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.
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
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
4
Q
Define affinity
A
- measure of strength between a ligand/drug to a receptor
-
5
Q
What is the Measurement used to define affinity ?
A
Affinity is measured by Kd.
- the lower the Kd , the greater the affinity
6
Q
Define Kd
A
Concentration of ligand at which 50% of all available receptors bound.
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.
8
Q
Define ligand efficacy
A
Ability for ligand to cause a measurable biological response
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
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
11
Q
Compared to a full agonist , a partial agonist has …
A
Lower intrinsic efficacy
12
Q
Define Bmax
A
Found on the binding curve
- maximum binding max
- make sure it doesn’t touch the line
13
Q
Should Emax touch the line ?
A
No
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
15
Q
What are the two factors that affect how a drug gets into the body ?
A
1) absorption
2) distribution
16
Q
What are the two factors that affect how a drug gets out of the body ?.
A
- metabolism
- elimination
17
Q
What are the two major methods of administration of drugs ?
A
1) enternal delivery
2) parenteral delivery
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)
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)
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
21
Q
Is there little or a lot of absorption of drug in the stomach ?
A
VERY LITTLE
22
Q
What is the first organ that tends to receive the drug ?
A
Stomach
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
Describe the small intestines environment that makes it suitable for majority or drug to be absorbed
6-7 m in length
2.5 cm diameter
Total surface area for absorption : 30-35 m^2
26
What are the 4 major mechanisms involved drug molecules leaving the gut lumen to the vascular system ?
1) passive diffusion
2) Facilitated diffusion
3) primary and secondary active transport
4) pinocytosis ( ingestion of liquid into a cell)
27
What class of drugs would go through passive diffusion to enter the vascular system ? And give an example
- 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
Give examples of molecules that travel into the vascular system via facilitated diffusion from the gut ?
Glucose
Amino acids
Neurotransmitters
( molecules with ionic charge )
29
What major group of transmembrane proteins aids facilitated diffusion ?
Solute carrier transport ( SLC)
30
What are the two types of SLCs?
- organic anion transporters ( OAT) and organic cation transporters ( OCT)
31
Where are OATs and OCTs mainly expressed ?
- GI tract
- hepatic tissues
- renal epithelia because these are the main places for absorption and elimination
32
What does secondary active transport rely on ?
- 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
What type of molecules are transported by endo/ectocytosis ?
- large molecules
| - one example would be vitamin b12 and insulin
34
What are 3 physio chemical factors that can affect drug absorption ?
- GI length / surface area ( the greater the surface area , the more absorption)
- drug lipophilicity / pKa value
- density of the SLC expression in GI
35
What are 3 GI physiology factors that affect drug absorption ?
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
What is first pass metabolism,
Reduces availability of drugs reaching systemic circulation - therefore affects therapeutic potential
37
Describe first pass metabolism that occurs in gut wall / liver
- some drugs metabolised by two major enzyme groups
1) cytochrome P450s - phase 1 enzyme
2) conjugating enzymes - phase 11 enzymes
-
38
Which organ is there a larger expression of the phase 1 and phase 11 enzymes ?
In the liver
39
Define bioavailability
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
When an IV route is used , what do we assume bioavailability to be?
1 because there are no physical or metabolic barriers to overcome .
41
What are the units for oral availability?
F
42
What is the formula for oral availability ?
F = Amount reaching systemic circulation / Total amount of drug given by intravenous administration
- F lies between 0 and 1
- F(oral) = AUCoral/ AUCiv
43
Why do we calculate oral availability ?
Informs choice of administration route
44
Describe the first stage of drug distribution
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
What are a few barriers to diffusion of drugs from capillaries to intersitial fluid to cell membranes to targets ?
- interacts with plasma / tissue proteins
- local permeability
- non target binding
46
What is a factor that affects diffusion of drugs across capillaries ?
- 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
What are major factors a affecting drug distribution?
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
Why when drugs bind to plasma or tissue proteins , they are distributed well to their target sites ?
- because only free drug molecules can bind to target sites
| - binding In plasma / tissue decreases free drug available for binding
49
What are the simplified three main body compartments ?
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
Increasing penetration by drug into interstitial and intracellular fluid compartments leads to...
- Decreasing plasma drug concentration
| - increase Vd( volume of distribution)
51
What does a smaller Vd mean ?
- less penetration of interstitial / intracellular fluid compartment
52
Larger Vd values mean..
Greater penetration of drug into interstitial / intracellular fluid compartments
53
How to calculate volume of distribution ?
Vd = Drug dose / concentration of plasma drug at t=0
54
What can vD be affected by ?
- changes in body weight
- pregnancy
- cancer patients
- renal failure
- geriatrics
- neonates , pre term , paediatrics
55
What does area under the curve indicate ? ( in regards to bioavailability)
Amount of drug in circulation
