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Scientific Basis Of Drug Action > Pharmacokinetics 1 > Flashcards

Pharmacokinetics 1 Flashcards

1
Q

What is the difference between pharmacodynamics and pharmacokinetics?

A

Pharmacodynamics= what the drug does to the body; how much, how often and how long?
Pharmacokinetics= what the body does to the drug; absorption, distribution and elimination

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2
Q

Why is pharmacokinetics important?

A

-essential in adjusting dose size and frequency for patients; depends on age, weight, liver + kidney function
-models concentration of drug in blood or plasma or other tissue of interest over time

*pharmacokinetics try to achieve minimal effect concentration (EMC)
*limited by maximum ‘tolerated’ concentration (above which= toxicity)

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3
Q

What does ADME stand for?

A

A- absorption- in
D- distribution - around
M- metabolism } elimination
E- excretion } elimination - out

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4
Q

Blood, plasma, serum

A

*Blood- one of the connective tissues; consists of cells, platelets and fragments suspended in the plasma. Plasma= blood is in liquid form and can be circulated in the body
*Plasma- viscous fluid; blood’s liquid portion- comprises 91% of water + the rest of solutes and proteins
*Serum- clear liquid part of the blood that remains after removing blood cells and clotting proteins (allows scientists to grow human cells etc)

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5
Q

blood in test tubes; 3 sections

A

-Centrifuge blood in test tube- plasma on top= involving dissolved components in the blood; proteins, glucose, drugs etc
-if blood in a test tube is left- will clot = top part is serum; may contain drugs that do not bind to plasma proteins

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6
Q

Why measure drug concentrations?

A

-intensity of pharmacological effect is often related to the concentration of the drug at the receptor site - usually in the tissue cells
-plasma drug concentration helps to adjust drug dose to optimise drug regimens
-helps with therapeutic equivalences + to ensure required outcome

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7
Q

What is absorption?

A

The transfer of a drug from its site of administration to the circulation
-with oral dosing this is from the intestine to the hepatic portal vein
^portal venous system= responsible for directing blood parts from parts of the gastrointestinal tract to liver
- many drugs that are absorbed through the GI tract are substantially metabolised by the liver before reaching general circulation= first pass effect
Bypass portal= avoid first pass metabolism

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8
Q

Routes of administration;
*enteral vs parenteral
*vascular vs extravascular

A

External routes=
-oral (PO)- portal
-Sublingual- bypass portal
-Rectal- partially bypass portal

Parenteral routes=
-intravenous (IV). -subcutaneous (SC)
-intramuscular (IM). -topical/transdermal
-inhalation/nasal

Extravascular=
-all routes of admin except those in which drug is directly going into ocular blood; e.g. IM, SC, IP, Oral, Rectal + Topcial

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9
Q

What is bioavailability (F)?

A

-refers to the amount of intact drug available to have its desired effect (fraction of administered dose to reach the systemic circulation)

• Defined as the fraction (F) of drug entering the
circulation
– If you administer a dose of 100mg but only 50mg
reaches the systemic circulation, then F = 0.5.
• Usually calculated as AUC oral/AUC iv

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10
Q

Bioavailability (F)- graph

A

-relative F= comparison between different formulations of a drug
-absolute F= assessed with reference to IV dose

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11
Q

Concept of AUC?

A

AUC- area under the plasma concentration vs time curve
-measure of the total quantity of drug entering the systemic circulation

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12
Q

Intravenous administration

A

-blood= site of measurement for pharmacokinetic purposes
-for IV= fraction (F)- of the dose reaching the site of measurement is 1 (assumed to be 100% bioavailable)
-all other dosage routes can be measured relative to an intravenous dose

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13
Q

Oral Bioavailability

A

(F) Oral Bioavailability = AUC oral x Dose iv
•Influenced by different processes and may be expressed as:
F = Fa x Fg x Fh
Where:
Fa = fraction absorbed into enterocytes (cells of the intestinal tract)
Fg= fraction of drug that enters enterocyte but escapes gut metabolism
Fh= fraction of drug that enters liver but escapes liver metabolism

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14
Q

Hepatic first pass metabolism

A

-gut wall + liver= major drug metabolising organs
-a compound can have 100% absorption but 0% bioavailability
-bioavailability < absorption

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15
Q

Why is the rate of absorption important?

