chapter 2 Flashcards
why is verapamil a better choice for managing hypertension in a tachycardic and tachypneic patient with brochial asthma?
Verapamil may be a better option for individuals with certain comorbidities, such as asthma or chronic obstructive pulmonary disease (COPD), as it doesn’t have the same potential to worsen bronchoconstriction as propranolol, a beta-blocker.
“action of the drug on the body”
Pharmacodynamics
- specific molecules in a biologic system with which drugs interact to produce changes in the function of the system
- selective
- modifiable
Receptors
- Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects.
- Receptors are responsible for selectivity of drug action.
- Receptors mediate the actions of pharmacologic agonists and antagonists.
The Receptor Concept
Natural ligands are presently unknown, may be useful targets in the future for drug development
Orphan Receptors
molecules that translate the drug into a change in cellular activity
receptor interaction
- E.g. enzymes - adenylyl cyclase
Effector
best characterized drug receptors, mediate the actions of endogenous chemicals such as neurotransmitters, autacoids, hormones e.g. GABA receptors (benzodiazepines)
Regulatory proteins
receptor for antineoplastic drug methotrexate
dihydrofolate reductase
receptor for statins
HMG-Coa reductase
drug receptor for Digitalis
Transport protein (Na/K atpase)
drug receptor for tubulin (colchicine)
-antiinflammatory
Structural proteins
useful drug targets for cocaine ang psychostimulants
Dopamine transporter
useful drug targets for norepinephrine and serotonin (antidepressants)
Na/K ATPase
overall transduction process that links drug occupancy of receptors and pharmacologic response
Coupling
Receptor that does not bind drug when the drug concentration is sufficient to produce maximal effect; present if ~ > EC50
Spare receptor
Specific region of the receptor molecule to which the drug binds
Receptor site
A molecule to which a drug may bind without changing any function
Inert binding molecule or site
eg. psychoactive drugs
-bind to diff site of a receptor causing diff response
-affect interaction of drug and receptor
Allosteric Modulators
As dose increase, the increment diminishes
EC50
A drug that activates its receptor upon binding
Agonist
An agonist that activates the same receptor as other drugs in its group but also causes additional downstream effects that are not seen with other agonists in the group
Biased agonist
A drug that binds to the receptor without activating it and thereby prevents activation by an agonist
Pharmacologic antagonist
A pharmacologic antagonist that can be overcome by increasing the concentration of agonist
Competitive antagonist
A pharmacologic antagonist that cannot be overcome by increasing agonist concentration
Irreversible antagonist
A drug that counters the effects of another by binding to a different receptor and causing opposing effects
Physiologic antagonist
A drug that counters the effects of another by binding the agonist drug (not the receptor)
Chemical antagonist
A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist
Allosteric agonist, antagonist
A drug that binds to its receptor but produces a smaller effect (Emax) at full dosage than a full agonist
Partial agonist
Activity of a receptor absence of an agonist ligand
Constitutive activity
A drug that binds to the nonactive state of a receptor molecule and decreases constitutive activity
Inverse agonist
opiod agonists
morphine
methadone
fentanyl
hydromorphone
meperidine
oxycodone
sufentanil, alfentanil, remifentanil
codeine
hydrocodone
like morphine but higher potency
hydromorphone, oxymorphone
dose dependent analgesia
oxycodone
like fentanyl but shorter duration if action
sufentanul, alfentanil, remifentanil
less efficacious than morphone, can antagonize strong agonist
codeine
hydrocodone
lagpata nlng table sa ppt ka opioids ahhahahaha
mwa
A graph of the increasing response to increasing drug concentration or dose
Graded dose-response curve
A graph of the increasing fraction of a population that shows a specified response at progressively increasing doses
Quantal dose-response curve
in graded dose the concentration that causes 50% of the maximal effect. In quantal dose the conc. that causes a specified response in 50% of the population under study
EC50
The concentration of drug that binds 50% of the receptors in the system
Kd
in graded dose response curves, the dose that causes a specified toxicity. In quantal dose
response in 50% of the population under study
response curves, the dose that causes 50% of the
TD50
the largest effect that can be achieved with a particular drug, regardless of dose, Emax
Efficacy, maximal efficacy
the amount or concentration of drug required to produce a specified effect, usually EC50 or ED50
Potency
T/F
When EC50 is high, it implies that the drug is less potent because it takes a higher concentration of the drug to produce a significant effect.
