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Cell Physiology And Pharmacology Unit > Pharmokinetics ( absorption + distribution) > Flashcards

Pharmokinetics ( absorption + distribution) Flashcards

1
Q

Define ligand

A
  • a substance that can interact with a targe protein or REcepetor - usually bind to a specific site on the signalling protein.
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2
Q

Define agonist

A
  • a substance that has affinity and binds to a recepetor and activates the receptor to then produce a measurable response
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3
Q

Define antagonist

A

Ligand that have affinity for a receptor or target protein but do not produce a biological response

  • they block the effects of agonists
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4
Q

Define affinity

A
  • measure of strength between a ligand/drug to a receptor

-

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5
Q

What is the Measurement used to define affinity ?

A

Affinity is measured by Kd.

  • the lower the Kd , the greater the affinity
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6
Q

Define Kd

A

Concentration of ligand at which 50% of all available receptors bound.

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7
Q

Define intrinsic efficacy

A
  • the ability of a ligand to generate an activate form of the receptor - often a conformation change. This is exhibited by agonists only.
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8
Q

Define ligand efficacy

A

Ability for ligand to cause a measurable biological response

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9
Q

Define agonist potency’

A
  • potency is described as the the concentration of a drug that evokes 50% of its maximal response (Emax)
  • EC50 is used to represent this concentration
  • the lower the value of EC50 the more potent the drug/ ligand is because a lower concentration of drug/ligand is required to generate 50% of maximal response
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10
Q

Define partial agonist

A
  • Ligands that evoke responses that are lower than the maximal response of a full agonist
  • they have a lower Emax value
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11
Q

Compared to a full agonist , a partial agonist has …

A

Lower intrinsic efficacy

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12
Q

Define Bmax

A

Found on the binding curve

  • maximum binding max
  • make sure it doesn’t touch the line
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13
Q

Should Emax touch the line ?

A

No

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14
Q

What is the mnemonic used to remember the factors that affect entry and removal of a drug from the body ?

A

A - absorption

D - Distribution

M - Metabolism

E - Elimination

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15
Q

What are the two factors that affect how a drug gets into the body ?

A

1) absorption

2) distribution

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16
Q

What are the two factors that affect how a drug gets out of the body ?.

A
  • metabolism

- elimination

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17
Q

What are the two major methods of administration of drugs ?

A

1) enternal delivery

2) parenteral delivery

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18
Q

What is enteral delivery

A
  • delivery of drugs into internal environment of the body
  • VIA GI TRACT
  • can also be via sublingual tissue ( beneath the tongue )
  • can also be rectal administration ( upper part of the large intestine)
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19
Q

What is parenteral delivery ?

A

Delivery of drugs via all other routes that are not the GI.

  • this includes intravenous ( via the veins)
  • subcutaneous ( hypodermis)
  • intramuscular ( deep into muscle)
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20
Q

What is the mnemonic used to remember the 9 routes of administration!

A

OI! It IS SIR!

O - Oral

I - intravenous

I - intramuscular

T - transdermal

I - intranasal

S - subcutaneous

S - sublingual

I - inhalation

R - rectal

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21
Q

Is there little or a lot of absorption of drug in the stomach ?

A

VERY LITTLE

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22
Q

What is the first organ that tends to receive the drug ?

A

Stomach

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23
Q

Describe the stomachs environment

A

Surface area quite small 0.75-1m^2

24
Q

Where does the majority of enteral drug absorption take place ?

A

Small intestine

25
Q

Describe the small intestines environment that makes it suitable for majority or drug to be absorbed

A

6-7 m in length

2.5 cm diameter

Total surface area for absorption : 30-35 m^2

26
Q

What are the 4 major mechanisms involved drug molecules leaving the gut lumen to the vascular system ?

A

1) passive diffusion
2) Facilitated diffusion
3) primary and secondary active transport
4) pinocytosis ( ingestion of liquid into a cell)

27
Q

What class of drugs would go through passive diffusion to enter the vascular system ? And give an example

A
  • lipophillic molecules
  • eg steroid drugs
  • protonated/deprotonated species can also diffuse. Valproate( anti epileptic drug) is a weak acid with a pKa = 5. In the gut at pH 6 - 10% of valproate protonated ( unionised ) version can passively diffuse.
  • over trasit time (4-5 hours) it diffuses into capillary bed
28
Q

Give examples of molecules that travel into the vascular system via facilitated diffusion from the gut ?

A

Glucose

Amino acids

Neurotransmitters

( molecules with ionic charge )

29
Q

What major group of transmembrane proteins aids facilitated diffusion ?

A

Solute carrier transport ( SLC)

30
Q

What are the two types of SLCs?

A
  • organic anion transporters ( OAT) and organic cation transporters ( OCT)
31
Q

Where are OATs and OCTs mainly expressed ?

