Learning Objectives Module 2A, B, C Flashcards
ED50
- The median effective dose
- The dose needed to produce a specific therapeutic response in 50% of patients
- Also referred to as standard or average dose
- ## This dose does not apply to everyone as some patients will respond to lower or higher doses then average
TD50
- Median toxicity dose
- The dose needed to produce a given toxicity in 50% of a group of patients
- Lethal doses observed in preclinical studies (cells and animals as we don’t test the lethal dose in humans)
- We determine this from adverse effects which are reported in clinical trials as toxicities are monitored closely and will happen before death
The dose response relationship:
- Looks at an individuals response to a drug
a) Phase 1: very few target cells have been affected by the drug
b) Phase 2: Shows the linear relationship between amount of drug given and degree of response obtained - Not all drugs have a linear relationship but most do
c) Phase 3: plateau - No further response occurs with a higher dose
- This is as all receptors are occupied so you have already obtained 100% of the indication
- Even though there is no further response there still will be adverse effects and more signs of toxicity
Onset
- the time it takes to reach the effective dose
- How fast the drug gets absorbed and enters the blood
Intensity
- how strong the drug is
- The stronger the intensity the more plasma concentration you will receive with less drug
Duration
- time drug lasts in therapeutic window
- How strong the bond between drug and receptor is (affinity)
Therapeutic Window (TW)
- the range of drug plasma concentration when the drug gives the desired effect with no fear of toxicity
- Based on population as we don’t know the therapeutic window for a specific patient
- There are empirical dosing regimens designed to put the drug Css (steady state) in the therapeutic range
Therapeutic range (TR)
*the range of dose where most of the population will get the desired effect with no fear of toxicity
- Based on population as we don’t know the therapeutic window for a specific patient
- There are empirical dosing regimens designed to put the drug Css (steady state) in the therapeutic range
Therapeutic index (TI)
*The ratio of toxic plasma concentration (Cp) to effective Cp values
tells us how large or small the room we have to “play” with drug dosing
- Compares the amount of drug which causes the indication to the amount which causes toxicity
- A ratio and has no units
Wide vs narrow TI
- The ratio of toxic plasma concentration (Cp) to effective Cp values
- Compares the amount of drug which causes the indication to the amount which causes toxicity
- A ratio and has no units
a) Wide TI; safe, regular monitoring unnecessary - The ratio of toxic Cp to effective Cp is large
b) Narrow TI: not very safe and drug monitoring is necessary for safety - The ratio of toxic Cp to effective Cp is small and toxicity could come when indication occurs
elements of the dosage regimen
- Amount of drug
- Route of administration
- Dosing interval
- Formulation
Determinants of the dosage regimen
- Activity toxicity
- Therapeutic window
- Side effects
- Toxicity
- Cp vs response - Pharmacokinetics:
- Absorption, distribution, metabolism, excretion - Clinical factors
- State of patient: age, weight, condition, other disease states
- Management of therapy: multiple drug therapy
- Convenience of regimen
- Compliance - Other factors
- Route of administration
- Dosage form
- Tolerance- dependence
- Pharmacogenetics
- Drug interactions
- Cost
Pharmacokinetics:
What the body does to the drug
Pharmacodynamics
What the drug does to the body
relationship between PK and PD
PD couldn’t happen without PK and it can happen anywhere in the table but usually during the distribution phase
- PK is everything before the drug receptor interactions an PD is anything during and after
Linear PK (pharmacokinetics
proportional increase in Cp (drug plasma concentration) with increased dose
Non linear PK
disproportional increase of Cp with increased dose (this leads to unpredictable response of a drug
What are the primary PK parameters
determined by physiology/ dont change with the dose of the drug
1. Absorption rate constant (Ka)
2. Oral bioavailability
3. Hepatic clearance
4. Renal clearance
5. Volume of distribution
Absorption rate constant (Ka)
- Determined by blood flow at absorption site, gastric emptying, GIT motility
Oral bioavailability
Determined by gastric emptying, acid secretion, enzymatic activity, GIT motility
Hepatic clearance (ClH)
- Determined by hepatic blood flow (Qh), binding in blood (Fu(b)), intrinsic clearance (Clint)
- Liver clearance
Renal Clearance (ClR)
- Determined by renal blood flow (fu(b)), active secretion/ reabsorption, urine pH and flow, glomerular filtration
- Kidney clearance
Volume of distribution (Vd)
- Determined by fu(b), tissue binding, partitioning tissue perfusion, body composition and size,
- Vd is a characteristic of a drug
- Affected by physiology
What are the secondary PK parameters
- Elimination half life
- Elimination rate constant
- fraction excreted unchanged
Elimination half life equation
T 1/2 = 0.5 0.693 x volume of distribution/ systemic clearance
Elimination rate constant
K = systemic clearance/ volume of distribution
Fraction excreted unchanged
Fe= renal clearance/ systemic clearance
What are the derived PK parameters
- Area under the curve (IV)
- Steady state concentration
- Area under the curve (oral)
- Average plateau concentration(IV)
- Tmax,/ Cmax
the different transport mechanisms across polarized epithelia
- Transcellular: through the cell
i) Paracellular: through tight junctions
ii) Passive diffusion - Endo/ exocytosis
- Carrier mediated
- Active
- Facilitated diffusion
drug characteristics that determine transport across plasma membranes
- We know what qualities a drug need to undergo passive diffusion (small, non ionized, lipid soluble), passive diffusion is the easiest as it will do it itself
- Transport it dependent on size, ionization, and solubility of the drug
- This is why protein binding effects distribution of drugs
Explain the fundamental principles of drug action
i) Pharmacokinetics
ii) Pharmacodynamics
iii) Pharmacology
Pharmacokinetics
describes the ADME which bring a drug to the site of action
Pharmacodynamics
explains the relationship between the drug concentration at the site of action and the response
Pharmacology
- 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
Drug (2 types also)
- A chemical that interacts with molecules in the body to affect a physiological function
- Are promiscuous as they bind to many receptor
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
Receptor:
- The macromolecule which a drug must bind to have an effect
- When the drug binds it changes the receptor to cause a biological function
inert binding site:
- Molecules to which drug bind but the binding doesn’t cause any change which we can detect in the biologic system
- Eg. Albumin
Affinity:
how avidly the drug binds to the receptor (the want for the DR complex)
- on a graph is also the same as Kd and EC50
Capacity:
the maximum response that is possible in the body
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
Selectivity:
- Refers to the relative potency of a drug for the receptor subtypes of the same endogenous binding site
- Eg. Cox-1, cox2
Efficacy (intrinsic activity)
- the ability of drug once bound to receptor
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
Pharmacophore:
- 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
List the broad categories of receptor types
- Ligand gated ion channel
- GPCRs
- Kinase
- nuclear
Ligand gated ion channel
responds in milliseconds
- 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
G-protein coupled receptor
seconds
- 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
Kinase- liked and related receptors
hours
- 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
different types of Kinase-linked receptors
i. Receptor tyrosine kinases: most common
ii. Receptor serine-threonine kinases
iii. Cytokine receptors
Nuclear receptor
hours
- 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
Explain 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)
- The rate of change of the reactant concentration is directly proportional to the concentration of the reactants in both directions
What is K12 vs K21
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
If there is a small vs large Kd in relation to affinity
- If have a small Kd then high affinity
- If high Kd then have a low affinity
