pharmakon =
poison/drug
logio =
study of
the study of substances (includes drugs) that interact with living systems through chemical processes, esp binding to regulatory molecules and activating or inhibiting normal body processess
pharmacology
science involving using substances to prevent, diagnose, or treat disease
medical pharmacology
branch of pharmacology dealing with the undesirable effects of chemicals on living systems, from cells to humans, to environments and ecosystems
toxicology
the relation of an individual's genetic makeup to their response to specific drugs
pharmacogenomics
any substance that changes biological function through chemical (covalent and non covalent) interactions
drug
drug that activates
agonist
drug that inhibits
antagonist
the target molecule that must be selective and able to change function when bound by endogenous ligand or drug
receptor
receptors (target molecules) must be two things
1. selective
2. able to change function when bound to a endogenous ligand/drug
3 drug actions that are receptor independent
1. osmotic agents move water
2. antacids neutralize acid
3. chemical antagonists are drugs that interact with other drugs
examples of organic drugs
carbohydrates, proteins, lipids, DNA/RNA
example of inorganic drugs
lithium, iron, heavy metals
the usual size of drugs
100-1000 MW
drugs interact with receptors via-
chemical bonding
rare, strong and often (virtually) irreversible
covalent bonds
more common, uses ionic bonds, hydrogen bonds, dipole moments
electrostatic bonds
quite weak, important in lipid-soluble/ non-polar drugs, crossing lipid membranes, and interacting with non polar amino acids/receptor pockets
hydrophobic bonds
drugs that bind to the same receptor molecule but do not prevent binding of the agonist
allosteric inhibitors/ (or activators)
some receptors will exist in the active form without being induced by an agonist (drug). this activity is called-
constitutive activity
agonists drugs that activate theirs receptor-effector systems to the maximum extent of which the system is capable; there is a shift of almost all of the receptor pool to the Ra-D pool
full agonists
bind to the same receptors and activate them, but do not evoke a full response, no matter how high the concentration
partial agonists
when a drug may act either as an agonist (if no full agonist is present) or as an antagonist (if a full agonist is present) it has a low --
intrinsic efficacy
(ex: partial agonists do not stabilize as fully as full agonists, therefore a large portion of the receptors are still in the inactive form)
intrinsic efficacy is independent of --
affinity for the receptor
blocks the access of agonists to the receptor and prevents the usual agonist effect. no change is observed, so the drug will appear to be without effect
antagonist
fix the fractions of the active and inactive form of the receptor. do not displace endogenous ligand from the agonist, but prevents any more bind of the agonist to the inactivated receptor; basal activity stays the same
neutral antagonist
drug that has higher affinity for the active site than the endogenous ligand and may displace the agonist and decrease basal activity
inverse agonist
drugs permeate into the circulation from the (3 sites)
gut, alveoli, or larger barriers (IM, sub-cut, cutaneous)
describes passive flux down concentration gradient
Fick's Law
Fick's law equation
Flux (molec/time) = (C1-C2) x (A x permeability coefficient / thickness)
C1-C2 is always a
positive number (because you are going down a concentration gradient)
reuptakes norepinephrine from synapse. it is a target of cocaine and some tricyclic antidepressants
NET
reuptakes serotonin from synapse. it is a target of selective serotonin reuptake inhibitors and some tricyclic antidepressants
SERT
transports dopamine and norepinephrine into adrenergic vesicles in nerve endings.
VMAT
VMAT is a target of
reserpine and tetrabenazine
transports many xenobiotics out of cells. if there is an increased expression, it may lead to resistance to certain anticancer drugs.
MDR1
inhibition of MDR1 increases blood levels of--
digoxin
secretes leukotrienes; can cause resistance to anticancer and anti fungal drugs
MRP1
the most important limiting factor for permeation; why?
