Intro to Pharmacology Flashcards
what is pharmacology
the study of the effects of drugs on the function of living systems
what is a drug
a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which when administered to a living organism produces a biological effect
what was the first textbook of pharmacology
de materia medica
who wrote de materia medica
pedanius dioscorides
what did paul ehrlich do
- modern chemotherapy
- german physician scientist
- determined how to differentiate healthy tissue from invading pathogen by gram staining
- made salvasan (arsphenamine) to tx syphilis
what did alexander flemming do
- st marys in london
- staphylococcus cultrues contaminated with mold
when was FDA created
1938
what are the divisions of pharmacology
basic and clinical pharmacology and organ system pharmacology
what makes up basic and clinical pharmacology
pharmacokinetics and pharmacodynamics (PKPD)
what are the sub disciplines of pharmacology
- pharmacology
- pharmacogenetics
- pharmacogenomics
- pharmacoepidemiology
- pharmacoeconomics
what is involved in pharmacokinetics
-absorption
- distribution
- metabolism
- excretion
what is involved in pharmacodynamics
- drug-receptor interactions
- signal transduction
- drug effects
what is pharmacoepidemiology
the study of drug effects at the population level
- concerned with variability of drug effects between individuals in a population and between populations
- made possible with big data sets
what is pharmacoeconoics
the study of cost and benefits/detriments of drugs used clinically
- made possible with big data sets
what is the difference between pharmacology and toxicology
pharmacology is the beneficial effects of drugs and toxicology is the adverse effects of drugs
what does the FDA do
adminsitrative body that oversees drug evaluation process
FDA grants approval for marketing ______
new drug products
to get FDA approval for marketing what evidence is needed
safety and efficacy
safe does not mean complete absence of _____
risk
FDA shares responsibility with _____ for food safety
USDA
what did the dietary supplement health and education act of 1994 do
- prohibited full FDA review of supplements and botanicals as drugs
- established labeling requirements for dietary supplements
the burden of safety and efficacy is on the _____ for supplements
manufacturer not the FDA
what is the definition of drug by the FDA
a substance other than food recognized by an official pharmacopoeia or formulary intended:
- for use in the diagnosis, cure, mitigation, treatment or prevention of disease
- to affect the structure or any function of the body
- for use as a component of a medicine but not a device or a component, part or accessory of a device
what is a generic drug defined by the FDA as
the same as a brand name drug in dosage, safety, strength, how it is taken , quality, performance, and intended use
before approving a generic drug product what does the FDA base evaluations off of
substitutability or therapeutic equivalence of generic drugs based on scientific evaluations
what is the drug development process
- chemical synthesis and in vitro screening
- preclinical testing
- phase I
- phase II
- phase III
- phase IV
when are healthy subjects tested in the drug development process
phase I
when are disease subjects tested in drug development process
phase II
when is broad testing done done in the drug development process
phase III
when is marketing and post marketing surveillance done
phase IV
who said “a drug will not work unless it is bound”
paul ehrlich
what are the protein targets for drug binding
- receptors
- enzymes
- carrier molecules
- ion channels
- specific circulation plasma proteins
what are the “other” targets for drugs
ion chelators
what are the nucleic acid targets for drug binding
- RNA and DNA
what are receptors
protein molecules which function to recognize and respond to endogenous chemical signals
- may also bind xenobiotics
what are xenobiotics
foreign chemicals that does not exist in the body otherwise
what are receptors classified based on
ligands
what are the receptors in the autonomic nervous system
- adrenergic receptors
- cholinergic
what are the adrenergic receptors
-alpha1
- alpha 2
- beta 1
- beta 2
- beta 3
what are the cholinergic receptors
muscarinic
what are the vascular system receptors
- angiotensin II receptors (AT1 and At2)
- endothelin receptors (ETa and ETb)
- prostaglandin receptors (DP, EP, FP, IP, TP)
- histamine receptors (H1, H2, H3)
what are the steroid receptors
- estrogen receptors (ER alpha, ER beta)
- androgen receptor
- glucocorticoid receptor (cortisol)
- mineralocorticoid receptor (aldosterone)
- retinoid X receptor (RXR)
- constitutive androstane receptor (CAR_
for a drug to be useful
- must act selectively on particular cells and tissues
- must show a high degree of binding site specificity
for a protein to function as a receptor
- generally shows a high degree of ligand specificity
- bind only molecules of certain physicochemical properties such as size, shape, charge, lipophilicty
what does angiotensin II do
selectively activates angiotensin II receptors in vascular smooth muscle to cause contractiona
angiotensin II does not affect smooth muscle in:
the GI tract, genitourinary tract or uterus
angiotensin II receptors selectively bind:
angiotensin II
angiotensin II does not bind:
angiotensinogen or angiotensin IV
describe electrostatic bonds
- weaker: hydrogen bonding and van der waals forces (dipoles)
- stronger: ionic bonding
- most common bonds
describe hydrophobic bonds
- less common
- weak associations of hydrophobic compounds with hydrophobic domains of receptors
describe covalent bonds
- relatively rare
- permanent, lasting bonding
- aspirin and cyclooxygenase
- omeprazole and proton pump
describe lipophilic properties of drugs
- more soluble in fat than blood
- steroids
- readily diffuse across membranes
- more likely to be metabolized by gut and liver
describe hydrophilic properties of drugs
- more soluble in blood than fat
- small molecules, weak acids/bases
- ionized at physiologic pH (7.4)
- not as easy to diffuse across plasma membranes
- more likely to be excreted unchanged by kidney
what is pKa
the pH at which the concentrations of ionized and unionized species are equal
what is the example of a weak acid and what would the pKa be
aspirin
- 3.5
what is an example of a weak bases and the pKa
