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Pharm 1 : PPt 1 and pdf

Terms in this set (183)

Chirality
D and L pairs, refers to a molecule with a center of three-dimensional asymmetry
50% of all drugs are
chiral, enantiomeric pairs
enantiomers
molecules having opposite shapes, are pairs of molecules existing in forms that are mirror images of each other (right and left hand) but cannot be superimposed.
Structure-activity relationship (SAR)
relationship between drug structures and biological activities forms the basis of rational drug design
Structure activity relationship uses
computer enhanced molecular modeling and information concerning three-dimensional receptor structure may combine to improve the effectiveness of rational drug design approaches.
racemic mixture
a mixture of equal amounts of two enantiomers
Three major types of chemical forces/bonds
covalent, electrostatic, hydrophobic
covalent bonds
very strong, frequently irreversible in biological conditions, ex. DNA-alkylating chemotherapy drugs
electrostatic bonds
weaker than covalent, more common than covalent bonds in drug-receptor interactions:
strong electrostatic bond
interactions between permanently charged ionic molecules
weaker electrostatic bonds
hydrogen bonding
weakest electrostatic bonds
induced-dipole interactions, ex. van der waals forces
hydrophobic interactions
generally weak, significant for driving interactions : 1. between lipophilic drugs and the lipid component of biological membranes, and between drugs and relatively nonpolar (not charged) receptor regions, "like prefers like"
Henderson-Hasselbalch equation
10^pH-pKa=(up/p) , usefule in determining how well an ionzable drug will cross biological membranes.
most drugs are
weak acids or weak bases
lipid diffusion depends on
adequate lipid solubility
drug ionization reduces a drug's
ability to cross a lipid bilayer
pH-pKa = 3 , weak acid
99.9% ionization, log[A-]/[HA] 1000/1 conc. ratio
pH-pKa = 2, weak acid
99% ionization, log[A-]/[HA] 100/1 conc. ratio
pH-pKa = 1, weak acid
90.9% ionization, log[A-]/[HA] 10/1 conc. ratio
pH-pKa = -1, weak acid
9% ionization, log[A-]/[HA] 1/10 conc. ratio
pH-pKa = -2, weak acid
1% ionization, log[A-]/[HA] 1/100 conc. ratio
pH-pKa = -3, weak acid
0.1% ionization, log[A-]/[HA] 1/1000 conc. ratio
pH-pKa = 0, weak acid or weak base
50% ionization, 1/1 conc. ratio
pH-pKa=-3, weak base
99.9% ionization, log[B]/[BH+] 1/1000 conc. ratio
pH-pKa= -2, weak base
99% ionization, log[B]/[BH+] 1/100 conc. ratio
pH-pKa= -1, weak base
90.9% ionization, log[B]/[BH+] 1/10 conc. ratio
pH-pKa = 1, weak base
9% ionization, log[B]/[BH+] 10/1 conc. ratio
pH-pKa = 2, weak base
1% ionization, log[B]/[BH+] 100/1 conc. ratio
pH-pKa= 3, weak base
0.1% ionization, log[B]/[BH+] 1000/1 conc. ratio
pharmacodynamics
what the drug does to the body, relates the drug concentration to its effect
pharmacokinetics
what the body does to the drug, relationship between drug dose and tissue conc., involves ADME processes and modeling, useful in determining proper dosing
pharmacology
study of drugs
what is a drug?
mimics endogenous ligand
affinity
the amount of "attraction" between a compound and a receptor
intrinsic activity
relative degree of response elicited by the interaction of a compound at a receptor, how much it responds to the receptor site, drug agonist has some intrinsic activity, a drug antagonist has low to none intrinsic activity
Efficacy
how well a compound elicits a specific, normally desired effect
specificity
selectivity of a compound for a specific receptor types and/or subtypes. ex. beta blockers- beta 1 or beta 2 receptors, propanolol has all beta receptors, metoprolol has beta 1
affinity equals
is the fraction of receptors bound per the amount of drug concentration
Kd
dissociation constant; how much ligand is necessary to occupy 50% of receptors
potency is
fraction of maximal effect per drug concentration
EC 50 with a low drug concentration
means high potency
EC 50 with a high drug concentration
means low potency
dose-response curve
a graph of the magnitude of an effect of a drug as a function of the amount of drug administered
agonist
a substance which interacts at a receptor to elicit a response
Antagonist
a substance which blocks the response of an agonist at a receptor
competitive antagonist
Drug competes with the agonist for binding to the receptor. If it binds, there is no response from that receptor.