A

-influences peak plasma concentration= strongly influences effects of a drug which is important to take into consideration other PK parameters as well as AUC
-cmax, tmax and AUC are considered when determining whether different versions of drugs are ‘bioequivalent’

MTC/MSC= maximum therapeutic/ safe concentration
MEC= minimum effective concentration/ threshold concentration

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16
Q

AUC

A

AUC A> B: B INEFFECTIVE
AUC A> B: EQUALLY EFFECTIVE

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17
Q

Factors affecting absorption:

A

-disintegration and dissolution of the compound
-intestinal morphology
-physiochemical properties of the compound
-transporters
-metabolic enzymes

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18
Q

What is dissolution?

A

The process by which a drug moves from the solid state into solution
-the drug must be in solution to be absorbed

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19
Q

Absorption from the small intestine

A

The small intestine= designed to be the major drug absorbing organ due to surface area modifications

Luminal Folds (3 fold increase)
Villi (10-fold increase)
Microvilli (20-fold increase)

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20
Q

Microvilli and tight junctions:

A

The intestinal wall epithelial cells have many finger-like projections on their luminal surface (microvilli)= forms the brush border membrane

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21
Q

What is transcellular absorption?

A

-the major route of drug absorption
-compound passes through the cell membrane
-requirement for adequate lipophilicity

-the relative physiochemical properties of a drug or series of drugs can be related to ADME
-ADME properties of most drugs = depends on the ability of the drug to pass through membranes via simple diffusion
-largely governed by size (MW), lipophilicity (logP) and ionisation (pKa)

22
Q

What is lipophilicity and LogP?

A

-Log P- partition coefficient- a quantitative measure of lipophilicity
-solubility of the unionized form of the drug in a lipid phase and water is compared and expressed as a ratio
-equilibrium is established and the concentrations of the non-ionized species in the two phases are measured

LogP= log ([drug octanol]/ [drug water]

23
Q

Membrane partition- ionisable compounds

A

-only unionised drug can cross the membrane by passive diffusion
-hence why absorption is dependant upon pKa and logP of the unionised compound

24
Q

Ionisation constant: pKa

A

-the ADME properties of a drug depend heavily upon the ionisation state of the drug in the physiological fluids
-most drugs either weak acids or weak bases= likely to be part ionised and part unionised at physiological pH
-unionized part is charged= attracts water molecules= forming large complexes= cannot cross the membrane because they are less lipid soluble (drugs are better absorbed in unionized form)
-ionization constant (pKa) = reflects the tendency of an acid to donate a proton

25
Q

PKa values of acidic and basic drugs

A

PKa is a measure of the tendency of an acid to give up a H+: AH ⇌ A- + H+
PKa of a base= tendency of the conjugate acid form of the base (BH+) togive up a H+ BH+ ⇌ B + H+
Low pKa = readily gives up a H+
- Acid with low pKa = strong acid
- Base with a low pKa = weak base
High pKa = does not readily give up a proton
- Acid with a high pKa = weak acid
- Base with a high pKa = strong base
Many drugs are acids or bases

26
Q

Absorption of acids and bases in the GI tract

A

Acids with pKa below 3 and weak base with a pKa above 10= poorly absorbed from the intestine

27
Q

Permeation and hydrogen bonding + molecular size

A

-greater the number of hydrogen bonds= less likely absorption
-rate of permeation also depends upon molecular weight
-large molecules = have problems diffusing across membrane
-molecular weight greater than 500= most likely to be incompletely absorbed
-good absorption= need low molecular weight <500 + some lipophilicity

28
Q

Rule of 5

A

“Rule of 5”=
• From review of 2245 compounds with superior
physicochemical profile (dataset of >50,000) concluded
poor absorption more likely if:
• Molecular weight > 500
• logP > 5
• Number of H-bond donors > 5
• Number of H-bond acceptors > 10

29
Q

Transceullar absorption

A

-to be transcellulary absorbed = a drug must permeate membranes
Membrane permeation depends upon:
-area of absorptive surface
-lipophilicity
-pKa
-hydrogen bonding
-molecular size

30
Q

Paracellular absorption:

A

Drug passes through the gaps between cells (tight junction)
-no membrane permeation
-requirement for low molecular weight (<300) + water solubility
-poor paracellular absorption from the colon
-pores between cells larger in dog than in rat and man

