Pharmacology Basics Flashcards
Bioavailability + What Effects It
- fraction of administered drug that reaches systemic circulation (1 for IV drugs)
- Affected by …first pass effect, solubility of drug, chem instability, nature of drug formulation
Bioequivalence
- describes 2 drugs of diff formulation if they have the same bioavailability
- Compare conc v time for ea drug
- Used when testing generic v brand name
Dosing Interval
Time b/n maintenance doses
Factors That Affect Rate of Absorption (5)
- 1-Release of drug from pharm prep
- Dep on shape, size, compression and additives (ex- enteric coating for delayed release)
- Disintegrated and dissolved
- 2-Membrane permeability
- More lipophilic/less polar groups = more permeable
- Ionization = less permeable
- 3- SA in contact w/ drug
- Highest= SI and lungs
- Lowest= eyes, nasal cavity, buccal cavity, rectum, stomach, large intestine
- 4- Blood flow to site of absorption
- Highest= SI, lungs, muscle, buccal cavity, nasal cavity
- Lowest = eyes, stomach, large intestine, rectum, subcutaneous
- 5- Destruction of drug at or near absorption site
- Ex) bacteria in GI tract, enzymes in GI wall, liver enzymes (first pass effect)
Factors That Affect Drug Distribution (6)
- 1- Organ blood flow
- Lungs, kidneys, liver, brain, muscle
- 2- Barriers to drug diffusion
- Capillaries w/ tight junctions require diffusion - so only lipophilic drugs age
- 3- Plasma protein binding
- Not pharm active
- Also limits filtration - can only filter unbound drug
- 4- Tissue protein binding
- Can act as reservoir for later (ex- Z pack)
- 5- Accumulation in adipose tissue
- Especially if drug has high lipid content
- 6- Ion trapping
Ion Trapping
- Basic drugs accumulate/trapped in acidic solution (ex- cytosol)
- Acidic drugs accumulate/trapped in basic solution (ex-breast milk)
- Can be used to distribute drugs to urinary compartment for inc urinary excretion of poisons (alkalization or acidification of urine)
Factors That Influence Membrane Permeability to Drug
- More lipophilic/less polar groups = more permeable
- Ionization = less permeable
- BUT do not want too lipophilic either
Volume of Distribution +What Effects It
VD = Amount of drug admin/[D]p
Apparent - not real volume
More restricted throughout body = smaller VD
Tissue binding/dist into fat - inc VD
Plasma protein binding - dec VD
Loading Dose
=VD ([D]target) /B
- Use VD initial - conservative- avoid toxicity
- Use VD final - emergency - need therapeutic range immediately
One compartment behavior vs two compartment behavior
- One Compartment- Body acts like fixed beaker; fast equilibration to all parts of body
- VD reached in minutes and easy to calc- just determine conc at time of administering
- Two Compartment- Body acts like a beaker getting bigger w/ time; initially drug goes to certain compartments THEN slow equilibration to all body
- VD reached after delay
- VD hard to calc b/c use conc after equilibration and do not know the amount of drug still in body at this time
Drug Clearance
Cl = rate of drug elimination / [D]p
Cl total = Cl renal + Cl hepatic
Effects on Renal Elimination
Normally eliminated if drug is unbound- filtered into urine or if drug delivered to kidney by secretion into renal tubules
Reduced if renal disease, competition b/n drugs for secretion, plasma-bound drug not filtered, reabsorption of lipophilic drugs
Effects on Hepatic Elimination
Normally due to metabolism by liver enzymes or secretion of drugs into bile
Reduced if ionization (less taken into hepatocytes), competition b/n drugs for metabolism or bile transport, liver disease, genetic variation in enzymes
Increased if induction of liver enzymes (by same or diff drug or environmental chemicals), genetic variation in enzymes
Therapeutic Range v Therapeutic Ratio
Ratio: Highest [D]p that is safe / lowest [D]p that is effective
Range: Conc between peaks (toxic threshold) and troughs (therapeutic threshold)
**Want your [D] ss to be in this range
Maintenance Dose
amount of drug taken at regular intervals
Dosing Interval Max
= 1.44 (t1/2) ln(TR)
- Max dosing interval w/o toxic peak or non-ejective trough
- For practical purposes, round to lowest manageable dose time (ex- if DI max is 35 hrs say once daily)
Steady State
- Tss = time needed to reach steady state [D] given repeated dose admin using specific MD/DI
- tss = 4 (t1/2)
- [D]ss - drug conc at steady state
- Want it to be in therapeutic range
- When rate of drug admin = rate of drug elimination
[D]PSS = B x MD/DI x Cl
Plasma Half-Life
- t1/2 = .693 (VD) /Cl
- Use VD final
MD/DI Equation
