1
Q
What are the 3 fundamental principles of drug action
A
i)Pharmacokinetics
ii) Pharmacodynamics
iii) pharmacology
2
Q
Pharmacokinetics
A
describes the ADME which bring a drug to the site of action
3
Q
Pharmacodynamics:
A
explains the relationship between the drug concentration at the site of action and the response
4
Q
Pharmacology
A
explains the general properties of drug receptors and drug-receptor interactions at the basis of drug action
- The study of what drugs are, what drugs do and how drugs work
- This is done through chemical processed, mainly through binding to regulatory molecules
- When they bind to the regulatory molecules they will either activate or inhibit normal body processes
5
Q
What is a pharmacologist
A
Studys action of drugs on physiological system, organs, cells, subcellular macromolecules
6
Q
What is pharmacotherapeutics
A
- Study of the therapeutic uses and effects of drugs to relieve suffering or prevent disease
7
Q
What is pharmacy
A
- Study of drug preparation, formulations
- Includes patient counselling
8
Q
What is pharmacognosy
A
- Study of medicine from natural sources
9
Q
What is toxicology
A
- Study of toxins/ poisons
10
Q
Example of pharmacology in action
A
Ask about a person drinking grapefruit juice
- We are asking this as grapefruit inhibits one of the enzymes CYP 3A4 which breaks down statins and other drugs which means they will get to much of the drug and more likely to experience toxic effects
11
Q
What are the fundamental principles of drug action
A
i. Pharmacokinetics explains an effective concentration at the site of action
ii. Pharmacodynamics explains the relationship between drug concentration and the response
iii. Pharmacology explains the binding of the drug to the receptor
12
Q
What is a drug
A
- A chemical that interacts with molecules in the body to affect a physiological function
- Are promiscuous as they bind to many receptors
13
Q
Two sources of drugs
A
a) Endogenous sources
- From the body (hormones, neurotransmitters)
- Anything with activity must bind to a receptor to fulfill its action
b) Exogenous
- Not from the body
- Plants (phytochemicals), marine life, micro-organisms, fungi, synthetic
- Most of the drugs that are prescribed are synthetic meaning man made
14
Q
What is a receptor
A
- The macromolecule which a drug must bind to have an effect
- When the drug binds it changes the receptor to cause a biological function
15
Q
What to receptors determine
A
- The quantitative (how much) relationship between dose/ concentration and effect
- Promiscuous meaning that they will bind to many ligands
- Responsible for drug selectivity and they mediate the actions of drugs
16
Q
What is an inert binding site
A
- Molecules to which drug bind but the binding doesn’t cause any change which we can detect in the biologic system
- Eg. Albumin
17
Q
Where can receptors be placed
A
- They can be many different places
- Extra/ intracellular, or transmembrane
18
Q
What is an agonist
A
- Drugs that occupy receptors and activate them at full strength
19
Q
What is a partial agonist
A
- Drugs that occupy receptors and activate them but less than the full amount
20
Q
What are antagonist
A
- Drugs that occupy receptors and do not activate them
21
Q
Explain the drug receptor interaction
A
- They need to be close enough to interact
- The affinity( how much they are attracted to eachother) is important as in they are in equilibrium in the biophase
- This interaction obeys the laws of mass action
22
Q
What is signal transduction
A
- Getting a cellular signal across a cell membrane
- Moves from external to internal and allows for drug activity
23
Q
What are the different types of interactions
A
a) Covalent
- Strongest
- Two atoms (one from drug and one from receptor) share an electron pair
- Often leads to an irreversible binding and often requires receptor destruction and function is resumed when there is synthesis of new receptors
b) Ionic
- Formed through electrostatic forces of ions with opposite charges
- Strength is decreased greatly due to distance
c) Hydrogen
- Most common
- The attraction between a hydrogen bond donor (H) and a hydrogen bond acceptor (N or O)
- Weak alone but can be stronger with many
- The basis to many drug-receptor interactions
d) Hydrophobic interactins
- Van der waals
- Very week
- Occur between non polar functional groups
- Contribute to but not responsible for D-R interactions
24
Q
What is the pharmacophore
A
- The critical portion of the drug molecule that participates in the D-R binding
- Associated with the pharmacological effect
- The rest of the molecule will then be tweaked to have favourable PK
25
What are ion channels (two types)
- Allow the passage of specific ions
i. Ligand-gated: require binding of a ligand to open
ii. Voltage gated: require a threshold change in membrane potential
26
What are enzymes
- When a drug binds to an enzyme it is either a substrate for it (metabolized by it) or changes it its metabolic activity
27
What is a transporter