epinephrine
-8.7
what are enantiomers
1 pair for each chiral carbon
what is carvedilol
alpha 1, beta 1, and beta 2 adrenergic receptor antagonist used to treat heart failure
what does R (+) carvedilol do
blocks alpha adrenergic receptors
what does S (-) carvedilol do
blocks beta adrenergic receptors
what does R,S (+/-) carvedilol do
blocks alpha, Beta adrenergic receptors
what is affinity
tendency of a drug to bind the receptor
what is the dissociation constant (Kd)
concentration required for 50% saturation of available receptors
higher the Kd, _____ the affinity
lower
what is efficacy
tendency of a drug to activate the receptor once bound
efficacy is generally expressed as:
dose-response curves or concentration effect curves
highly effective drugs generally have ___ affinity
high
an agonist possesses _____
significant efficacy
full agonist = elicits ___ response
maximal
partial agonist = elicits _____, even when ______
partial response, 100% of receptors are occupied
antagonist possesses ____ efficacy
zero
what do allosteric agonists and antagonists do
- bind to the same receptor but do not prevent binding of the agonist
- may enhance or inhibit the action of agonists
what does the addition of an antagonist to an agonist do to the dose response curve
shifts it to the right
where do competitive agonists and antagonists bind on the receptor
at the same site
where do allosteric agonists and antagonists bind on the receptor
different sites
what does an allosteric activator do
increase response to a drug
what does an allosteric inhibitor do
decreases efficacy
most receptors are in an ___ state
inactive
agonists have high affinity for _____ state and ______
activated; stabilizes it
what does a full agonist do to receptor action
- high affinity for Ra and stabilize Ra on binding
- shift nearly entire pool of receptors from Ri to Ra
- maximal effect is produced
what does a partial agonist do to receptor actions
- do not stabilize Ra as effectively
- significant fraction stays in Ri pool
- only partially effective no matter how high concentration
- some can act as agonist or antagonist
when would a partial agonist act as an agonist? antagonist?
- act as agonist if no full agonist is present
- act as antagonist if full agonist is present
what is an example of a partial agonist and describe it
-pindolol, beta adrenergic receptor antagonist when epinephrine is present, agonist when absent
what does an antagonist do as receptor actions
- Ra and Ri stay in same relative amounts as in the absence of any drug
- no change in effect measured
- block effects of agonist
what does inverse agonist do to receptor actions
- higher affinity for Ri than for Ra
- stabilize Ri on binding
- reduces any constitutive activity of receptor thus producing opposite effects as a conventional agonist
what is an example of an inverse agonist and describe it
- gamma- aminobutyric acid (GABA) receptors; diazepam agonist, flumazenil antagonist
what is the formula for drug- receptor binding
B = Bmax x C/ C + Kd
what is B in the drug receptor binding equation
drug bound to receptors at given concentration (C)
as dose increases:
binding increment diminishes
what is Bmax in the drug receptor binding equation
point at which all receptors are bound
what is the equation for concentration-effect (dose-response)
E = Emax X C / C + EC50
what does E stand for in the concentration effect equation
effect observed at given concentration
what is Emax in the concentration effect equation
point at which no further effect is achieved as dose increases further
what does EC50 stand for in the concentration- effect equation
concentration of drug that produced 50% of maximal effect/response
what does a competitive antagonist do
- bind to same site on receptor as agonist
- compete with agonist for binding
- with fixed agonist concentration, progressive increases in antagonist will decrease effect up to completely stopping it
what can overcome competitive antagonist
increasing agonist concentration
describe noncompetitive antagonists
- often bind covalently and irreversibly
- often allosteric inhibition but can be same binding site as agonist
will increasing agonist concentration overcome noncompetitive antagonist
not always
what does the addition of a noncompetitive antagonist to an agonist do to concnetration- effect curve
reduced max effect
what is an example of a chemical antagonist
ionic interaction between positively charged protamine and negatively charged heparin
- protamine antagonizes heparin
what is an example of a physiologic antagonist
different regulatory pathways mediated by different receptors resulting in opposing actions
- anticholinergic atropine can physiologically antagonize effects of beta blockers on heart rate
what does atropine do
increase heart rate
what do beta blockers do
decrease herat rate
what do pharmacokinetic antagonists do and give example
- one drug increases the metabolism of another
- rifampin increases metabolism of many drugs
what ways can drug- receptor actions be terminated
- dissociation of drug from receptor
- dissociation of drug from receptor but effects continue for some time
- covalently bound drugs require destruction of the drug- receptor complex and synthesis of new receptors
- desensitization
why do effects continue for some time after dissociation of drug from receptor
downstream activation of effects by kinase phosphorylation of downstream proteins
how do activated effectors be deactivated
phosphatase dephosphorylation of downstream proteins
what is another word for desensitization
tachyphylaxis
what are the mechanisms of desensitization
- change in receptors: phosphorylation of receptors
- translocation of receptors: beta- adrenergic receptor internalization
- exhaustion of mediators: NT depletion
- increased drug metabolism
- physiologic adaptation: BP lowering from a diuretic
- active extrusion of drug from cell: multi-drug resistnace (P-glycoprotein)
how long do rapid responses to drug effects take and what are examples
- seconds to minutes
- beta- adrenergic receptor activation
- nicotinic-acetylcholine receptor activation in nerve synapse
how long do intermediate responses to drug effects take and give example
minutes to hours
- receptor desensitization
how long do delayed responses to drug effects take and give example
- hours to days
- steroid induced increase in gene expression