A
  • GI tract
  • hepatic tissues
  • renal epithelia because these are the main places for absorption and elimination
32
Q

What does secondary active transport rely on ?

A
  • they do not utilise ATP
  • transport is driven by pre- existing electrochemical gradients across the GI epithelial membrane
  • examples : Fluoxetine/Prozac which are SSRi antidepressants that are co-transported with Na+ ion
  • pencillin which is co transported with a H+ ion
33
Q

What type of molecules are transported by endo/ectocytosis ?

A
  • large molecules

- one example would be vitamin b12 and insulin

34
Q

What are 3 physio chemical factors that can affect drug absorption ?

A
  • GI length / surface area ( the greater the surface area , the more absorption)
  • drug lipophilicity / pKa value
  • density of the SLC expression in GI
35
Q

What are 3 GI physiology factors that affect drug absorption ?

A

1) blood flow : this increases post meals and reduces drastically during periods of shock/anxiety/exercise
2) GI motility : slows down post meal , it is rapid with severe diarrhoea
3) Food / pH : Low pH can destroy some drugs and food can reduce or increase uptake

36
Q

What is first pass metabolism,

A

Reduces availability of drugs reaching systemic circulation - therefore affects therapeutic potential

37
Q

Describe first pass metabolism that occurs in gut wall / liver

A
  • some drugs metabolised by two major enzyme groups
    1) cytochrome P450s - phase 1 enzyme
    2) conjugating enzymes - phase 11 enzymes

-

38
Q

Which organ is there a larger expression of the phase 1 and phase 11 enzymes ?

A

In the liver

39
Q

Define bioavailability

A

Fraction of a defined dose which reaches its way into the systemic circulation

  • this fraction reflects all barriers to its absorption and post hepatic distribution
  • EQUATION : AMOUNT OF DRUG REACHING SYSTEMIC CIRCULATION / TOTAL AMOUNT OF DRUG BEING ADMINISTERED
40
Q

When an IV route is used , what do we assume bioavailability to be?

A

1 because there are no physical or metabolic barriers to overcome .

41
Q

What are the units for oral availability?

A

F

42
Q

What is the formula for oral availability ?

A

F = Amount reaching systemic circulation / Total amount of drug given by intravenous administration

  • F lies between 0 and 1
  • F(oral) = AUCoral/ AUCiv
43
Q

Why do we calculate oral availability ?

A

Informs choice of administration route

44
Q

Describe the first stage of drug distribution

A

1) bulk flow : drugs travel a large distance via arteries to capillaries
2) Diffusion : drugs diffuse from capillaries to interstitial fluid to cell membranes to targets

45
Q

What are a few barriers to diffusion of drugs from capillaries to intersitial fluid to cell membranes to targets ?

A
  • interacts with plasma / tissue proteins
  • local permeability
  • non target binding
46
Q

What is a factor that affects diffusion of drugs across capillaries ?

A
  • the type of capillary and their varying permeability
  • for example continuous capillaries have very tight gap junctions so limit drug diffusion
  • whereas fenestrated capillaries have fenestrations
  • and sinusoids have big fenestrations
47
Q

What are major factors a affecting drug distribution?

A

1) capillary permeability
2) presence of OATs /OCTs in capillary nd target tissue membranes
3) drug pkA and local pH
4) if drug is lipophillic / hydrophilic
5) . Degree of drug binding to plasma / tissue proteins

48
Q

Why when drugs bind to plasma or tissue proteins , they are distributed well to their target sites ?

A
  • because only free drug molecules can bind to target sites

- binding In plasma / tissue decreases free drug available for binding

49
Q

What are the simplified three main body compartments ?

A

plasma water in blood ( 3 litres )

2) extracellular water ( plasma water + interstitial water) = 14 litres
3) Total body water ( plasma water+ interstitial water + intracellular water) = 42 litres

50
Q

Increasing penetration by drug into interstitial and intracellular fluid compartments leads to…

A
  • Decreasing plasma drug concentration

- increase Vd( volume of distribution)

51
Q

What does a smaller Vd mean ?

A
  • less penetration of interstitial / intracellular fluid compartment
52
Q

Larger Vd values mean..

A

Greater penetration of drug into interstitial / intracellular fluid compartments

53
Q

How to calculate volume of distribution ?

A

Vd = Drug dose / concentration of plasma drug at t=0

54
Q

What can vD be affected by ?

A
  • changes in body weight
  • pregnancy
  • cancer patients
  • renal failure
  • geriatrics
  • neonates , pre term , paediatrics
55
Q

What does area under the curve indicate ? ( in regards to bioavailability)

A

Amount of drug in circulation

Cell Physiology And Pharmacology Unit (16 decks)

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