Unit 1 Flashcards
Dose Response Curve
X axis?
Y Axis?
Equation to find Response?
X: Potency/Dose*
Y:Efficacy/Power/Response*
Y is the more important variable; actual effect, who cares how potent something is if it works
Hyperbolic shape—relatively linear at low, levels off at high
EC50/ED50: 50% of response
Potency: dose half of response occurs
Emax: 100% response
Response = e/Emax= [D]/(ED50+[D})
Agonist effect in general, Partial Agonist versus Full Agonist, Examples
Agonists Has to do with the level of response when binding to a receptor…
Partial Agonist: Drugs that occupy the same receptor as a full agonist, but bring less than maximum response
Full Agonist: Drugs that occupy receptors, bring maximal response
example of a partial agonist is nicotine patches and such, example of a full agonist is pretty much most drugs (but in particular Dobutamine which has a similar effect to norepinephrine on the heart)
Antagonist—What do you need for it to be effective? Example?
Prevents binding of agonists. You need an agonist because there has to be something already binding otherwise it just kind of exists (will have a small basal response but still). Ex: Metoprolol (blocks heart norepinephrine receptors)
General Signaling pathway
Drug->Recognition and Binding to Receptor-> Signal Transudction via G-Protein or other Effect->Amplification->Physiological Response
Methods of Transduction and Amplification
- Ligand Gated ion channels
- G-protein coupled receptors (lead to enzymes)
- Kinase linked receptors or hormone receptors
Receptor Types
Proteins: Hormone, Neurotransmitter, Voltage gated ion channels
Nucleic Acids: lower specificity
Membrane lipids: Lower specificity
What is the consequence of drug receptor theory?
Receptors are responsible for selectivity of drug action; increase in benefit: risk ratio
Competitive Reversible Antagonist—effect on dose response curve?
Binds reversibly to the activation site of a receptor
shifts curve to right; need higher dose of agonist, but Emax remains the same, potency decreases
(basically it just outcompetes it at higher doses)
Noncompetitive Antagonist—effect on dose response curve?
Bind irreversibly or reversibly to allosteric site–changes receptor conformation–no shift but Emax is decreased by half, potency remains same because even though the effect is smaller same does still gives half of effect
Physiologic Antagonist
Activates or blocks a receptor that is opposite to that of activation of the receptor of agonist (ex: histamine)
Chemical Antagonist
Receptor binding NOT involved. Directly binds to agonist and prevents it from binding. Ex: EDTA (chelating agent) used to treat lead poisoning
Quantal Dose-Response (Effect) Curves
Arbirtarily defining some specific theraupeutic effect—determine minimum dose to produce response
-all or nothing: single given dose of a drug in one person must give desired effect
Benefit-Risk Ratio
- How safely can a drug be used in a clinical situation
- dosage necessary for good effect versus dosage necessary for toxic effect
Therapeuitic Index versus standard safety margin
Other name for Therapeutic index
TI: Compare midpoints in population (Effective Dose 50 and Lethal Dose 50)
TI= LD50/ED50
sometimes called therapeutic window (safe opening between minimum effective dose and minimum toxic dose)
Standard safety margin: look at extremes (ED99 and LD1) , safe in 99% how much to kill 1%
SSM [(LD1/ED99)-1]*100
Assessing Therapeutic Effects [Benefits]
Assessing Toxic Effects [Risks]
Benefits: ED50: gives desired effect in 50% of population (from dose response curve)
Risks: Compare toxic and desirable effects—LD50 is the dose that will kill 50% of the population—can also be a TD50 (dose that produces undesirable effect in 50% of patients)
Standard Safety Margin
SSM=[(LD1/ED99)-1]*100
percent by which dose effective in 99% of population must be increased to cause death in 1%
more conservative measure than therapeutic: takes into account extremes of the population
Adverse Reaction
And types:
A response to a drug that is not desired, is potentially harmful, occurs at usual therapeutic doses
