B1: Pharmacology Flashcards
Potency
The relationship between the amount of drug administered, and its effect.
Inversely related to ED50.
Determinants: Affinity for site of action, and ability to reach site of action.
*X-axis position on Effect-Log Dose curve.
Efficacy
The maximal effect produced by a drug.
Determinants: Intrinsic activity, characteristics of the effector, and limitations on the amount of drug that can be administered (often due to adverse side effects - example is Levodopa).
*Y-axis position on Effect-Log Dose curve.
Log-normal Distribution
Followed by most drug effects: dose response relationship in an entire relationship of patients.
Frequency of response (quantal: yes or no) vs log dose.
68% of people within one SD, 95% within two SD.
More often depicted as a cumulative frequency distribution
Hyporeactive
At the less reactive tail end of the frequency distribution.
Hyperreactive
At the more reactive tail end of the frequency distribution.
Hypersensitivity:
Allergic or inflammatory response to a drug.
Tolerance
Slowly developing resistance to a drug. Usually drugs activating receptors.
Common in agonists for G-protein coupled receptors.
ED50
Two definitions:
- Amount of ligand/drug to get to 50% effect (also known as Kact)
- Amount of drug for which 50% of the population has a positive response.
TD50
Toxic dose for 50% of the population.
LD50
Lethal dose for 50% of the population.
Therapeutic index
TD50/ED50
The percent of the population to have a toxic response compared to a positive effect. Higher therapeutic index means the toxic dose and effective dose are more widely spread, and therefore the drug is safer.
The shift in the EC50 value with an antagonist is defined as.. (EQUATION)
EC50’ = EC50 (1 + ([antagonist]/KI))
Where KI is the KD of the antagonist for the receptor
Qualities of a drug that allow its diffusion through cell membrane
- lipophilic
- unionized form (acid HA, base B form)
Rate of diffusion of drug through cell membrane determined by
- partition coefficient of drug into oil from H2O
- concentration gradient across membrane
Henderson - Hasselbach Equation
pKa - pH=log ([protonated]/[unprotonated])
Ion Trapping
- Acidic drugs accumulate on BASIC side of membrane
- basic drugs accumulate on ACIDIC side of membrane (bases charged when protonated BH+)
Facilitated Diffusion
- driven by concentration gradient
- NO energy required
- transport of substances with too slow of passive diffusion rate (glucose)
Active Transport (2 ex.)
- REQ energy (Na/K ATPase)
1. P glycoprotein: ATP binding cassette Carrier; binds to lipophilic drugs that entered cell via passive diffusion so mediates EFFLUX from cell; acts to limit oral absorption of drugs by transpotring them back to GI tract
2. Secondary active transport: uses electrochemical energy stored in a gradient to transport another molecule against its concentration gradient
Bioavailability (F)
Fraction of the dose that reaches the systemic circulation
- IV drug F=1
- oral drugs F
Qualities of a drug that allow its diffusion through cell membrane
- lipophilic
- unionized form (acid HA, base B form)
Rate of diffusion of drug through cell membrane determined by
- partition coefficient of drug into oil from H2O
- concentration gradient across membrane
Henderson - Hasselbach Equation
pKa - pH=log ([PROtonated]/[UNprotonated])
Ion Trapping
- Acidic drugs accumulate on BASIC side of membrane
- basic drugs accumulate on ACIDIC side of membrane (bases charged when protonated BH+)
Facilitated Diffusion
- driven by concentration gradient
- NO energy required
- transport of substances with too slow of passive diffusion rate (glucose)
Active Transport (2 ex.)
- REQ energy (Na/K ATPase)
1. P glycoprotein: ATP binding cassette Carrier; binds to lipophilic drugs that entered cell via passive diffusion so mediates EFFLUX from cell; acts to limit oral absorption of drugs by transpotring them back to GI tract
2. Secondary active transport: uses electrochemical energy stored in a gradient to transport another molecule against its concentration gradient
Bioavailability (F)
Fraction of the dose that reaches the systemic circulation
- IV drug F=1
- oral drugs F
First Pass Effect
Drug passes through liver where metabolism can occur.
-if metabolism by liver is large, F is reduced, and low potency of drug
Bioequivalence
Two drugs prepared w/ same active ingredients at same amounts and delivered by same route are bioequivalent if EXTENT and RATE of drug delivery to the circulation are the same.
How/where are most oral drugs absorbed?
- passive absorption (favors unionized state –acid HA form, base B form)
- upper intestine
Controlled release drugs: advantages/disadvantages
ADV: reduced frequency of admin, more stable drug concentrations in body, logical for short half life drugs
DIS: greater inter patient variability, if dosage form fails large amounts of drug are dumped into blood thus toxic.
Sublingual/Buccal Admin of drugs
- venous drainage from mouth to SVC, avoids liver / 1st pass effect
- lipophilic drugs (pass through membranes; normally would be inactivated in liver)
Transdermal admin of drugs
- epidermis is lipid barrier, ONLY lipophilic drugs absorbed this route
- hydrated skin more permeable
Absorption rate of lipophilic drugs depends on
- drug solubility in interstitial fluid
- area of capillary bed in vicinity
Intramuscular injection absorption depends on
- blood flow to muscle (enhanced by exercise)
- fat content in muscle
Rate and extent of drug delivery depend upon:
- regional blood flow (initially the highly perfused get most of drug- liver, heart, kidney, brain)
- capillary permeability of the drug (loose endothelial junctions=rapid diffusion into interstitial space)
ACIDIC drugs bind to what plasma protein?
Albumin (lots of pos. Charges)
BASIC drugs bind to what plasma protein?