lipid diffusion/ because of the large number of lipid barriers that separate the compartments of the body
determines how a drug readily moves between aqueous and lipid media
lipid : aqueous partition coefficient (amphiphobicity)
the ATP-binding cassette (ABC) family includes
P-glycoprotein or multidrug resistance type 1 (MDR1) transporter
multidrug resistance-associated protein (MRP)
BCRP
a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen molecule)
weak acid
a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton
weak base
pH of the gut
1-4
pH of systemic circulation
7.4
pH of bile
7.5 - 8.8
pH of urine
5-8; norm is 6-7
the component of a cell or organism that interacts with a drug and starts the events leading to drug effect; mediators of MOA
receptor
determines how much concentration of the drug is needed to form enough drug:receptor complexes to get a response
the receptor's affinity for the drug
may limit the maximum effect of a drug
the number of receptors
responsible for the selectivity of drug action or drug response
receptors
mediate actions of drug agonists and antagonists
receptors
mediate the actions of endogenous chemical signals such as neurotransmitters, antacids, and hormones
regulatory proteins
ay be inhibited (or activated) by binding a drug; mediate chemical reactions/structural conversions
enzymes
move things, often across membranes
transport proteins
proves tissue or cellular structure of cells
structural proteins
the transduction process that links drug occupancy of receptors and pharmacologic response
coupling
receptor activation promoted binding of a secondary activator (ex. GTP) that starts a cascade of events. this activation of intermediary response last longer than the actual drug-receptor complex being bound
temporal
there is a rate limiting/effector limiting step. other factor may limit coupling, such as availability of intermediates
spare in number
2 things cellular sensitivity to a drug depends on
1. affinity
2. degree of spareness
the total number of receptors present vs. the number of receptors needed to elicit the maximum effect
degree of spareness
type of antagonist that does not actually work on the receptor; Rely often on alteration of buffer systems, or on chemical interactions with another drug
chemical antagonist
Regulatory pathways usually overlap/are redundant; Can get the same outcome through multiple mechanisms
physiological antagonist
most often, drugs act at the ----- level
cellular
most common MOA of lipid-soluble drugs is by binding to DNA by way of ---
response elements
response elements are known as ----
gene active" receptors
two characteristics of the response elements that act as gene active receptors
1. gene expression takes time; anywhere from 30 minutes to an hour, so you won't see relief immediately
2. there is a slow turnover rate of the enzymes and proteins, so even after the agonist conc. has dropped, the enzymes and proteins may remain active i
the three cytoplasmic domains that are a part of the transmembrane proteins in dimerization and phosphorylation
tyrosine kinase, serine kinase, guanylyl cyclase
intensity and duration of agonist-activation is limited. the ligand binds and induces endocytosis of receptors from the cell surface. then these receptors are degraded
receptor down-regulation
large class of molecules, named for size (small molecules) and their ability to pass a signaling event from extra- to intra-cellular compartments
cytokine receptors
with cytokine receptors, the kinase activity is not ----. the external molecules mediates phosphorylation events
intrinsic to the receptor
example of the cytokine receptor system
JAK/STAT pathway
examples of ligands in voltage-gated channels
acetylcholine, serotonin, GABA, glutamate
examples of ligands that are sufficiently lipid-soluble to cross the plasma membrane and act on intracellular receptors
steroids (corticosteroids, mineralcorticoids, sex steroids, vitamin D), thyroid hormone
heterogenous groups of peptide ligands that act on cytokine receptors
growth hormone, erythropoietin (EPO), and interferon
not opened by agonist binding, but triggered by changes in membrane potential
voltage-gated ion channels
a family of proteins that function as molecular switches; intermediates in receptor-effector coupling
g-proteins
G-proteins bind and hydrolyze -----, which allows for signal amplification and increased signal longevity
GTP
large G proteins with three subunits are known as
heterotrimeric
receptors coupled to G-proteins are known as
GPCR- G protein coupled receptors
receptors for the GPCR family
adrenergic amines, serotonin, acetylcholine, peptide hormones, odorants, and visual receptors
complexes of two identical receptor polypeptides
homodimers
complexes of different isoform receptor polypeptides
heterodimers
the most famous/common intracellular 2nd messenger that mediates hormonal responses (e.g. moving stored energy from fat cells), renal water conservation, calcium homeostasis, HR, production of hormones, smooth muscle relaxation and many, many more
cAMP
G-proteins stimulate the catabolism of membrane-bound PIP2 into
DAG and IP3
stays at the membrane and activates kinases like PKC
DAG
Diffuses through the cytoplasm, binds calmodulin, and cascades further
IP3
only active in a few cell types such as intestinal mucosa and vascular smooth muscle
cGMP
when a G protein mediated response to drugs and hormonal agonists attenuates with time
desensitization
how much drug is required to equal the desired effect, or how do two drugs in dose compare to reach an effect
potency
used to compare potency
EC50 (the concentration of the drug when you have half of the maximum effect)
how great of an effect can be reached?
max efficiacy
dose at which 50% of the population will exhibit a specified effect
ED50
toxic dose for 1/2 of the population
TD50
lethal dose for 1/2 of the population
LD50
relates the dose of a drug required to produce a desired effect to that which produces an undesired effect; the ratio of the TD50 to the ED50
therapeutic index (TI)
a person's response to a drug that decreases rapidly
tachyphylaxis
4 considerations with varying/predicting drug responsivness
1. altered effective dose (amount of dose reaching the receptor)
2. Varying concentration of endogenous ligand
3. changes in number or function of the receptor
4. changes in response distal to the receptor
in order to identify a range of benefit with no (or acceptable) adverse responses you must...
titrate the dose