Non-competitive antagonist
bound irreversibly, most of the time covalently, to the receptor site rendering the receptor unusable. binds allosterically to different site of the molecule
inverse agonist
chemical substance that produces effects opposite those of a particular neurotransmitter
partial agonist/antagonist
has less effect than the endogenous ligand would, might also be an agonist at one location and an antagonist at another location
cell body
Largest part of a typical neuron; contains the nucleus and much of the cytoplasm, soma
dendrites
Branchlike parts of a neuron that are specialized to receive information.
axon hillock
Cone shaped region of an axon where it joins the cell body.
axon
the extension of a neuron, ending in branching terminal fibers, through which messages pass to other neurons or to muscles or glands
nerve terminal
The tip of the axon where neurotransmitters are released.
pre synaptic receptors
connects axon to neighboring cell
post synaptic receptors
a sensor on the surface of a neuron; captures messenger molecules from the nervous system and transmits information from one neuron to another
synaptic cleft
The narrow gap that separates the presynaptic neuron from the postsynaptic cell.
non-neuronal receptors
receptor regulates afferent neuron
ADP receptors
- P-type purinergic receptors
- binding of ADP to P2Y(12) activates GPIIb/IIIa on circulating platelets
insulin receptors
proteins, located on the surface of certain cell membranes, that bind insulin
LDL receptor
A protein on the surface of cells that binds to LDL particles and allows their contents to be taken up for use by the cell.
cholinergic receptors interact with
acetylcholine
adrenergic receptors interact with
norepinephrine
GABA receptors interact with
gamma amino butyric acid
receptor locations
cell membrane (inside and outside), cell cytoplasm, nuclear envelope
Have semi-specific receptors
anesthetics to membrane proteins and lipids, metal chelators (Pb2+ and Hg2+)
non specific receptor types
carbon monoxide (cell proteins and hemoglobin), alkalinizing drugs (OH--> Na+), acidifying drugs (H+--.> Cl-), mannitol
Specific receptors
curare and neuroleptics to membrane receptors, aminoglycosides antibiotics to ribosomes, penicillin bacterial cell wall enzymes, actinomycin to the nucleus, digitalis to membrane enzymes, polyene antibiotics to membrane sterols
Nature of receptors
responsible for the transduction of biologic signals, are cellular components (usually) that interact with other molecules to elicit some effect.
nature of receptors effect
may be some biologic response, or a biochemical change that eventually produces some effect
Non-receptor mediated drugs, not all drugs exert their effects via a receptor-mediated response, ex.
mannitol, methylcellulose, dextrans
mannitol
osmotic diuretic, is non-receptor mediated
methyl cellulose
bulk forming (osmotic) laxative, non-receptor mediated
dextrans
used IV to expand blood volume by pulling water from tissues into blood, non-receptor mediated
example of an enzyme shown to be specific to drug receptors
digitalis - acts on Na+ / K+ ATPase in heart muscles to increase force of contractions
Nucleic acids specific receptors
can act as receptors to some compounds such as the antibiotic actinomycin D.
membrane components like fungal ergosterol can bind agents like
amphotericin B
ATPase
controls the maintenance of normal cell volume and pressure, is the sodium-potassium adenosine triphosphatase or sodium-potassium pump, 3 Na+ in -->2 K+ out
Alterations in ligand structure will effect
affinity and intrinsic activity (SAR)
most drugs act on receptors, except:
some anesthetics, hypnotics, sedatives, alcohols, osmotically-active drugs, acidifying/alkalinizing agents, antiseptics
Receptors can be blocked by receptor antagonists which will exhibit
affinity, but low to no intrinisc activity, ex. atropine blocks muscarinic Ach receptors
Nonspecific receptors (like ethanol) require _______ for effect.
