Principles of Pharm (Ch 1) Flashcards
What four prehistoric practices influenced pharmacology?
shamanism
animism
spiritualism
divination
Who is the first recorded physician?
Imhotep
Who is the “father of western medicine?”
Hippocrates
Name 2 subcontinental medicine influence on pharmacology.
India (ayurvedic)
China (traditional chinese medicine)
What is the difference between the Rod of Asclepius vs Caduceus?
The Rod of Asclepius is associated with medicine; Caduceus is falsely associated with medicine but is actually representative of commerce/trade.
What is the Materia Medica?
A collection of work throughout history based on botany, medicinal substances, and is a precursor to pharmacology.
Who is the “Father of Toxicology”?
Paracelsus
What did Paracelsus say?
“The dose makes the poison”
What is the purpose of a controlled drug trial?
It evaluates therapeutic claims and prevents worthless patents of medicines.
Pharmacodynamics
What drugs do to the body
Pharmacokinetics
What the body does to the drug
Pharmacogenomics
The correlation between genetic profiling and predictive responses to drugs.
Toxicology
The study of toxin effects on living organisms.
Agonist
A drug that elicits a response when attached to a receptor
Antagonist
Blocks a receptor from functioning
Toxins
Biologic (living organisms)
ex.) mushrooms
Poisons
Non-biologic
ex.) lead
Allosteric
When the drug binds to a site outside of the active site.
Orthosteric
When the drug binds to the active site.
Name the 3 main bond types and rank them from strongest to weakest.
Covalent
Electrostatic
Hydrophobic
Name 3 types of electrostatic bonds
charged molecules
hydrogen bonds (partially +)
Van der Waals forces
Specific binding
binds at receptor site; has a maximum (plateaus)
Non-specific binding
drug binds anywhere besides the active site
ex) albumin
Describe the relationship involving bound drug concentration vs free drug concentration
the more drug that is given, the more drug that is bound (total binding)
specific binding: the more drug that is given, the more drug that is bound but there are only so many receptors to bind to (has a maximum)
non-specific binding: the more drug that is given, the more drug that is bound because it can bind anywhere outside of the receptor
ADME
absorption
distribution
metabolism
excretion
Drug concentration vs drug dose
concentration is the total amount of drug in the blood stream; the drug dose is how much drug you are giving
B max
maximum binding to receptor
Kd
dissociation constant
drug concentration at which 50% of receptors are bound; changes depending on the drug affinity to receptor sites
E max
maximum effect; can be variable
EC 50
50% of drug effect is seen; a single point on the curve
Explain why the Kd is not the same as EC 50.
You could have 1 receptor bound to have a maximum effect or you could have all of the receptors bound to have a maximum effect. The Kd changes based on drug affinity.
EC 50 never changes; it is where 50% of the maximum effect is seen.
They’re different concepts
Explain how a drug concentration curve might look (in terms of drug/receptor affinity) if the the Kd is low or high
A low Kd = high drug/receptor affinity (shift to the left)
A high Kd = low drug/receptor affinity (shift to the right)
Agonist + Allosteric Activator
an even greater response seen than just giving orthosteric agonist
Agonist + Competitive Inhibitor
more drug needed to achieve the same effect as if only giving agonist
SURMOUNTABLE
Agonist + Allosteric Inhibitor
Inhibitor is non-competitive; therefore, cannot be out-competed. shuts down the active site.
will not see the same response as if only agonist was given; a muted response is seen
INSURMOUNTABLE
Partial agonist
Binds with less affinity; gives a PARTIAL response
in the presence of a FULL agonist, partial agonist acts as an ANTAGONIST; it out-competes the full agonist
the more partial agonist that is given, the less of a response you will see
partial agonist vs full agonist curve forms ‘chanel symbol’
What is an example of opposing charge antagonism?
Protamine (+) and Heparin (-)
What is an example of a physiologic antagonism?
