Pharmacodynamics Flashcards
drugs are categorized (scheduled) based on what?
- safety concerns
- abuse potential
- ability to follow directions for their use
NAPRA I drug schedule
- perscription needed for sale by pharmacist
- includes perscription drugs, narcotics, controlled substances and targeted substances
- e.g. fentanyl patch
NAPRA II drug schedule
- perscription not required
- must be dispensed by pharmacist
- e.g. insulin
NAPRA III drug schedule
- client may obtain from pharmacy without need of pharmacist
- e.g. ranitidine (Zantac)
dispensing unscheduled drugs
- client may obtain at retail stores or pharmacy
- e.g. naproxen (Aleve)
what is a drug
any substance that brings about change in biological function through chemical actions
useful drugs must…
- be able to move from site of administration to target site
- be inactivated and excreted from the body to control duration of action
drugs - states of matter
- at room temp most drugs are solid
- some are liquids - inhalant anesthetics
- few are gases - NO
examples of proteins that are important receptors for drugs
- hormones (insulin, GFs, neurotransmitters)
- enzymes
- transporters (Na+, K+-ATPas)
- structural proteins (tubulin, nucleic acids)
physiological receptors normally respond to…
endogenous regulatory ligands
what makes up the signal transduction pathway
the receptor
its cellular target
any intermediary molecules
examples of drugs that do not act on receptors
- antacids: directly neutralize HCl in the stomach
- Osmotic diuretics: increase urine formation by osmotic forces in the lumen of renal tubules
what is affinity
the favorability of a drug-receptor binding interaction
in order for drugs to act selectively with receptor binding they need to possess adequate…
size, charge and shape and composition
drug selectivity - size
- lower limit = 100Da: minimum size needed to allow binding
- upper limit = 1000Da: max size allowing reasonable movement to sites of action
- very large drugs must be administered at target site
drug selectivity - charge
- drugs interact with receptors by chemical forces or bonds
- drugs that bind though weak bonds are more selective for receptors (require more precise fit)
- strength of interactions: covalent > ionic > H-bond > van der waals
drug selectivity - shape and atomic composition
- allow drug to fit with its receptors (e.g. lock and key)
- enantiomers exist for drugs with chiral centres, one usually produces more potent effects
the ideal drug would…
interact only with a molecular target producing desired theraputic effects but not with molecular targets producing adverse effects
cell-type distribution of receptors: very selective
- e.g. Ranitidine is a histamine blocker
- used to treat gastroduodenal ulcers by reducing HCl production
- limited effects in the body due to restriction of H2 receptors in the stomach
cell-type distribution of receptors: mildly selective
- e.g. Lidocaine is a Na+ channel blocker
- highly expressed in several tissues
- used as local anaesthetic to alleviate pain
- widespread adverse effects possible in CNS and heart if it reaches systemic circulation
what are the 2 main functions of physiological receptors
ligand binding via ligand-binding domain
message propagation via effector domain
what are the major types of drug receptors
transmembrane ion channels
transmembrane G-protein coupled
transmembrane enzymatic cytosolic domain coupled
intracellular
ion channels have key roles in…
neurotransmission
cardiac conduction
smooth and skeletal muscle contraction
secretion
why are ion channels required by cells
membrane lipid bilayers are largely impermeable to polar (charged) anions and cations
- e.g. Na+, K+, Ca2+ and Cl-
what are the major and minor mechanisms of action for ion channels that act as drug targets
major: voltage and ligand gated
minor: store, stretch and temperature regulated
ligand-gated ion channels as drug targets
- major ligand-gated channels in the CNS
- excitatory NTs (ACh or glutamate)
- Inhibitory NTs (glycine or GABA)
the nicotinic acetylcholine receptor - ligand-gated channel example
- found in skeletal muscle and neurons
- consists of 5 subunits in skeletal muscle
- opening of the channel occurs when 2 ACh bind to the a-subunits
- Na+ is the major electrolyte passed, some K+ too
voltage-gated ion channels as drug targets
- include Na+, K+, Ca2+, Cl-
- voltage-activated Na+ channels initiate APs in the axons of nerves and muscle cells
- when channel is inactivated (refectory period) it is incapable of opening until reset (polarized)
- local anesthetics bind to channels to prolong the refractory period
sulfonylurea receptor (SUR1) - example of an ion channel activated by intracellular molecules
- regulates ATP-dependent K+ channel in pancreatic B-cells
- sulfonylurea class oral hypoglycemics facilitate closure of the channel and secretion of insulin by binding the SUR1 receptor
steps that lead to insulin release from islet B-cells and SUR1 receptor
- glucose enters the cell
- glucose becomes hexokinase and increased ATP/ADP ratio
- since ATP is high ATP-K+ channel closes and depolarizes cell
- voltage-gated calcium channel senses voltage
- Ca2+ enters cell
- insulin released into the bloodstream
G-protein coupled receptors as drug targets
- most abundant type of receptors in the body
- most dedicated to sensory perception
- others have roles in regulating nerve activity, smooth muscle tension, metabolism, force and rate of cardiac contraction and secretion from glands
- activated by neurotransmitters (ACh, NE), eicosanoids (PGs), peptide hormones, opioids and more
- targets of many drugs with over half of all non-antibiotic drugs acting at these receptors
how do GPCRs work
- bind to a family of intracellular G proteins
- signals from G proteins are usually terminated by hydrolysis of GTP to GDP by inherent GTP-ase activity of the a-subunit
mechanism of how GPCRs activate their effector
- agonist binding receptor casues GDP-GTP exchange - G protein is activated
- a-subunit with GTP diffuses to the effector causing it to activate
- the agonist unbinds the receptor casuing GTP hydrolysis (loses phosphate) and the heteromeric G protein is reconstructed
Major role of G proteins is to activate effector molecules that produce secondary messengers, what are some well characterized effectors?