high drug concentrations (millimolar to molar)
Specific receptors require only _______ for effect
low concentrations (nanomolar to millimolar)
Metabophore controls
controls metabolism
ionophore controls
ionization
receptor binding states
high-affinity (nM agonist) the G protein is attached to the receptor not to GTP, low-affinity (mM agonist) the G protein is not attached to the receptor but attached to GTP
gap junctions
(communicating junctions) provide cytoplasmic channels between adjacent cells, a way of stimulating tissues with out requiring a nerve on every receptor, works by one innervating neuron input goes to one branch of receptors and releases sodium ionophore to stimulate the receptor
full agonist
Ability of a drug to produce 100% of the maximum response regardless of the potency
partial agonist
Medication that produces a weaker, or less efficacious, response than an agonist.
inactive/ antagonist
blocks or has not effect
inverse agonist
chemical substance that produces effects opposite those of a particular neurotransmitter
receptor agonists are measured by
a level of response using log drug amount on a graph
Receptor Occupancy Theory
the assumption that there is a correlation between the number of receptors being occupied by a drug and the physiological response
EC50
Concentration of the drug that produces 50% of maximal effect
receptor occupancy maximal effect
is usually reached with a small amount of receptor attachment, around 5-10 % of receptor connection
competitive antagonism
will push the curve to the right, causing an increasing amount of drug needed to reach same effect, maximal effect is still able to be reached
non-competitive antagonism
is pseudo-irreversible, pushes the curve to the right and down towards the X-axis
allosteric antagonism
binds to allosteric site on the receptor to prevent agonist action, non-competitive antagonism, pushes the curve to the right and down towards the X-axis
allosteric potentiation
Form of agonism where compound acts at an allosteric site and enhances affinity of the normal agonist at its binding site

Example - benzodiazepines
multi-subunit ligand-gated ion channels
protein subunits combine to form a membrane spanning central ion channel around a water channel.
receptors as enzymes:
ex. nicotinic acetylcholine, glutamate, GABAa, glycine, 5HT3 serotonin
G protein-coupled receptor systems
there are three components to this receptor response: 1. the receptor 2. the G protein that binds with guanosine triphosphate (GTP) and 3. the effector that is either an enzyme or an ion channel. The system works as follows: drug-- (activates) -- receptor -- (activates) --G protein -- (activates) -- effect
G proteins
A class of proteins that reside next to the intracellular portion of a receptor and that are activated when the receptor binds an appropriate ligand on the extracellular surface. defined by alpha subunit composition
G protein coupled receptor regulated by :
alpha and beta subunits
increase in adenylylcyclase
increases Ca2+ currents
decrease in adenylycyclase
increases K+ currents
alpha O subunit
decreases Ca2+ currents
alpha q subunit
increases phosholipase CBeta
alpha 13 subunit
increases Na+/H+ exchange
alpha t
increases cGMP - phosphodiesterase (vision)
alpha olf
increases adenylylclase (olfaction)
regulated by Beta subunits
receptor-operated K+ currents, adenylycyclase, phospholipase C B
cytosolic receptors
target the nucleus, regulation of transcription with steroids, retinoids, thyroid hormones
G protein coupled receptors have how many transmembrane loops?
7
G protein-coupled receptor signaling includes :
receptors, G proteins, scaffolding, components, effectors
G protein- coupled receptor signalling receptors :
biogenic amines, peptides, acetylcholline (M), eicosanoids, Wnt proteins, adhesion proteins, odorants, and photons
g protein coupled receptor G proteins are classified by subunit composition
alpha s, i, q, o; alpha1 alpha olf, alpha 12,13
g protein coupled receptor scaffolding
B-arrestin, caveolins, AKAPs, GKAPs, SNARFs
g protein coupled receptor components
effector substrates, protein kinases, phosphoprotein phospatases, phosphodiesterases
g protein coupled receptor effectors G alpha
regulated by G alpha subunits, increase and decrease adenylylcyclase, increase phospholipase C B
g protein subunits regulated by G Beta subunits
K currents, Pl-3 kinase
Receptors as enzymes : ligand binding outside the membrane
insullin - EGF, FGF. ANP, BNP, CNP, guanylins, cytokins, neurotropics, interferon gama
catalytic activities in the cytosol
tyrosine kinases, tyrosine phosphatases, serine/threonin kinases, guanylyl cyclases
Ion channels - ligands outside the membrane
acetylcholine, amino acids, serotonin (5HT3), GABA
Ion channels regulated by membrane potential in cytosol
voltage gated Na+, Ca2+, K+, cyclic nucleotide-gated
Ion channel cytoplasmic ligands in cytosol
ATP, Ca2+, Ca2+/calmodulin, cyclic nucleotides, NO-nitrosylation
Ion channel substrates
Na+, Cl-, Ca2+, K+
Calcium release receptors for enzyme regulation
NO synthases, myosin light-chain kinase, CaMKII, clacineurin, phosphodiesterases
Receptors regulating nuclear transcription
corticoid, estrogen, androgen, thyroid hormone, retinol
Drug receptor binding
D+R=DR, the interaction is governed by affinity and intrinsic activity
Association constant, Ka
the affinity of drug binding,
Ka=Kon/Koff
Dissociation constant, Kd
Concentration at which 50% of the receptors are occupied, is equal to 1/Ka or Koff/Kon
receptors with higher affinity require a lower
concentration of ligands, possible explanations are a higher density of receptors, higher sensitivity of tissue to the drug - like a saturated receptor at lower concentrations,
receptors with lower affinity require a higher
free concentration of the ligand, a lower desity of receptors or lower affinity of the receptors for that ligand.