31
Q

Active transport (uptake)

A

-drugs carried through the membrane by a transporter; energy dependant, not passive
-many transporters exist for nutrient molecules
-unlike passive absorption- can be saturated by high concentrations

32
Q

Active transport- Efflux:

A

P-glycoprotein (P-gp) initially discovered in cancer patients displaying MDR (Multi-Drug Resistance)
P-gp is found in high levels at the apical surface of cells associated with transport:
biliary canalicular membrane
brush border of the renal proximal tubules
apical surface of the intestinal epithelial cells
endothelial cells of brain and testis

P-gp can effectively act as a barrier to oral absorption

33
Q

Distribution:

A

Once absorbed a drug molecule is subject to distribution throughout the body via the circulatory system

34
Q

Volume of distribution (V d)

A

hypothetical volume into which drug is dissolved or distributed, V for a drug is constant
Defined as the volume that would contain the total body content of the drug at a concentration equal to that of plasma
Used to define dose required to achieve a particular drug [plasma]
A drug that partitions (distributes) into tissues readily has a low [plasma] is likely to have large Vd and vice versa

35
Q

Distribution: Body Fluid Compartments

A

Major compartments for drugs to distribute into are:
Plasma (5% of body weight)
Interstitial fluid (16%)
Intracellular fluid (35%)
Transcellular fluid (2%)
Fat (20%)

36
Q

Body fluid compartments

A

70kg healthy male subject
Extracellular fluid (ECF) 20% weight
-plasma 3L (4% of body weight)
-interstitial fluid 11L (16% of body weight)

Total body water 42L (60% weight)
-intracellular fluid 28L (40% of body weight)

37
Q

Volume of Distribution

A

Vd = amount of drug in body (A) / [plasma drug] (C)

Where:
A = mg (mass of drug)
C = mg/L (drug concentration)

Often further divided by patient’s body weight to give L/kg

Vd is used clinically to determine the loading dose needed for a particular blood concentration

The interactive website: https://www.icp.org.nz/volume-of-distribution/vd-and-loading-dose

38
Q

Examples of calculations using Vd

A

Values for Vd are determined experimentally and are constant in healthy humans
This means, given known values of Vd and the therapeutic range of a drug we can calculate an appropriate ‘loading’ dose.
e.g. If drug X has a volume of distribution of 15L and is effective once it reaches a plasma concentration of 8mg/L what i.v dose should we administer?
First:

Plasma concentration = mass in body (A)/ volume of distribution

Mass in body (A)(i.v. dose ) = plasma concentration (C0) x volume of distribution (Vd)

i.v dose = 8mg/L x 15L = 120mg

39
Q

What about an oral dose?

A

Drug X is going to be an OTC drug so needs to be taken orally. It has a bioavailability F= 0.6. What oral dose should be given?

Plasma concentration (C 0)= mass in body/ volume of distribution (Vd)

Mass in body (A)= C 0 x Vd
Mass in body for an oral dose (A)= F x oral dose= 0.6 x oral dose
So
0.6 (F) x oral dose = c0 x V d
Then = oral dose= c0 x Vd/ 0.6 (F)
= 8mg/Lx 15L / 0.6 (F) = 200mg

40
Q

Patterns of distribution:

A

1.)The drug may remain largely within the vascular system.
For example, plasma substitutes such as dextran are an example of this type, but drugs which are strongly bound to plasma protein may also follow this pattern.

  1. ) Some low molecular weight water soluble compounds such as ethanol become uniformly distributed throughout the body water.
    3.) A few drugs are concentrated specifically in one or more tissues that may or may not be the site of action.
    For example, iodine is concentrated by the thyroid gland.
    The antimalarial drug, chloroquine may be present in the liver at concentrations 1000 times those present in plasma.
    Tetracycline is almost irreversibly bound to bone and developing teeth. Consequently, tetracyclines should only be given to young children or infants in extreme conditions as it can cause discoloration and mottling of the developing second set of teeth.
    Another type of specific concentration may occur with high lipid soluble compounds which distribute into fat tissues.
  2. Most drugs exhibit a non-uniform distribution in the body with variations that are largely determined by the ability to pass through membranes and their lipid/water solubility.
    The highest concentrations are often present in the kidney, liver, and intestine usually reflecting the amount of drug being excreted.
41
Q

