L5, L7- Pharmacodynamics Flashcards
(T/F) drugs can stimulate, inhibit, and add cellular functions
F- drugs cannot add functions
list the 7 major drug targets
- ion channels
- G-protein-linked receptors
- enzyme-linked receptors
- nuclear receptors
- enzymes
- transporters
- structural proteins
list the types of ion channels
- voltage gated: regulated by change in membrane potential
- ligand gated- extracellular or intracellular mediator
local anesthetics act by…
- inhibiting V-gated Na channels on peripheral neurons that transmit pain to CNS => prevention of APs and pain perception
- lipophilic, crosses plasma membrane and binds to intracellular side
GABA(a) receptors function as a (1) and is made up of the following subunits: (2). GABA binds to (3) subunit to stimulate receptor and benzodiazepines bind (4) subunit to (stimulate/inhibit) receptor function.
1- Cl- channel (neuron inhibitor via hyperpolarization) 2- 2α, 2β, 1γ subunits 3- between α-β units 4- between α-γ units 5- stimulates (=> neuron inhibition)
about 60% of prescription drugs act by binding _____
G-protein-linked receptors
albuterol is a (1)-(agonist/antagonist) used for (3)
1/2- β2-agonist
3- asthma
propanolol is a (1)-(agonist/antagonist) used for (3)
1/2- β-antagonist
3- HTN
bethanechol is a (1)-(agonist/antagonist) used for (3)
1/2- muscarinic agonist
3- atonic bladder (to contract its SM)
ipratropium is a (1)-(agonist/antagonist) used for (3)
1/2- muscarinic antagonist
3- asthma
describe the make-up of G-protein and its general mechanism
- α, β, γ subunits bound to receptor and membrane
- α subunit is largest and binds GDP and hydrolyzes GTP
1) receptor activated, GDP is replaced by GTP
2) α subunit breaks off and binds effector
3) GTP hydrolyzed to GDP
4) α subunit returns to β, γ subunits on receptor
list the 3 signals of the three G proteins
- Gs: inc adenylyl cyclase => inc cAMP
- Gi: dec adenylyl cyclase => dec cAMP
- Gq: inc phospholipase C => IP3 and Ca2+ (+ DAG)
define qiq qiss acronym
Muscarinic Receptors (qiq): M1-Gq, M2-Gi, M3-Gq
Adrenergic Receptors (qiss): α1-Gq, α2-Gi, β1-Gs, β2-Gs
list some of the Ca2+ mediated response (hint- 5)
(usually via Gq)
- SM contraction
- inc force of cardiac muscle contraction
- exocrine gland secretion
- NT release from neurons
- hormone release
list the types of enzyme-linked receptors
- ligand-regulated transmembrane enzymes
- cytokine receptors
describe make-up of ligand-regulated transmembrane enzymes
- polypeptides
- extracellular hormone binding domain
- cytoplasmic enzyme domain: tyrosine kinase (largest group), serine/threonine kinase, guanylyl cyclase
list some classes of tyrosine kinase receptors
(most promote growth)
- insulin receptor
- epidermal GFR
- platelet-derived GFR
- nerve GFR
describe signalling of tyrosine kinase receptors
- 2 ligands bind 2 receptors => dimerization and phosphorylate each other’s Tyr (2 each)
- intracellular signalling proteins bind to phosphorylated Tyr
- signalling cascade activated
- regulation of transcription
tyrosine kinase receptors play an important role in (1)
(2) mutations can lead to cancer
1- cell growth and differentiation
2- gain of function
the first tyrosine kinase inhibitor is (1) and functions to (2)
imatinib- for leukemia (discovered in 2001)
list some of the types of cytokine receptors
(mostly peptides)
- growth hormone
- prolactin
- EPO
- interferons
cytokine receptors lack (1) and therefore require (2)
1- intrinsic enzymatic activity
2- intracellular tyrosine kinase or Janus-kinase (JAK) family
describe signalling of cytokine kinase receptors
- 2 ligands bind 2 receptors => dimerization and JAKs phosphorylate each other and the receptors (1 each, 4 total)
- STATs bind to receptor and JAKs phosphorylated them
- STATs dimerize, migrate to nucleus –> regulate transcription
nuclear receptors are (1) and can bind (2) and (3)- they regulate gene expression usually involved in (4) and (5)
1- ligand-activated transcription factors 2- ligands 3- DNA 4- metabolism 5- development
list the type of nuclear receptor families
- steroid hormones
- thyroid hormone
- vitD
most enzyme binding drugs are (activators/inhibitors)
inhibitors
describe mechanism of statins
- competitive inhibitor for HMG-CoA reductase to stop cholesterol biosynthesis –> diminish intracellular cholesterol
- upregulation of LDL receptors in hepatocytes => inc clearance of LDL from blood
(1) drugs bind tubulin to prevent its polymerization into (2). As a result cells are usually in (3) state. (1) are effective drugs for (4).