Alpha 1-acid glycoprotein (lots of neg charges)
Extent of protein binding can be affected by disease
- severe liver disease = hypoalbuminemia (reduces protein binding for acidic drugs)
- crohn’s or arthirits –> immune activation = increase alpha 1 acid glycoprotein (thus need to increase drug dose)
Tissue accumulation of drugs
- fat
- bone (tetracyclines and other divalent metal chelating agents)
Redistribution
Drug action is TERMINATED because the drug redistributes from its site of action to other tissues
-factor for: highly lipid soluble drugs, site of action in brain or cardovascular sys, admin via iv or inhalation
CYP2D6 Polymorphism
Who affected?
What drug?
- Who: patients suffer severe HYPOtension following admin of anti hypertensive debrisoquine
- Drug: debrisoquine
- Poor metabolizer (can be homo or heterozygous - homo = more severe); results in increased concentrations and decreased metabolism of debrisoquine
- Ultrafast metabolizer: gene duplication of NORMAL allele up to 13 times (more duplications = faster processing); more rapid drug clearance
- Metabolizes 25% drugs; including ANTIDEPRESSANTS
CYP2C19 polymorphism
-what drug classes affected?
- ANTI CONVULSANTS (phenytoin) = poor metabolizers have increased drug levels and side effects
- PPIs (omeprazole) = poor metabolizers have higher drug levels higher gastric pH, and better control of GERD **this case the poor metabolizers have a better short term outcomes
- ANTI PLATELET DRUGS (clopidogrel) = activated by CYP2C19; those with even 1 slow allele have less active drug and >50% increase in MI and stroke; omeprazole decreases activation of clopidogrel, increasing risk for cardiac events
Receptors
Two functions: 1) Binds drugs (or ligands, L) 2) Transduces binding into a response.
Many drugs produce their effects via receptors, because they are
CYP2C9 Polymorphism
- POOR metabolizer: 2 variants *2 and 3 (1=normal)
- Warfarin (anticoagulant) cleared by CYP2C9
- 3 much larger impact on warfarin clearance and dosing than *2
- *2 and *3: decrease warfarin clearance, increase warfarin half life, increase risk of bleeding, need lower maintainance doses
- no ultrafast variant
Vitamin K receptor polymorphism (VKORC1)
- VKORC1: required for clotting factor maturation; warfarin is a competitve inhibitor
- haplotypes and clades of VKORc1 = predictors of warfarin dose (10 common SNPs)
- Genetic Variants: A clade=(haplotypes H1, H2) need less drug, lower VKORC1 expression; B clade=(haplotypes H7,H8,H9)need more drug, increased VKORC1 levels
Pseudocholinesterase Polymorphism
- Variant responses to SUCCINYLCHOLINE (depol. Muscle relaxant) due to reduced activity of pseudocholinesterase
- atypical patients experience apnea and paralysis for 2-3 hours (due to decreased activity of pseudocholinesterase)
TPMT Polymorphism
- if TPMT polymorphism then not as much 6Mercaptopurine is inactivated as anticipated, thus more 6MP active = bone marrow toxicity
- Low activity allele has 2 SNPs in TPMT gene (normal/normal-(phenotype)norm risk bone marrow supression; normal/slow-elevated risk; slow/slow-high risk)
SLCO1B1 (OATP1B1) polymorphism
- OATP1B1: organic anion transporter that imports many drugs and endogenous compounds blood to liver
- Low activity variants in SLCO1B1 gene=decreased drug uptake into the liver, thus higher drug levels in the plasma
- strongest genetic evidence to date is for SIMVASTATIN (drug used to inhibit cholesterol biosyn)
- Low activity variants have increased simvastatin blood levels and increased risk for skeletal muscle toxicity
- some drugs are strong inhibitors of OATP1B1, thus increasing the risk for simvastatin toxicity (such inhibitors can further enhance the risk in those with low activity alleles)
Not all drug metabolism leads to drug inactivation
Example - Tylenol 3 w/codeine
- CYP2D6 activates a portion of codeine to morphine
- 2D6 poor metabolizers will not get the expected pain relief
- ultrafast metabolizers generate too much morphine from codeine
Prodrug
Drugs that are converted to their active form by metabolic enzymes
Phase I Metabolism
Oxidation, reduction, dealkylation, hydrolysis
Often introduce or reveal a functional group
*Not necessarily first
Enyzmes usually in smooth ER
Phase II Metabolism
Conjugation of the drug or drug metabolite to an endogenous substrate molecule
Most enzymes are cytosolic
Makes metabolites usually more polar (easier to excrete), inactive/less toxic
Some enzymes inducible, Vmax limited by conventional enzyme kinetics and conjugant supply
First-Pass Effect
Applies to ORALLY administered drugs
Portal venous system transports drugs to liver; significant metabolism (hepatic or intestinal) can occur prior to reaching circulation
Can greatly reduce oral bioavailability of a drug (F)
Cytochrome P450
- what is it?
- where is it?
- how is it named?
- human P450s
- metabolism
- major CYP450s
-Phase I: hemeprotein, major catalyst
-Anchored to the cytoplasmic face of smooth ER
-Many isoforms (~10-20 P450s per every P450 Reductase)
-CYP2B10: Cytochrome P450; 2=gene family (>40%); B=gene subfamily (>55%); 10=isoform
-18 families; 3 involved in drug metabolism - CYP1, CYP2, CYP3
-Broad substrate specificity - each isoform can have several to hundreds of drug substrates
CYP3A - 50% of drugs
CYP2D6 - 25%
CYP2C9 - 15%
CYP1A2, CYP2E1, CYP2A6, CYP2C19 -