Lock and Key
receptor structure (the lock) has a region with a particular shaped pocket at which an appropriately shaped molecule (the key) can interact
What does a receptor do?
it exists to interact with some normal endogenous ligand. Drugs mimic or inhibit normal body compounds
D + R=DR
D= drug concentration
R= free receptor concentration
DR= concentration of receptor molecules occupied by drug molecules
KD
equilibrium dissociation constant. which is equal to Koff/Kon.
KA
the reciprocal of the equilibrium dissociation constant= 1/KD. the smaller the KD the higher the affinity
What do you do to increase the likelihood a compound will interact at a given receptor?
increase the concentration which will increase the random mention of a particular molecule to bring it as close enough to the receptor site to interact. The stronger the interaction the greater the affinity
the concept of interaction at the receptor site is based mainly on the ligand's shape and chemical makeup
Most ligands bind very briefly with the receptor site and then are knocked out of the site by collisions with other molecules that are jostling around in the surrounding area.
a drug with high affinity may only interact with a receptor zone briefly
concentration of the ligand molecules in the surround-
ing area is high, the likelihood of continued receptor-ligand interaction increases. the greater the drug concentration at a receptor zone, the more likely it is that a drug molecule will be occupying the receptor site at any given time
Can a drug with high affinity and low intrinsic activity bind to a receptor?
No it needs to have high affinity and high intrinsic activity
Dose-response curve
the dose of the drug is assumed to be proportional to the concentration of the drug at the receptor zone. The log of the dose is directly proportional to the response and is seen as a straight line through the middle range of the plot.
What happens when you reach the maximum in the curve dose-response?
It loses its logarithmic relationship between dose and response. Every response has a maximum, and as this maximal response is neared, increases in occupied receptors produce less and less of an increase in response. At some point the response reaches its maximum, and no further increases in drug dose produce a greater effect. Which does not mean that all the receptors are occupied, just that it has reached its max for a response.
Can PH change the conformation of certain proteins?
yes, which then alters the shape of a ligand binding zone on the protein
The interaction of the ligand at the specific binding site causes some conformational change in the receptor complex, thereby altering the function of the protein complex.
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Proteins have many functions within the body, includ- ing enzymes, channels, and transporters. If a particu- lar receptor zone is located on one of these proteins, the normal e!ect of that specific protein may be altered by the induced conformational change. "erefore an enzyme whose normal conformation does not allow it to interact with its substrate may be activated when a specific ligand binds to a receptor site. Or, conversely, an enzyme that is normally active may be shut o! when a specific ligand interacts at a receptor zone on the molecule.
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Agonist Reaction
The interaction of a ligand with a receptor zone that invokes some functional change in the receptor complex is an example of an agonist reaction.
What happens when an exogenous molecule interacts with a specific receptor?
it blocks the body's endogenous ligand from inter-
acting with the receptor for as long as the exogenous compound occupies the receptor. exogenous agonists are given to increase the normal agonistic stimulation of the receptor and blocking the endogenous agonist is of no consequence
Partial agonist
drug with a good affinity but intrinsic activity that is less than normal. while they occupy the receptor site, they are keeping the normal agonist from interacting with the receptor.