adenylyl cyclase
guanylyl cyclase
phospholipase C
various ion channels
what 2nd messengers does adenylyl cyclase produce
cAMP - acts on PKA
what 2nd messengers does PLC produce
DAG - activates PKC
IP3 - causes calcium release
what are the major G proteins and their actions
G-stimulatory: activates Ca2+ channels, activates adenylyl cyclase
G-inhibitory: activates K+ channels, inhibits adenylyl cyclase
Go: inhibits Ca+ channels
Gq: activates phospholipase C
G 12/13: diverse ion transporter interactions
what is the action of G-stimulatory protein
activates Ca2+ channels
activates adenylyl cyclase
B-agrenergic receptor: an important G protein receptor
- binds catecholamines (epinephrine and norepinephrine) - endogenous ligands
- stimulates the production of the second messenger cAMP and cellular effects
what are some key G protein-mediated second messengers
cGMP
cAMP
IP3
DAG
what is the action of the B-adrenergic receptor B1
- found in SA node of heart, cardiac muscle and adipose tissue
- increases heart rate, contractility and lipolysis
what is the action of the B-adrenergic receptor B2
- in bronchial smooth muscle - dialates bronchioles
- GI smooth muscle - constricts sphincters and relaxes gut walls
- uterus - relax uterine wall
- bladder - relaxes bladder
- liver - increases gluconeogenesis and glycolysis
- pancreas - increases insulin rate
what is the action of each B-adrenergic receptor B3
- found in adipose tissue - increases lipolysis
Receptors with enzymatic cytosolic domains as drug targets
- roles in cell metabolism, growth and differentiation
- tonic activation can cause tumors
- receptors form dimers or multisubunit complexes
- activity includes adding/removing phosphate groups from specific aa’s
how to GPCRs differ from transmembrane enzymatic cytosolic domain coupled receptors
GPCRs have 7 membrane-spanning proteins where enzymatic cytosolic domains have a single membrane-spanning protein
transmembrane receptors with enzymatic cytosolic domains example - receptor tyrosine kinases
- largest group of this receptor class
- endogenous ligands of RTKs include insulin, PDGF, VEGF
- effectors include SH2 domains on other signalling molecules like Grb2
- drugs that target these receptors include TK inhibitors
- anticancer agents target BCR-Abl TK
mode of action for receptor tyrosine kinases
- ligand binds RTK
- RTK’s dimerize and cross-phosphorylate one another
- phosphorylate other cytosolic proteins downstream
transmembrane receptors with enzymatic cytosolic domains example - tyrosine kinase-associated receptors
- includes cytokine receptors such as y-interferon
- hormones are ligands - GH and prolactin
- receptors have no intrinsic enzymatic activity
- dimerization allows for binding of an intracellular tyrosine kinase (e.g. JAK)
- JAK’s phosphorylate other proteins (STAT) which translocate to the nucleus
types of intracellular receptors as drug targets
nuclear hormone receptors
NO synthase and soluble guanylyl cyclase
intracellular receptors - nuclear hormone receptors
- bind steroid hormones - lipophilic so they diffuse through PM to bind TFs
- affect gene transcription in the nucleus
- have slow but long-lasting effects
types of nuclear hormone receptor
- lag on: slow onset of cellular effects
- lag off: slow offset of cellular effects
what happens when the steroid hormones binds to the nuclear hormone receptor
kicks off the chaperon protein and the receptor can move to the nucleus
intracellular receptors - NO synthase and soluble guanylyl cyclase
- important in the CV system
- NO binds the N-terminal domain of soluble GC and enhances activation of cGMP
- cGMP produces vasodilation effects of vascular smooth muscle
what are some roles of drugs that exist outside the plasma membrane
communication
cell surface adhesion
structural roles
drug receptors that serve as role in communication
- ACE inhibitors bind and cause vasoconstriction
- acetylcholinesterase inhibitors prevent the breakdown of ACh, used to treat alzheimer’s
when drug binds receptors that serve as role in cell surface adhesion..