Protein Binding and Vd

A

Binding of drugs to proteins in blood is a major determinant of PK and source of drug-drug-interactions
Drug-drug interactions can involve competition for protein binding – i.e. dislodging a bound drug from a protein increases its unbound (active) concentration
Particularly dangerous for drugs with a narrow therapeutic index – i.e. digoxin (95% bound)

42
Q

Plasma Protein Binding (PPB)

A

Drugs can bind to macromolecules in the blood – known as plasma protein binding (PPB) – restricted to plasma
Only unbound compound is available for distribution into tissues, “Active” drug = unbound – can bind to target so it is pharmacologically active
Acids bind to basic binding sites on albumin, bases bind to alpha-1 acid glycoprotein

			0-50% bound 	= negligible

			50-90%	                  = moderate

			90-99%	                  = high

			>99%               	= very high
43
Q

Plasma Protein Binding (PPB)

A

Acidic drugs tend to have higher PPB than neutral/basic drugs.
The more lipophilic a compound the higher the degree of PPB

44
Q

Protein binding of the drug

A

Free drug
pharmacological effect
Elimination

Protein-bound drug
not available to exert pharmacologic effects or distribute to tissues or
unavailable for elimination

45
Q

Protein Binding and Vd

A

The fraction of drug that is free in aqueous solution can be less than 1%,
Small differences in protein binding (e.g. 99.5 versus 99.0%) can have large effects on free drug concentration and drug effect.
Differences are common between human plasma and plasma from species used in preclinical drug testing

46
Q

Barriers to drug distribution:

A

Blood brain barrier (BBB)
Only lipid soluble drugs can enter brain and CSF
‘Leaky’ in disease – eg penicillin in meningitis
Within the penicillins, penetration is as low as 1% with intact (non-inflamed) BBB and may rich above 30% in the presence of inflammation. Penicillin G has approx. two-thirds of its CSF elimination via an efflux pump.
Placenta
Allows passage of lipid and some water soluble drugs - eg opioids, antiepileptics, sodium valproates took by pregnant women affected their babies development!
Enzymes in placenta inactivate some drugs

47
Q

Factors Affecting Distribution

A

Rate of Distribution:
Membrane permeability
Blood perfusion

Extent of Distribution:
Lipophilicity (logP)
pKa
Extent of protein binding
Size

Only unionised unbound drug in the plasma can distribute into tissues and therefore is pharmacologically active

Go on slide 66 for calls

48
Q

Volume of distribution (V):

A

100 mg of drug A, B, and C is administered IV in a subject, the plasma concentration at time zero (Co) was estimated as follows:
Drug A = 10 mg/L
Drug B = 2 mg/L
Drug C= 1 mg/L

What is the volume of distribution of drug A, B, and C?
Drug A = 10 L
Drug B = 50 L
Drug C = 100 L

𝐶_𝑜=𝐷𝑜𝑠𝑒/𝑉.

𝑽=𝑫𝒐𝒔𝒆/𝑪_𝟎

49
Q

Why C0 of drugs A, B, and C is not the same?

A

Considering the
dose of all three drug was same, i.e., 100 mg
They were all administered through the same route, i.e., IV
They were given to the same subject and
assuming no changes in subject physiology

50
Q

Salt factor:

A

Drugs may be administered as salts to increase solubility - but doses are defined in terms of mass of parent drug
Therefore, need to adjust dose given to take account of “salt factor”

Dose of salt form of drug = (Dose of Drug Required)/(Salt Factor)

e.g. theophylline is generally administered as aminophylline – aminophylline contains 80% w/w theophylline
- So, the salt factor = 0.8
If we want to administer 400mg of theophylline we would require:
Dose of salt form (aminophylline) = (400 mg)/0.8=𝟓𝟎𝟎𝐦𝐠 aminophylline

51
Q

Testing ourself:

A
  1. A patient requires a dose of 250mg of Drug X; Drug X is only available as a salt (75% w/w). How much of the salt form of the drug do we need to administer?
  2. Why do we need to ensure the correct concentration of drug in the blood?
  3. For a given dose of drug which patient-related factors may affect the concentration observed in blood?

Scientific Basis Of Drug Action (16 decks)

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