • Unbound free fraction of drug and its metabolites can diffuse through capillary slits into Bowman’s capsule.
  • Only about 20% of renal blood supply serves the glomerulus, and this process is rate-limited by the overall glomerular filtration rate (normally about 125 ml/min).
52
Q

What is proximal tubular secretion?

A
  • The remaining 80% of renal blood flow journeys through the peritubular capillaries of the proximal tubule.
  • Suitably charged drug molecules and their polar metabolites are then actively transported into the tubular lumen by Organic Anion Transporters (OATs) - for deprotonated weak acids, or Organic Cation Transporters (OCTs) - for protonated weak bases.
53
Q

What is distal tubular reabsorption?

A
  • As water is resorbed along the length of the tubule, drug metabolite concentration increases. If it is in a lipophilic form then it will passively be reabsorbed back into the bloodstream.
  • Results in a lower rate of effective elimination.
54
Q

What is clearance?

A
  • Clearance = the overall rate of elimination of a drug from the body.
  • Total body clearance includes all those contributions made by drug biotransformation and excretion, but for the majority of drugs, the contribution made by sweating, exhalation and other routes is minor - the major elimination routes are hepatic and renal.
  • So total body clearance = hepatic clearance + renal clearance.
55
Q

How is rate of elimination (i.e. Clearance) modelled and measured?

A
  • Use the concept of apparent volume of distribution, with the plasma compartment representing the whole body.
  • So clearance measured a ‘the volume of plasma that is completely cleared of the drug per unit time’.
56
Q

Why is clearance important pharmacologically?

A
  • Clearance affects:
    • how long the drug stays in the body
    • among with Vd, what dosing levels are required to reach the therapeutic range
    • how toxic levels of the drug are reached
  • The balance between the rate of absorption/distribution and metabolism/excretion determines the level of drug in the plasma, which in turn determines the balance between therapeutic benefit an the risk of any side effects.
57
Q

Which factors affect elimination and thus clearance (rate of elimination)?

A

‘Royal’ acronym HRH:

  • Heart - cardiovascular/circulatory factors affecting blood flow to main organs of elimination
  • Renal - factors affecting renal elimination
  • Hepatic - factors affecting hepatic elimination
58
Q

Which 2 values are important in determining drug half life?

A

Vd and CL

59
Q

What is drug half life (t1/2)?

A

The amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it had when it was first measured.

60
Q

What is the equation for drug t1/2?

A

t1/2 = (0.693 x Vd) / CL

0.693 usually rounded up as 0.7 in exams.

61
Q

Why is drug half-life clinically important?

A
  • By incorporating both Vd and CL, the half-life tells you how long the drug will stay in the body and what your repeat dosing regime is going to be lik to achieve therapeutic concentration.
62
Q

Which factors affect drug t1/2?

A
  • All the other factors affecting Vd and CL.
  • Heart - cardiovascular/circulatory factors affecting blood flow to main organs of elimination.
  • Renal - factors affecting renal elimination.
  • Hepatic - factors affecting hepatic elimination.
63
Q

Elimination, clearance and half-life processes have to obey linear/first order kinetics. What does this mean?

A
  • The rate of the process (e.g. Metabolic/renal clearance) is dependent on the concentration of the molecules being eliminated.
  • I.e. Low drug concentration results in a slower elimination rate as fewer molecules are available to be metabolised/excreted.
  • This is why log plots of half life vs time go down in a curved fashion - the rate slows as the concentration drops.
64
Q

When is drug clearance said to be non-linear/zero-order?

A
  • When the CYPs or any enzymes or transporters are working at their maximum rate. That is, for a high concentration of the drug, the kinetics are no longer concentration dependent and are said to be saturated as they cannot work any faster.
  • Related to the fact that CYPs and transporters involved in clearance are generalists. For some of the drugs they deal with, it takes a long time to process them or transport them, which then has the effect of slowing clearance down.

ESA 1 - ICPP (18 decks)

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