Drugs that act on different receptors to oppose the effect
ex) Epi > B receptors (increase HR) & ACh on muscarinic receptors (slow down HR)
Inverse agonist
favors Ri (inactive receptor configuration)
in PRACTICE – acts as an ANTAGONIST
terminates constitutive activity (vs competitive antagonist, which keeps constitutive activity)
What are some receptors that inverse agonists bind to?
histamine receptors (H1/H2)
beta-adrenergic receptors
GABA receptors
5-HT receptors
dopamine receptors
Beta-1 agonists
direct: epi, norepi
indirect (mimic): amphetamines, cocaine
Beta-1 partial agonist
pindolol
acebutolol
Beta-1 antagonist
propanolol
atenolol
Beta-1 inverse agonist
carvedilol
nadolol
Optical isomers
mirror images (have the same chemical formula; but NOT the same effects)
ex) L and R glove
Racemic mixtures
a mixture of several different optical isomers
ex) R-Ketamine + S-Ketamine
R is usually more toxic and S is 4x more potent and the purified form
What are 4 factors that influence receptor interactions?
size
electrical charge
shape
atomic composition
What is the relationship between bond strength and specificity?
inversely proportional
the stronger the bond, the less specific the receptor site is; the weaker the bond, the more specific the receptor site
think lock and key
ex) covalent bonds are the strongest but contain the least specific receptor sites, while hydrophobic bonds are the weakest and have the most specific receptor sites
receptor vs receptor site
receptor: binding agent to the receptor site
receptor site: where the binding agent attaches to on cell surface
name 3 duration of drug action scenarios
- only as long as drug binds to receptor
- longterm downstream effects last until downstream effectors go away
covalent bonds – receptor is degraded which leads to: - desensitization
what makes a receptor “good”
- selective
- can alter its composition (in order for downstream effect to occur, when receptor binds to ligand, it has to change)
what makes a receptor “bad”
- inert binding sites – receptor sites that, when bound to a drug, does not produce an effect
- is a drug carrier (albumin)
describe albumin as a drug carrier
when plasma is bound to a protein, it CANNOT cross barriers (too large)
can only cross barriers in its free form (unbound form)
if 90% of your drug is bound to albumin and 10% of the drug is free, you’ll need to give a higher dose of the drug to see an effect
decreased levels of albumin (malnourished/liver damage) will increase risk for toxicity/side effects
if multiple drugs are given together, some drugs may compete for albumin binding and displace other drugs (ex. phenytoin vs carbamazepine) and this will result in both drugs having a higher free concentration
binding sites on albumin depends on the type of bonds
albumin binds mostly to ____ drugs
acidic
alpha 1 acid glycoproteins binds mostly to ______ drugs
basic
lipoproteins binds mostly to ______ drugs
neutral
how many binding sites does albumin have?
binding site 1 and 2
compare and contrast potency vs efficacy
potency
a small amount of drug with a maximal effect = high potency
a high amount of drug with a minimal effect = low potency
EC 50 (concentration) or ED 50 of a drug required to produce 50% of drug’s maximal effect
efficacy
greatest possible response a drug can deliver
depends on interaction with receptor
must also take into account toxicity
the clinical effectiveness of a drug depends not on its POTENCY, but on its MAXIMAL EFFICACY
explain the dose-response curve in terms of potency and max efficacy (figure 2-15)
drugs A, C, and D equally have the same efficacy
however, A > C > D in terms of potency
B is the most potent but has minimal efficacy
explain ED 50, TD 50 and therapeutic index in terms of drug-response curves in regards to population
ED 50 = at 50% of population get desired indication of drug (ex. 500 people in study; 250 people get therapeutic effect of drug)
TD 50 = where 50% of population achieve a toxic side effect of the drug
Therapeutic ratio = TD50/ED50 (distance between TD50 curve and ED50 curve; the wider the gap, the safer the drug and the narrower the gap, the less safe the drug
what are the 4 main causes of drug variation?