- Drugs bind to transported often interfere with the movement of other molecules across plasma membranes or between organelles
28
4 mechanisms of drug signaling
i. Ligand gated ion channel: responds in milliseconds
ii. G-protein coupled receptor: seconds
iii. Kinase- liked and related receptors: hours
iv. Nuclear receptor: hours
29
What are ligand gated ion channels
- Found on cell membranes
- The channel opens only when a ligand is bound to it which lets ions pass through
- Fastest channels
- Drugs still compete with endogenous ligands
30
What are G-protein coupled receptors
- A single ligand can produce a large response as these receptors amplify signal transduction
- The duration depends on longevity of GTP binding to the g-protein not the receptors affinity for the ligand
- Found on plasma membranes and over 1000 types so they are grouped
31
Kinase linked receptors (three types)
- When activated they cause changes in gene expression
- The endogenous ligands include hormones, neurotransmitters, cytokines…
- The ligand binds and this causes a cascade of phosphorylation that leads to changes in gene transcription rates
- The three groups
i. Receptor tyrosine kinases: most common
ii. Receptor serine-threonine kinases
iii. Cytokine receptors
32
What are nuclear receptors
- Ligand gated transcription factors
- They are intracellular meaning the drug must cross the plasma membrane to interact with either the nucleus or cytoplasm
- When bound it causes changes in gene transcription rates
- Examples that use nuclear receptors are vitamin D, hormones, corticosteroids
- There are 4 subfamilies which are grouped by molecular action
33
What are the short and long term adverse effects of corticosteroids
1. Short term (2weeks)
- Insomnia/ restlessness: take in the morning
- Hypertension: monitor
- Hyperglycemia: monitor in diabetes patients
- Stomach upset: take with food
- Psychosis: with high doses (pulse therapy), monitor and are more susceptible if they have a history of mental health
2. Long term: much worse conditions
34
What is the law of mass action
- It describes the drug receptor interaction
- Describes the equilibrium between the concentration of the reactants (D and R) and the concentration of the drug-receptor complex (D-R)
35
Law of mass action equation
36
What does the law of mass action state
- The rate of change of the reactant concentration is directly proportional to the concentration of the reactants in both directions
a) The rate where the components associate (K12) depends on the drug and receptor concentrations individually
b) The rate where the D-R complex dissociates (K21) depends on the concentration of the D-R complex
Rate is how fast or slow a reaction occurs and gives a comparative amount of the reaction rates
37
What is the reaction rate
- The measure of how fast or slow a reaction occurs
38
What is the reaction rate constant
- A comparative amount of the reaction rates of reactants and products
39
What does Kd tell me
- How frequently dissociation occurs
- The dissociation constant
- Tells us how strong the interaction with receptor the drug had
40
Kd equation
41
What does Ka tell me (and equation)
- How frequently association occurs
The association constant
42
What is affinity
- The ability of a drug to interact with a receptor
- Depends on the nature of the bond interaction which depends on the properties of the drug and receptor
- The physicochemical properties include: molecular size, stereochemical orientation of functional groups, electrochemical properties (ionic and dipole interactions), molecular shape (stereoisomers)
43
What does it mean to Kd is there is high or low affinity
a) High affinity: the Kd will be small as magnetic attraction is strong
b) Low affinity: the Kd will be large as the magnetic attraction is weak
44
What does a Kd mean in comparison to an index of affinity (small vs large kd)
a) Small Kd means there is not much different between the rate of dissociation compare to association
- Enjoys being in the D-R complex
- High affinity
- The higher the affinity of drug for receptor the lower the concentration at which it produces a given level of occupancy of the receptor
- Don’t need much drug to produce the response as it likes being in the receptor
b) Large Kd means there is more dissociation as it is faster then the association
- Does not like being in the D-R complex
- Low affinity
- Need a lot of the drug before a response occurs
- The lower the affinity of a drug the higher the concentration needs to be to produce occupancy at the receptor (effect occurs)
45
What is capacity
- Rt
- The total concentration of receptors in the body that a drug can bind to
- Finite number of receptors
46
What does the occupancy theory state
- Have a finite number of receptors in the body and these responses depend on ho many of the receptors are occupied
- If all receptors are occupied this means that there will be a maximum pharmacological effect and if the drug concentration increases it will not result in an increase in the drug response
