Chapter 1: Basic Principles Flashcards
What is Pharmacology?
Study of chemical interactions with living systems
-Medical Pharmacology: Substances used to prevent, diagnose, and treat disease
What is Toxicology?
Study of undesirable effects of chemicals on livings systems
-Toxins: Organic from living things
- Poisons: Inorganic from nonliving
Paracelsus: Father of toxicology
-Any compound can become poisonous if excessive amounts were taken in
History of Pharmacology
-First Recorded physician- Imhotep
-Still use traditional Chinese Medicine: Use of plants and animals (ex. Rhino horn used for fertility, Bear bile- Covid)
-People confused Rod of Asclepius and Caduceus
-Material Medica: First textbook of pharmacology
-Want Controlled Drug trials
>Avoid anecdotal evidence (Imermectin for COVID)
Pharmacodynamics
Effect of drug on the body (Why are we taking it?)
Pharmacokinetics
Effect of body on drug (ADME)
A: Absorption- Move across a barrier
D: Distribution- Where is the drug going to end up
M: Metabolism- Activate vs. Inactivate
E: Elimination- How do we get rid of it?
What is an agonist?
Molecule that binds to a receptor site that elicits a response similar to endogenous ligand
-Degree of response may differ from endogenous ligand
What is an antagonist?
Block endogenous ligand from binding to the receptor site
-Does not elicit a response
Allosteric Site
Molecule binds at a site away from orthosteric site, but still on same protein
Causes a conformational change change of the orthosteric site
-Activator vs Inhibitor
Orthosteric Site
Drug binds to the same site as the endogenous ligand
Bond Strength
- Covalent Bond Strongest (50-150 kcal/mol)
- Ionic (5-10)
- Hydrogen Bond (2-5)
-Van der Waals Forces - Hydrophobic: Not really bonds- just trying to stay away from water (0.5-1)
Bond Strength Relationship with Specificity
Inverse Relationship
-Strong bond=Less Specific
What is a racemic mixture?
Combination of R:S Isomers
-R:S isomers interact differently with receptor site so can cause different responses/side effects
-Sterioisomeres
Partial Agonist
Effect is much weaker than full agonist
- Absence of Full Agonist- Agonist
- Presence of Full Agonist- Antagonist
>Why? Competing for same receptor sites
Inverse Agonist
Agonist that favors (greater affinity) the INACTIVE form of receptor; suppresses response
- Acts as an antagonist b/c binds to inactive receptor so less active receptors available
-To have this; need to have constituent activity at the site with endogenous ligands still acting on site
>If site doesn’t have activity, then inverse agonist can’t occur
Competitive Antagonist/Inhibitor
Bind to same site so inhibits response by competition
Surmountable: Increase Agonist concentration and will achieve same Emax/response
-Increase EC50 or ED50 (move EC50 to the right on log dose vs response curve)
Non-Competitive Antagonist/ Allosteric Inhibitor
Binds to a different site causing a change to orthosteric site
-Receptor was a square, but now a circle so agonist
unable to bind
Insurmountable: No increase in agonist concentration will elicit same response
- Emax: Decreases
- EC50: Stays the same (i.e changing the scale)
Irreversible Inhibitor
Binds to the same site, but unable to break connection
ex) covalent bond forms so inhibitor it does’t leave
Can be competitive or noncompetitive
Insurmountable: No increase in agonist
concentration will elicit same response because it is decreasing the amount of available sites
- Emax: Decreases
- EC50: Stays the same (i.e changing the scale)
Beta 1 Receptor
Think Heart
-Agonist: increases heart rate
>Direct: Epi, Norepinephrine
>Indirect (mimic): Cocaine, Amphetamine (Blocks reuptake in synapse so epi stay longer)
-Partial: consider them anatagonist
>Pindolol, Acebutolol
-Antagonist: Keep same/constituent activity ~70 BPM
>Propanolol, Atenolol
-Inverse: further decrease constituent activity (decrease HR)
>Carvedilol, Nadolol
Duration of Drug Action Scenarios
- Only act as long as drug binds receptor
- tightly bound=longer duration; vice versa - Long term downstream effects last until downstream effectors go away
-Elicits a downstream effect: Cascade
-Covalent bonds- receptor degraded (lysosome) - Desensitization- Constantly being signaled; response will shut down (GPCRs)
Good vs. Bad Receptor
Good:
- Selective: Only bind 1 ligand so not competing with other ligands
- Alteration: Changes shape/conformation that elicits cascade
Bad:
- Non-regulatory molecules that bind drugs with no detectable change in function
> Drug Carriers: Good for carrying stuff around body
Drug Carriers
Plasma Proteins (Albumin):
- Free drugs cross borders; bound drugs don’t
- Decreased levels based on nutrition, liver funct.