allows cell-cell interaction for inflammation and coagulation
drug receptors that serve a structural role for the cell
- antineoplastics such as some microtubule inhibitors are used for cancer therapy (interfere with mitosis)
how do cells integrate multiple signals to produce a coherent cellular response
- secondary messengers allow signalling convergence to generate coordinated net cellular functions
- different ligands that bind to the same receptor can cause different downstream effects
signal amplification at drug receptors
- the magnitude of a cellular response to a ligand is usually greater than the initiating stimulus
- e.g. epinephrine
- e.g. cardiac muscle cell “trigger calcium”
cellular recognition of receptors
- causes drug-induced activation or inhibition of the receptor
- long lasting effect on subsequent responsiveness to drug binding
- prevent overstimulation of the pathway and cellular damage
what are some mechanisms of receptor regulation
tachyphylaxis: repeated administration of the same dose reduces its effect
desensitization: decreased ability of the receptor to respond
inactivation: loss of ability of the receptor to respond
refractory: a period of time is required between consecutive stimulations for the receptor
down-regulation: removal of receptor from sites where subsequent interactions could take place
what has the biggest influence on the affinity of a drug
the “off” rate (Koff) - the rate at which the drug unbinds the receptor
what is the Kd in drug-receptor binding
- the dissociation rate constant - Koff/Kon
- it corresponds to the ligand concentration where 50% of receptors are bound by the drug
what equations can be used to express the relationship between free and bound receptors
[L][R]Kon = [LR]Koff
[LR]/Ro = [L]/Kd+[L]
(fraction of total receptors bound by ligand)
what symbols represent the different states of receptors
Ro = total receptors
R = unbound receptors
RL = bound receptors
when [L] = Kd then…
[LR]/Ro = 0.5
occurs when 50% of receptors are bound by ligand
maximum ligand-receptor binding occurs when…
[LR] = [Ro]
or
[LR]/Ro = 1
if one drug has a lower Kd than another that indicates that…
it has tighter ligand-receptor binding or greater affinity
for many drugs the effect is proportional to…
the concentration of receptors bound by drug
Graded DR relationships - DR of an individual
- scalar relationship
- deals with efficacy and potency
what is efficacy (Emax)
the maximal response produced by the drug at that receptor
what is potency
- the drug concentration which elicits 50% of the maximal response
- function of affinity and efficacy
Quantal DR relationships - DR of a population of individuals
- plots the % of the population that responds to a given dose of drug as a function of the drug dose
- responses are either present or absent
- useful for predicting effects of a drug in a given population
what is the theraputic index
TD50/ED50
gives an estimate of the relative safety margin of a drug
what is meant by the median effective, toxic and lethal dose
ED50: the dose required to produce a therapeutic effect for 50% of the pop
LD50: the dose required to produce a lethal effect for 50% of the pop
TD50: the dose required to produce a toxic effect for 50% of the pop
what are agonists
drugs that bind receptors and stabilize them on an active conformation
what are the unstable forms of a receptor
R* = unbound active receptor
DR = bound inactive receptor
the following equation provides a quantitative description of potency and efficacy…
D + R <–> DR <–> DR*
- shows that more potent drugs have a greater affinity (lower Kd)
- more efficacious drugs (larger Emax) cause a greater proportion of there receptors to be activated
full vs partial agonism
full: can elicit maximal responses at a given receptor
partial: not able to achieve the same maximal response, even with increasing agonist concentration
true or false - a partial agonist may show greater potency (higher affinity) than a full agonist at a given receptor
true
explain the difference in receptor activation for a full, partial, competitive antagonist and inverse agonist
full: drug binding leads to DR*
partial: drug binding leads to DR* or DR
competitive antagonist: D binding leads to DR
inverse: D binding inactivates receptor (DR)
characteristics of a receptor antagonist
- usually binds to the active site
- has affinity for the receptor
- inhibits the action of the agonist by preventing its binding to the receptor
- has no effect on the absence of the agonist
- can bind reversibly or irreversibly with the active site
what are competitive receptor antagonists
- bind reversibly to active site
- do not stabilize receptor in active conformation
- increases the Kd for the agonist (decreases its potency) - causes agonist ED50 to be shifted right
- does not affect efficacy (Emax)
what are non-competitive receptor antagonists
- bind irreversibly to the active site covalently or with very high affinity
- irreversible binding cannot be outcompeted by the agonist
- depress the efficacy (Emax)
- some produce a decrease in potency (right shift)
what are the 2 types of non-receptor antagonists
chemical and physiologic
chemical antagonists
- inactivates the agonist by modifying or sequestering it
- e.g. treating an acidic protein with a basic molecule (neutralizes it)
physiologic antagonists
- 2 drugs the bind different receptors and produce opposite effects
- e.g. a drug that raises BP and one that lowers BP
what are allosteric modulators
- molecules that act indirectly to influence the effects of an agonist at its receptor
- bind to sites distinct from the agonist (allosteric site)
- binding alters Kd for agonist and alters the conformational change needed for receptor activation
positive allosteric modulators
enhance agonist effects - make them more potent - shift left
negative allosteric modulators
act similarly to non-competitive antagonists
the concept of spare receptors in DR binding
- its possible to achieve maximal effects with less than 100% receptor occupancy
- where EC50 value is less than Kd
- possibly because receptor remains active after non-agonist departs - allowing one agonist to activate many receptors