- However if all the target receptors are occupied toxicity and adverse effects can occur due to drug promiscuity
47
What is affinity
- The strength of attraction between D and R
48
What is capacity
- How many receptors are in the body to illicit an effect
- The magnitude of effect
49
If we rearrange the occupancy theory reaction to what does it tell us
- The rate of a process depends on the total number of receptors (Rt), equilibrium constant (Kd), and drug concentration [D]
- Same equation as a hyperbola
a) This is the mathematical relationship which describes all drug receptor interaction
- Not linear relationship
- At some point there will not a proportional increase between concentration and rate due to saturated receptors
50
How to turn the drug receptor interaction equation into a dose response curve and what defines thie shape of this curve
- Take the log concentration
- Affinity and capacity define the shape
51
What do affinity and capacity represent in the dose response curve
a) Affinity: the concentration that produces 50% of the response
b) Capacity: the maximum response that is possible in the body
52
What is specificity
- The ability of drug to produce an action at a specific site
- Refers to the relative potency (measure of drug activity) of a drug between the receptors of two or more different endogenous binding sites
53
What is selectivity
- Refers to the relative potency of a drug for the receptor subtypes of the same endogenous binding site
- Eg. Cox-1, cox2
- A1/a2
54
Explain the difference between specificity and selectivity
a) Selectivity shows a molecule with greater affinity to for one receptor
b) Specificity is like selectivity but goes a step further where no increase in the molecule of interest can activate the other receptor
55
What is the 2 stage model in response
a) Drug must have affinity for the receptor
b) Drug must have intrinsic activity or efficacy
56
What is intrinsic activity (efficacy)
- The ability of drug to elicity a response when it binds to the receptor
- After the drug binds to the receptor it can do full action (agonist), partial action (partial agonist), or no action (antagonist)
| E= Effect
a= intrinsic activity
57
what does it mean when intrinsic activity is 1, 0-1, or 0
i) 1: full response
ii) 0-1: partial response
iii) 0: no response
58
What is occupation of receptors governed by
- Affinity
59
What determines the ability of drug once bound to receptor
- Efficacy
60
What is efficacy dependent upon
a) Drug receptor coupling
- What type of receptor, what signal transduction goes on, what kind of bonds
- Full agonists usually have stronger bonds
b) Drug concentration
- Concentration range may dictate binding
61
What is the efficacy spectrum
i. Full agonist: produces maximal response
- a=1
ii. Partial agonist: produces a response but not full
- a<1
iii. Antagonist: produces no response
- a=0
62
Can drugs have same or different affinity and intrinsic activity
- Two drugs can have same affinity but different intrinsic activity
- Two drugs can have different affinity but same intrinsic activity
63
What are the classification of antagonism
1. Receptor antagonism (interaction occurs at receptor site)
a) Reversible
Competitive
Non competitive
b) Irreversible
2. Chemical antagonism
3. Pharmacokinetic
4. Physiological or functional
64
What are competitive reversible antagonism
- A drug antagonizes the action of a second drug by competing for the same receptor site
- The drug with highest affinity wins
- In the body drugs will also have to compete with the bodies ligands
65
ways to change Competitive reversible antagonism
- Can be overcome by increasing the drug concentration
- The second drug changes the affinity of the original drug (have to give more of the 1st drug in presence of second drug)
66
What is non competitive reversible antagonism
- One drug antagonizes the action by binding to a different receptor site in a way that prevents the agonist action of the other
67
What is irreversible antagonism
- Binds with the receptor permanently
- The receptor lifespan as a cell will aid in determining the duration of action
- Potential to change both affinity and intrinsic activity ( efficacy) of the opposing drug
68
What is chemical antagonism
- One drug antagonizes the action of a second drug by binding to and inactivating the second drug rather then the receptor site
69
What is pharmacokinetic antagonism
one drug antagonizes the action of another drug by reducing the concentration of drug at the site of action
- Pharmacokinetic interaction as it affects the ADME process
70
What is physiological or functional antagonism
- One drug antagonizes the action of another drug by producing a response that opposes the other using different receptors
71
What is desensitization
- Diminished effect occurs in the course of a few minutes
- Doesn’t happen to often
121
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