- Other drugs may displace (kick) one another off
Types:
- Albumin: Binds mostly to acidic (release H+)
- alpha-acid glycoprotein: Binds mostly basic (release OH-)
- Lipoprotein: neutral drugs (cholesterol)
What is potency?
Concentration of drug (EC50/ED50)required to produce 50% of maximal effect
- Sedation vs. very drowsy
- More potent: reaches EC50/ED50 with less drug dose
Maximal Efficacy
-Greatest possible responses drug can deliver
- Emax higher
- Ex) Cardiac output increase comparing diff ionotropes
-Must also take into account drug toxicity
Median Effective Dose (ED50)
Drug dose when 50% of population elicits the response we want
Median Toxic Dose (TD50)
Dose of drug when 50% of population begin to elicit negative side effects
Median Lethal Dose (LD50)
Dose of Drug when 50% of population dies
Therapeutic Index
Establishes margin of safety of drug
Calculation: TD50/ED50
-Larger number/Wider margin means drug is safer
-Smaller number/Narrow margin: Probably should closely monitor patient (Digoxin)
Bmax & Kd
Bmax: 100% of target receptors bounds
Kd: Drug concentration that binds 50% of target receptors
Emax vs. EC50
Emax: Maximal drug response/effect
EC50: Concentration of drug that results in 50% response/effect
Ex) Pain scale
Variations in Drug Response
- Drug-Drug Interactions
-Ex) Phenytoin & Carbamazepine - Individual patient responses vary
-Idiosyncratic
-Unusual: genetics (pharmacogenomics); hyporeact vs. hyperreact - Tolerance: response changes over course
Ex) Morphine
-Tachyphylaxis: Quick tolerance (nitric oxide)
4.Chemical Antagonist: interacts directly with the drug being antagonized to remove or prevent it from binding with its receptor site - Physiology Antagonism
Causes of Variation
- Alteration in conc of drug that actually reaches the receptor (Pharmacokinetics- ADME)
-Age, weight, sex, disease state - Variation in conc of endogenous receptor ligand
Ex) Differing amount of epi circulating in body in diff people so B-blocker dose needed may be diff
3.Alteration in # or function of receptors
-Less receptors to begin w/ or receptor # decreasing - Changes in components of response downstream to receptor
- Post receptor process: use up messenger more quickly
- Largest & most important cause of variation
-Body has natural ability to compensate
Physiologic Antagonism
Two different receptors causing a squelching of the intended response
Ex)
-Beta: Sympathetic response
-Muscarinic: Parasympathetic response
Henderson Hasselbach Equation
PH= PKA + LOG (A-)/(HA)
-log function so 1x, 10x, 100x, 1000x
PH > PKA: Favors Unprotonated
PH < PKA: Favors Protonated
Acidic Drugs
Release H+ into solution
Protonated form is uncharged
Unprotonated form is charged
“Trapping” in urine
OD with weak acid give NaHCO3 (Bicarb)
-Want to alkalinize urine
Basic Drugs
Absorbs H+ from solution
Protonated: Charged
Unprotonated: Uncharged
“Trapping” Drug in Urine
OD with weak base give Ascorbic acid (Vit. C)
-Want to acidify urine
Agonist mimic (indirect agonist)
Effects downstream inhibitors
Ex) usually blocks enzyme down the cascade
-Cocaine, amphetamine act like beta agonist but aren’t really effecting same receptor
Understand Log dose vs. Response Curve
A: agonist alone
A+B: Competitive inhibitor
A+C: Allosteric/Noncompetitive Activator
A+D: Noncompetitive Inhibitor