Superagonists
compounds that elicit greater effects at a specific receptor zone than the defining receptor agonist (fentanyl)
Physiologic agonist
Ketamine and propofol- both produce a loss of consciousness but act at different receptor sites
coagnoists
agonistic drugs may not be able to elicit a specific response on their own but instead require the action of multiple compounds to produce an effect. More than one is required for an effect
Selective agonists
act primarily at only one specific receptor zone, whereas nonselective agonists may act at many di!er-
ent receptor types (isoproterenol)
Competitive antagonism
the antagonist interacts at the same receptor site as the normal agonist, it blocks or decreases agonist interaction at the receptor zone. Must possess affinity, but no intrinsic activity
Law of mass action
the more molecules in the area around the receptor that can bind to a receptor (greater concentration), the greater the likelihood that the receptor will be occupied by one of the molecules at any given time.
Law of mass in regards to antagonism
then the more mol-
ecules of antagonist present, the greater the likelihood that an antagonist molecule will be bound to the receptor at any given time. If the antagonist concentration is increased even further, it becomes even less likely that an agonist molecule can "compete" for receptor binding
What makes a competitive antagonist so interesting?
competitive antagonist can be used to decrease the normal effects at a particular receptor zone and then an agonist that acts at that specific site can later be added to compete away the added competitive antagonist (think neuromuscular drug as it blocks acetylcholine from binding to the site and causing a contraction)
first way a noncompetitive antagonist can occur
1. Once a receptor site has been occupied by an irreversible agent, no concentration of agonist molecules around the site will allow the site to be reclaimed by an agonist. In effect, it appears as if the receptor has been removed from the system.the maximal response of the tissue to the agonist will be decreased because there are not enough noninhibited receptors remaining to elicit a maximal response, even if all were stimulated with an agonist.
2nd way a noncompetitive antagonist can occur
2. a compound interacts with the receptor complex at a different binding site from the agonist site, called the allosteric site. this can cause a conformational change in the receptor complex and thus alter the binding site of the normal agonist. as the concentration of the allosteric antagonist decreases, the receptor complex may return to its previous conformation and again function normally.
Allosteric inhibition
An example of allosteric inhibition is the decrease in affinity of glycine at the glycine receptor complex when strychnine binds to an allosteric site. "e binding of strychnine to its allosteric site decreases the affinity of glycine for its bind- ing site, thus diminishing the glycine-based inhibition of the pathway.
Allosteric potentiation
Not a form of antagonism. A compound acts at an allosteric site and enhances the affinity of the normal agonist at its binding site. (benzodiazepines and some anesthetics act at allosteric sites on the GABAA complex to increase the affinity of GABA for its binding site)
Inverse agonists
produce e!ects that appear as if an antagonist has been delivered to a receptor zone. effect of these compounds can be reversed by the addition of a competitive antagonist.
example of constitutive receptors
An agonist can open an ion channel while the inverse agonist binds and closed the channel
Partial agonists/antagonists
compounds act as agonists at one type of receptor and antagonists at other receptors (nalbuphine)
Most receptors are proteins
and are synthesized by protein synthesis mechanisms. After synthesis, these receptor molecules may be functional on their own or may require further assembly with other components, such as other protein subunits, to produce a functional receptor complex. "e receptor proteins may be stored in an inactive form inside the cell or in the cell membrane until needed. "e number of active receptors present appears to be controlled and can be increased or decreased as needed by the cell.
Up-regulation
Happens when a normally present receptor agonist decreases at a receptor zone below some point, the body begins to produce more receptor zones in order to catch more ligands. Makes the cell hypersensitive. So a sudden release of receptor agonist in this zone can cause overstimulation and cell injury or death
Down-regulation
If a receptor zone is experiencing excessive stimulation from an agonist, it can decrease the number of available receptors. If the receptors were located on the cell membrane, these receptors may be internalized and stored for future use or destroyed. So If you discontinue the drug suddenly without tapering off there can be inadequate receptor stimulation. You need to taper so that the receptor sites can adjust
Physiologic tolerance
can be seen with the administration of some drugs. In this situation administration of a drug may lead to physiologic changes in the number of receptors to the compound (down-regulation). As the number of receptors decreases, larger doses of the drug may be required to elicit the same e!ect
Ionophores
ligand-gated ion channels that are formed from multiple protein subunits that span the entire cellular membrane in their active site. The protein subunits surround a central ion passageway or pore through which specific ions can pass.
