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Dosage at which 50% of people have therapeutic effect
Dosage at which 50 % of people have toxicity
Dosage at which 50% of people die/lethal effect
Define the "therapeutic window"
Efficacy without unacceptable toxicity
Equation for the Therapeutic Index
TI= TD50/ ED50
wide therapeutic window
small therapeutic window
D+ R = DR
What is DR?
DR= drug-receptor binding without effect
D + R = DR*
What is DR*
drug binding with response
What does a FULL AGONIST do?
- 1. elicits maximal response
- 2. Stabilizes DR*
What does a PARTIAL AGONIST/Mixed agonist-antagonist do?
- Activates receptor but not with maximal efficacy
- Stabilizes DR and DR*
What does an INVERSE AGONIST do?
- 1. Inactivates free active receptors
- 2. Stabilizes DR in the case of R*(natural form)
What does an ANTAGONIST do?
1. Stabilization of DR; prevention of DR*
What does a competitive antagonist do?
- 1. Has reversible binding at active site
- 2. Competes with agonist binding to site
What does non-competitive active site antagonist do?
- 1. Has irreversible active site binding
- 2. No DR*- prevents agonist binding to site
Name two types of non-receptor antagonists?
Give an example of each?
- Chemical- agonist inactivation (PROTAMINE)
- Physiologic- mediates opposite response of agonist (B-blocker to reverse tachycardia in hyperthyroidism)
What is the allosteric site?
Binding site other than the drug/enzyme's active site
What does a non-competitive allosteric antagonist do?
- 1. Binds reversibly or irreversibly to allosteric site
- 2. Prevents conformational change required for receptor activation
What is pharmacodynamics?
Name 3 factors that affect PD
- What the drug does to the body
- 1. drug-receptor interaction
- 2. patient's functional state
- 3. placebo effects
What is pharmacokinetics?
What are the 4 principles of PK
- What the body does to the drug.
- 1. Absorption
- 2. Distribution
- 3. Metabolism
- 4. Elimination
Are non-ionized molecules more or less readily absorbed by the body?
- More readily absorbed.
- Ionized molecules are hydrophilic and have difficulty penetrating membranes
What is the pka?
pH at which 50% of the drug is ionized.
What is pH trapping?
Once a drug is ionized in the plasma- the drug is trapped and will not return to the GI system.
Determined by the pka and pH gradient across the membrane
Name the 4 types of DR bonds and their relative strength.
- 1. van der Waals: shifting electrons, transient + and - charges; weakest
- 2. Hydrogen: H atoms bound to nitrogen or O2..
- 3. Ionic: Atoms with excess of electrons attracted to + atoms = net positive
- 4. Covalent: Two bonding atoms share an electron. Strongest
Nonionized molecules are __________
Ionized molecules are ___________
- lipophilic (lipid soluble) (HA)
- hydrophillic (difficulty penetrating lipid membranes)
What are factors that affect drug absorption?
Whether po, IV or transdermal admin
1. concentration (↑ concentration, ↑ absorption)
- 2. Circulation at site of admin (↑ circ, ↑ absorption)
- 3. Drug solubility
- 4. Surface area
What factors affect drug distribution?
- 1. BMI
- 2. Age (elderly-low, infants-high)
- 3. Protein binding (highly bound drugs stay in the plasma longer)
- 4. Hydration
What is First Pass Metabolism?
- Portion of the drug is lost in liver metabolism and not bioavailable to plasma.
- Primarily po drugs have first-pass effects.
Name three possible CYP450 interactions and their possible results
- 1. competition (toxicity is possible due to increased metabolism)
- 2. induction (lower concentrations, need to give more drug in order to have effect)
- 3. Inhibition (drug cannot be broken down, levels elevate)
True or false:
Nonionized, lipophilic drugs are favored for oral absorption.
CYP450 inhibitors will _________ the drug effect. Example of two CYP Drug inhibitors:
Slow down substrate drug metabolism and increase drug effect.
Amiodarone and Warfarin leading to increased bleeding risk
CYP 450 inducer will ___________ drug effect
These will speed up substrate drug metabolism and decrease
- 1. increase transcription or translation
- 2. decrease degredation
- 3. induction by another drug or autoinduction
Name some disadvantages of PO administration of drugs
1. Absorption challenges: harsh GI enviroment, slow delivery, First pass metabolism
Which types of drugs are favored for PO admin?
- 1. non-ionized, lipophilic drugs
- 2. weak acids for absoprtion from stomach
- 3. weak bases for absorption from sm intestines
Facts about rectal administration
- 1. when oral admin isn't possible
- 2. 50% of drug will bypass liver (1st pass)
- 3. Erratic absorption
- 4. Irritation of the rectal mucosa
Transdermally absorbed drugs need to have ____________________
Advantages of transdermal admin.....
- No hepatic first pass
- No harsh GI environment
- COntinuous admin (slow release) makes stead state easier to achieve
Low Vd drugs ___________within the plasma/vascular space
High Vd drugs ____________ in the vascular space
do not stay (are poorly concentrated)
High Vd drugs are __________distributed in the the tissue
Low Vd drugs are ___________ in the tissue/non-vascular compartments
For drugs to be metabolized they must be _______ in plasma. Drugs that are _________ cannot readily be metabolized.
- highly protein-bound
Name the 2 biotransformation reactions.
- 1. Phase I= oxidation/reduction
- 2. Phase II=conjugation/hydrolysis
3 most important parameters for accessible concentration of drugs
- 1. clearance (metabolism and excretion)
- 2. Vd (apparent space in the body)
- 3. Bioavailability (the fraction of drug absorbed into systemic circulation
Equation for drug clearance (CL)
CL=(metabolism + excretion)/Drug-plasma
What is first order kinetics?
1. Increase in plasma concentration = matched increase in clearance
What is zero order kinetics?
Increase in plasma concentration with no increase in clearance b/c the enzymes that metabolize the drugs become saturated...
What is T1/2?
half-life is the time it takes for the plasma concentration to be reduced by 50%
What is the formula for half-life T1/2
T1/2=0.693/k and k=elimination rate constant
What is the Cmax?
peak plasma concentration
What is the Cmin?
min plasma concentration
If the Vd of drug is low, you need to give ____(dosage of drug).
Generally, it takes about ____ half-lifes for a drug to reach steady state and ____ half-lifes for it to be eliminated.
What is a pharmacokinetic drug interaction?
When a drug inhibits metabolism of another drug.....leading to toxicity
What is a pharmacodynamic drug-drug interaction?
Drug causes another drug to work more at a certain receptor but not r/t concentration of the drug.