Extension effects: therapeutic effect lats longer than intended
Side effects: Predicitable, dose-dependent reactions unrelated to therapeutic goal
Idiosyncratic reacitons: genetically determined abnormal response to a drug, unpredictable
Drug allergy: adverse response of immunologic origin, unpredictable, dose independent
Drug Effects on Fetus and Categories
A: Controlled substance causes no risk
B: No evidence of risk in humans (ex: opioids in early term, acetaminophen)
C: Risk cannot be ruled out—no studies available, or adverse effect has been demonstrated in animals (ex: antidepressants)
D: Positive evidence of human fetal risk: definitely caues harm, but may cause more benefit than harm in life threaning situations (think ACE inhibitors, oral anticoagulants)
X: Shit is bad news. Contraindicated in pregnancy. Positive evidence of human fetal risk. Risks involved outweigh benefit. Ex: HMG CoA reductase inhibitor
Drug-Drug Interaction risk factors
A. Pharmacokinetic drug interacitons: result in elevated drug concentrations, lead to toxicity
B. Narrow therapeutic index
C. Patient demographics: elderly, high risk clinical situation, renal/hepatatic disease, multiple prescribing physicains
Pharmacokinetic Interaciton Stages
Absorption: Decrease motility (slow passage)–lower peak plasma drug levels, increase in rate of absorption (less important)
Distribution
Metabolism
Excretion
Pharmacodynamic Interacitons types
Antagonist effects: 2 drugs iwth opposite pharmacologic effects given together
Synergistic/Additive Therapeutic effects: drugs with similar therapeutic effects given
Synergistic/additive side effects: see above but with side effects
Indirect Effect: effect of one drug indirectly affects anothers action
Pharmaceutical Interacitions
Occurs when 2 drugs mixed in same IV fluids
Summary of Drug Drug Interactions and what to do
Minimize this shit happening
Document all patient drug use
Minimize number of drugs given (maxiximize benefit;risk ratio)
Be vigilant, cautious
First physiological factor influencing drug distribution
A. Special anatomic considerations, (tissues w/ tight junctions: GI mucosa, blood brain barrier, placenta, renal tubes)
-drugs that can’t pass through membranes won’t be able to move between comparments
GI Mucosa: Negigible absorption of drg int oblodo if adminsitered oral
Blood brain barrier/ placenta: limited distribution of drug from blood into brain or into fetal circulation
Renal tubules: filtration at glomerlus, reduced reabsorption of drug back into blood, enhancing excretion via urine
Second physiological factor influencing drug distribution
Influence of pH on Drug distribution
Overview: weak acid, weak base drugs affected by lipid solubility
acid: release proton, become charged
base: take up proton, become charged
drug absorption: acids become nonionized in acid medium, bases become nonionized in base medium, nNONIONIZED FORMS ARE MORE READILY ABSORED IONIZED FORMS DO NOT CROSS LIPID MEMBRANES
Henderson-Hasselback equation pH= pKA + log ([A-] or [B]/HA or BH+] can predict how much of drug is ionized and absorbed
General Rules of thumb when looking at pH influence
pH lower than pKa of drug: relatively more protons and the protatonated form of the weak acid [unionized-lipopholic…so shit will bind a lot) or weak base (ionized)
pH higher than pKa—fewer protons sso unprotatonated form of weak acid [ionized—wont bind] and weak base [unionized, lipophilic, will bind]
Ion Trapping & Clinical Significance
At equilibrium: unionizaiton of drug is the same on both sides of the membrane, but total concentration of drug is greater on sidew here ionization is greater—drugs trapped where they are predominaly ionzed. ACIDIC TRAPPED IN BASIC, BASIC TRAPPED IN ACIDIC
Clinical significance of ion trapping: uncommon
- greater potential to concentrate basic drugs (like opioids) in more acidic breast milk
- foresnic pathology: weak base toxins are found concentrated in acidic stomach conditions
- alteration of urinary pH to ion trap weak acids or bases and hasten renal excretion