- alteration in concentration of drug that reaches the receptor (based on rate of absorption, age, weight, sex, disease state [i.e. liver disease])
- concentration of endogenous receptor ligand (affected by health/disease state) – not everyone has the same amount of receptor ligands
- number or function of receptors
+concentration of native ligands - downstream proteins are the biggest cause of variation
weak acid
acid releases proton (H+) into solution
weak base
absorbs proton (H+) from solution
if pH < pKa; favors _______ form
protonated
if pH > pKa; favors ______ form
unprotonated
how does the Henderson Hasselbach predict a drugs charge?
pH and pKa are related to determine the charge of a drug;
if a drug’s pH < pKa it favors the protonated form and depending on whether or not the drug is a weak acid or a weak base will determine if the drug is charged or uncharged
if a weak acid is protonated, the drug is ______
uncharged
if a weak base is protonated, the drug is ______
charged
protonated weak base =
charged; pH < pKa
protonated weak acid =
uncharged; pH < pKa
WAP-U
WBP-C
weak acid, protonated = uncharged
pH < pKa
weak base, protonated = charged
ASA, a weak acid
pKa = 3.5
what form is ASA in in the stomach? pH = 1.5
uncharged
pH < pKa (1.5 < 3.5)
protonated
ASA, a weak acid
pKa = 3.5
what form is ASA in in the intestines? pH = 6.5
charged
pH > pKa (6.5 > 3.5)
unprotonated
morphine, a weak base
pKa = 7.9
what form is morphine in in the stomach? pH = 1.5
charged
pH < pKa (1.5 < 7.9)
protonated
morphine, a weak base
pKa = 7.9
what form is morphine in in the blood? pH = 7.4
charged
pH < pKa (7.4 < 7.9)
protonated
what is a monoclonal antibody?
produced from a single clone that produced antibodies (plasma cell)
decrease adverse effects by only binding to antigen binding site (highly specific)
target proteins on cell surface and modulate vital functions
can also cause cell death by various mechanisms (apoptosis)
how is a monoclonal antibody produced?
- isolate target antigen
- inject antigen into mouse
- mouse will make antibodies against antigen
- once enough antibodies are produced, mouse’s spleen cells (plasma cells) are harvested
- plasma cells + myeloma cell fused = becomes immortal cell
- isolate, culture, and propogation occurs
- propogate the positive clones either in vitro or in vivo (mouse) and harvest the monoclonal antibodies once enough are produced
describe the structure of a monoclonal antibody
“Y” shaped
antigen binding sites (on the tips of the arms of the ‘Y’)
Fab domain = arms of the “Y”
Fab domain contains the variable portions (these sites are for particular protein binding)
Fc (constant) = stem of the “Y”, binds immune cells and activates immune cells
-mab
monoclonal antibody drug
monoclonal antibodies indications
cancer: lung, colon, kidney, glioblastoma
rheumatoid arthritis, psoriasis, Chrons disease, ulcerative colitis,
describe the role of the FDA
oversees development processes of FOOD and DRUG Administration
grants marketing of product approval
must be “SAFE and EFFECTIVE”
+non-drugs just have to be SAFE, not necessarily effective
reviews all claims and makes recommendations
oversees OTCs/BTCs and herbal supplements
list the differences in the regulation of Rx drugs vs OTC/non-Rx drugs
Rx drugs:
+provider has to Rx
+viewed as Rx drugs are “more effective” by the public
+misuse has higher potential for harm
+regulated by FDA
OTCs:
+freely available to public
+low risk for harm/abuse; HOWEVER, any drug in excess can kill you
+ does not equate to “safe”
what happens during years 0-4 pre-clinical testing?
in vitro studies
finding a lead compound
testing lead compound in animals to see efficacy
“what does the drug actually do?”
IND (investigational new drug) then clinical testing
phase 1 clinical testing population
20-100 subjects
“college students”
pharmacokinetics
phase 2 clinical testing population
100-200 patients
does it work on the target patients?
ex) cancer drug tested on cancer patients only
phase 3 clinical testing population
1000-6000 patients
does it work double blind?
phase 4
only accessible after NDA approval; patent expires after 20 years of filing application