The pore may be normally open or normally closed, with the action of a ligand binding to an associated location on the structure forcing the pore into the opposite state. the ligand binding site may be intracellular, extracellular, or located within the channel and may require more than one molecule of ligand to bind to di!erent binding sites on the complex to fully activate the channel.
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One specific example is the neuromuscular nicotinic acetylcholine receptor1 located on skeletal muscle at the neuromuscular junction. Acetylcholine released from somatic cholinergic nerve terminals at the synapse binds to two receptor sites on the nicotinic receptor on the postsynaptic membrane, stimulating an allosteric change in the pentameric receptor complex that opens the ion channel and allows sodium ions to enter the cell from the extracellular fluid. "is initiates a local depolarization, which can then lead to the initiation of muscle contraction.
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Metaphores
transmembrane receptors that are composed of an external binding site and an internal enzymatic component. Interaction of an extracellular ligand to the binding site causes a modification of the intracellular component of the protein that then initiates one of several known metabolic conversions of intracellular compounds, such as the direct conversion of GTP to cGMP. "is then acts as a second messenger inside the cell, triggering addi- tional biochemical processes. Directly links some enzymatic function to the ligand interaction
G-Protein Coupled Receptors
This class of receptor is responsible for detecting specific extracellular ligands and initiating an intracellular response. May control biochemical pathways inside the cell in response to an external signal. initiates a series of changes that may lead to control of a specific enzyme. most common found in the cell membrane
Many drugs, hormones, neurotransmitters, and other signaling compounds act as ligands at
specific G-protein coupled receptors
How does the G -protein work?
When a ligand binds to the extracellular binding site, a conformational change occurs that triggers the substitution of GTP on the G-protein in place of GDP. This then activates the G-protein complex, allowing the separation of the G-protein from the transmembrane protein. The G-protein can then migrate and interact with various effector macromolecules, leading to their activation or inhibition. the G-protein then undergoes hydrolysis, converting the GTP to GDP and deactivating the e!ector molecule. the G-protein complex then recombines with the transmembrane protein in preparation for another round of activation.
Steroid receptors
are intracellular receptors. Very lipid soluble, and easily cross the cell membrane and enter the cell via passive diffusion. Once inside the cell, the steroid molecule binds to a specific inactive protein complex. the binding of the steroid to the complex causes an attached inactivating protein to dissociate from the complex. The activated complex is then transported into the nucleus of the cell where it usually forms a dimer with another activated receptor complex. this dimer then binds to specific regions of the nucleic DNA and can increase or decrease transcription of specific genes into RNA for translation into proteins. So it is slower and last longer
Example of how transporter proteins transport molecules that are too large or not lipid soluble
One specific example involves the serotonin selective reuptake inhibitors, such as fluoxetine. these agents act on a transport protein known as SERT which is found on serotonin nerve terminals and is responsible for serotonin reuptake back into the nerve terminal. Inhibition of serotonin reuptake leads to altered function of serotonergic neurons and is commonly used to treat depression.
Most agents that do not rely on receptors for e!ect seem to instead rely on their physical or chemical properties to alter normal body function
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Current theory on anesthetics
Current theories place increasing importance on evidence of receptor interac- tions as the primary mechanism of the general anesthetic agents, both inhalational and parenteral. Although lipid solubility of the agents is undoubtedly important, it may be more related to getting the agents to their required site of action than actual e!ect. "e general anesthetics appear to elicit their primary e!ects by increasing inhibitory signals or decreasing excitatory signals in the brain and/or spinal cord.
Many of the general anesthetic agents (e.g., the barbiturates, propofol, etomi- date, isoflurane, desflurane, and sevoflurane) all appear to act, in large part, by binding to the GABAA receptor complex at specific sites and causing an allosteric potentiation of GABA binding to its receptor site. this causes increased inhibitory activity believed to induce an anesthetized state. Other general anesthetic agents (e.g., nitrous oxide, xenon, ketamine) appear to act to decrease excitatory signaling through NMDA glutamate receptors and nicotinic acetyl-
choline receptors in the brain or spinal cord.
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