1- vinca alkaloids
2- microtubules
3- arrested in metaphase (centrioles and mitotic spindles can’t pull chromosomes apart)
4- anticancer drugs
antacid mechanism
neutralize gastric acid
(1) binds (2) in the bladder [(2) is a metabolite of the anticancer drug cyclophosphamide] to prevent (3)
1- Mesna
2- acroleine
3- hemorrhagic cystitis
mannitol mechanism
- inc osmolarity of various bodily fluids
- promote diuresis or reduction of cerebral edema
____ is used in hypercholesterolemia treatment to bind bile acids and prevent their reabsorption
cholestyramine, colestipol, colesevelam
dimercaprol mechanism
cheleates heavy metal (mops them up for urinary excretion)
what are structural analogs of pyrimidines and purines used for
- incorporated in nucleic acids to alter their function
- used in cancer and antiviral chemotherapy
define the two types of dose-response curve
- Graded: effect (y-axis) v dose (x-axis)
- Quantal: % people where drug prevents event (y-axis) v dose (x-axis)
(T/F) the effectiveness of a drug curve and the binding to receptor curve are always correlated and equal
F- due to signal amplification and spare receptors, maximum effectiveness (Emax) can be reached before 100% receptors are bound to drug (Bmax)
in other terms, EC50 < Kd
why can Emax be reached at a lower concentration than for Bmax to be reached
- Spare Receptors
- Signal Amplification
define the x-axis in dose response curve for in vivo experiments and whole animal experiments
in vivo- log([drug])
whole animal- log(dose)
define efficacy
- the magnitude of response a drug produces
- maximum efficacy = Emax, can also be used to define efficacy of the drug
- way more important in determining clinical effectiveness then potency
define potency
- [drug] necessary to produce an effect at a given magnitude (efficacy)
- the lower the EC50, the higher the potency
- very little effect on the determining the usefulness of a drug (clinical effectiveness)
list the types of anatagonism
Receptor Antagonism (binds receptor)- competitive, noncompetitive (allosteric site)
Nonreceptor Antagonism (doesn’t bind receptor)- functional (indirect or physiological), chemical
define the types of competitive antagonism
- antagonist binds the same binding site as the agonist
- Reversible: weak bonds, effect can be surmountable by inc drug dose (equal efficacy, higher EC50)
- Irreveresible: covalent bonds, effect is insurmountable (lowered efficacy)
phenoxybenzamine mechanism of action and purpose of treatment
- irreversible competitive antagonist for α-adrenoreceptors
- to Tx pheochromocytoma
aspirin mechanism of action and purpose of treatment
- irreversible competitive antagonist for COX enzyme
- to Tx pain, coagulation
omeprazole mechanism of action and purpose of treatment
- irreversible competitive antagonist for H+/K+ ATPase enzyme (PPI)
- to Tx GERD
define noncompetitive antagonism
- antagonist binds to allosteric site (non-binding site of agonist) on receptor
- lowers efficacy / Emax
- insurmountable by inc [drug]
ketamine mechanism of action and purpose of use
- noncompetitive antagonist of NMDA receptor
- IV anesthetic
define the types of functional antagonism
(a nonreceptor antagonism type)
- Indirect: binds to macromolecule in downstream signaling pathway to reverse effects of agonist
- Physiological: induces signaling cascade with opposing effects to agonist
a molecule that inhibits PKA function and therefore blocks the effects of β-adrenoreceptor agonist is an example of what type of antagonism
indirect functional antagonism
what is the best / common example of physiological functional antagonism
using epinephrine (–> inc BP, bronchodilation) to reverse the effects of histamine (–> dec BP, bronchoconstriction) in an allergic reaction
define chemical antagonism
antagonist reacts chemically with agonist to form an inactive product (neutralizes the agonist)
what is the best / common example of chemical antagonism
protamine is pos. charged protein and counteracts effects of neg. charged heparin, an anticoagulant
define partial and full agonist- include what happens in the presence of both
- Full => maximum response
- Partial => submaximal response
- if both are present, partial agonist acts as a competitive antagonist
- Note- no effect on potency
define Inverse Agonist
- many receptors have constitutive activity
- inverse agonist reverse this baseline activity
give some classic examples of inverse agonists
- famotidine (Pepcid)
- metoprolol (β1 antagonist - HTN)
define the criteria for a drug to be considered selective
drug binds its first target (=> therapeutic effects) with at least 10-fold difference in affinity than its second target (=> adverse effects)
_____ is the term used to describe the event at which a drug’s effect diminishes in the course of a few minutes
desensitisation, tachyphylaxis
define drug tolerance
gradual dec in responsiveness to a drug, taking days - weeks to develop
define refractoriness
related to loss of therapeutic efficacy
define drug resistance
loss of effectiveness of antimicrobial or antitumor drugs
list the factors involved in desensitization and tolerance
- change in receptors: activate ion channels (rapid desensitization), G-protein-coupled receptors (desensitization, via phosphorylation mechanism)
- internalization of receptors (endocytosis of receptors upon repeated drug exposure)
- exhaustion of mediators (tachyphylaxis due to depleted stores)
- inc metabolic degradation (tolerance)
- physiological adaptation (drug effect opposed by homeostatic response)
define TD50 and LD50
TD50- dose required to produce toxic effect in 50% of animals (median toxic dose)
LD50- dose required to cause death in 50% of animals (median lethal dose)
give equation for therapeutic index
TI = TD50 / ED50 (humans)
TI = LD50 / ED50 (animals)
define therapeutic window
from minimum effective concentration to minimum toxic concentration