MD/DI = [D]P(target) x Cl/B
Efficacy vs Effectiveness
- Efficacy - meas drugs ability to prod desired effect in ideal setting (clinical trial of homo group)
- Effectiveness - meas drugs ability to prod desired effect in everyday clinical practice (hetero group of pts)
Adverse drug reactions vs adverse drug events
- ADR- response to drug (DIRECT; noxious, unintended, happens when normal dose given)
- Type A- common and predicted
- Type B- uncommon and unpredictable
- ADE- injury resulting from use of drug (indirect and broader)
Drug Evaluation Process (4 Phases)
- Phase 1 - establish safe clinical dosage range on 20-100 healthy volunteers; pharmacokinetic info
- Phase 2- study in 100-200 people w/ target disease; determine efficacy usually fail
- Phase 3- study much larger number of people w/ target disease; further establish safety and efficacy for FDA approval (FDA approval is only based on safety and efficacy) expensive
- Phase 4- post-marketing surveillance; final drug safety eval
3 General Drug Mechanisms
- Antagonize/block endogenous proteins
- Activate endogenous proteins
- Unconventional mechanisms
- ex- disrupt protein structure, react chem w/ small molecules, bind free molecules, enzymes themselves, antisense action
2 Types of Acetylcholine Receptors
- Muscarinic- G protein coupled so SLOWER response
- Nicotinic - gated ion channel so FASTER response
AJ Clark’s Receptors Theory Assumptions (4) and Rule
- 1- interaction b/n ligand and receptor is reversible
- 2- all receptors for given ligand are equivalent (same affinity) and independent
- 3- response is dir proportional to #occupied receptors
- 4- ligand only exists in 2 states (free or receptor-bound)
When receptors are 50% occupied the [L]= Kd
Kd
- equilibrium constant for dissociation of receptor-ligand complex
=[L][R]/[LR]
Fractional Occupancy v Fractional Response
Both = [L]/ [L] + Kd
Occupancy used when you want to know how much ligand/drug you need to get 50% receptors bound
- EC50 -conc needed to get 50% receptor occupancy
Response used when you want to know how much ligand/drug you need to get 50% rate of desired bio effect
- ED50 - dose needed to get 50% effect
Dose Response Curve
- Plot receptor occupancy or bio effect v. [ligand]
- Shows saturation in relation to [ligand]
- Saturation inc from 10-90% in 2 order of magnitude inc in [ligand] REGARDLESS OF AFFINITY
Quantal Dose Response
- You define what is considered a bio response/effect then look at relationship b/n dose and desired response in population
- You can define and ED50 for a population; you decide what effect is
- Ex) if you want your drug to dec BP by 50% in population that is you defined ED50
Spare Receptors
- Amplification of signal duration –> left shift (means half max response ED50 is attained when [L] «_space;Kd AKA does not take as much [L] to get same effect as it does to get 50% receptor occupancy)
- B/c some cells have “spare receptors” that help generate max bio response at lower conc of ligand
Effects of Pos and Neg Cooperitivity
- Pos cooperativity - binding of 1 ligand enhances binding of subsequent ligand
- Steeper curve - small change in [L] causes large change in bio response
- Neg cooperativity - binding one ligand diminishes binding of subsequent ligand
- Broader curve- less change in bio response for give change in [L]
Potency v Efficacy
- Potency - amount of ligand needed to produce effect of certain magnitude; usually defined using EC50
- How much ligand do you need to get to EC50?
- Efficacy- more clinically important b/c want max bio effect
- Which drug has overall highest bio response?
Agonist
Antagonist (2 types)
- Agonist- drug that binds to rec and prod bio effect that mimics endogenous ligand -ACTIVATES RECEPTOR
- Antagonist- drug that binds to rec and blocks action of endogenous ligand; no intrinsic activity of own
- Competitive - dec potency but can be overcome by inc [ligand]
- Non competitive - do NOT affect potency; cannot be overcome by inc [ligand]
Partial Agonist
Inverse Agonist
- Partial Agonist - have efficacy but less than that of endogenous ligand; may still have higher affinity but less effect than ligand
- Inverse Agonist - bind and stabilize the inactive conformation of a receptor
- Can actually dec activity level of the receptor below the baseline activity when no ligand present
- Inverse Agonist - bind and stabilize the inactive conformation of a receptor
Tachyphylaxia v Tolerance
- Tachy- ACUTE dec in response to a drug (esp seen in CNS drugs - neurotransmitters)
- Tolerance - CHRONIC dec in response to drug