True
T/F
The Emax is a characteristic of the drug and does not change based on the value of EC50.
True
T/F
if Emax is reached Increasing the C further is unlikely to significantly increase the observed effect
True
indicates the total concentration of
receptor sites (i.e., sites bound to the drug at infinitely high concentrations of free drug)
Bmax
(the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding
Kd
T/F
If the Kd is low, binding affinity is high
True
T/F
The EC50 and Kd may be identical but need not be
T/F
the sensitivity of a cell or tissue to a particular concentration of agonist depends only on the affinity of the receptor for binding the agonist
False.
the sensitivity of a cell or tissue to a particular concentration of agonist depends not only on the affinity of the receptor for binding the agonist (characterized by the Kd) but also on the degree of spareness—the total number of receptors present compared with the number actually needed to elicit a maximal biologic response.
maximal response occurs without occupancy of all receptors because of?
spare receptors
indicates the total concentration of receptor sites (ie, sites bound to the drug at infinitely high concentrations of free drug) and Kd (the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding is observed.
Bmax
logarithm of the dose or concentration
abscissa
for this receptor the relationship between drug occupancy and response can be simple because the ion current produced by a drug is often directly proportional to the number of receptors bound
ligand-gated ion channels
for this receptor the occupancy-response relationship is often more complex because the biologic response reaches a maximum before full receptor occupancy is achieved.
those linked to enzymatic signal transduc- tion cascades
After treatment with a low concentration of antagonist, the curve is shifted to the
right
T/F
High agonist concentrations can overcome inhibition by a competitive antagonist. This is not the case with an irreversible (or noncompetitive) antagonist, which reduces the maximal effect the agonist can achieve, although it may not change its EC50.
True
T/F
True
The concentration (C′) of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of com- petitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antago- nist.
(the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding
KD
A drug that counters the effects of another by binding to a different receptor and causing opposing effects
Physiologic antagonist
e.g. glucocorticoid (hyperglycemia) & insulin
A drug that counters the effects of another by binding the agonist drug (not the receptor)
Chemical antagonist
e.g. Heparin (negatively charged) & Protamine (positively)
example of physiologic antagonist
for bradycardia, isoprotenol, B-adrenoreceptor.
increase HR by mimicking sympathetic stimulation of heart
note. atropine a competitive antagonist is better
Why do some drugs produce effects that persist for minutes, hours, or even days after the drug is no longer present?
if pharmacodynamics:
1. Receptor interaction
2. Downregulation and disensitization
3. Active metabolites (Some drugs are converted into active metabolites that continue to interact with receptors, thereby extending the drug’s effect even after the parent compound is eliminated.)
if Pharmacokinetics: ADME
How do cellular mechanisms for amplifying external chemical signals explain the phenomenon of spare receptors?
“not all receptors need to be occupied by a drug or ligand to elicit a maximal response”
Spare receptors are receptors that are present in excess of what is needed to produce a maximal cellular response.
In other words, even if only a fraction of the available receptors are occupied by the ligand, the signal amplification mechanisms are capable of producing a full or maximal cellular response.
Why do responses to other drugs diminish rapidly with prolonged or repeated administration?
- Pharmacodynamic Tolerance (One mechanism of pharmacodynamic tolerance is receptor desensitization or downregulation)
- Metabolic Tolerance (The body may increase the production of drug-metabolizing enzymes or adapt in other ways to expedite drug clearance)
- Tachyphylaxis (is a rapid development of tolerance)
Basic mechanisms of transmembrane signaling
1.intracellular- receptor
2. transmembrane receptor protein whose intraceccular act. is regulated by extracellular domain
3. transmembrane that use protein tyrosine kinase
4. ligand-gated transmembrane ion channel
5. transmembrane receptor protein that stimulates a GTP transducer protein (G protein)
Basic mechanisms of transmembrane signaling
- lipid-soluble ligand that crosses the membrane and acts on an intracellular
- receptor - transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain
- transmembrane receptor that binds and stimulates an intracellular protein tyrosine kinase
- ligand-gated transmembrane ion channel that can be induced to open or closeby the binding of a ligand
- transmembrane receptor protein that stimulates a GTP transducer protein (G protein)
Family of receptors
- Intracellular receptors
- Enzyme- linked receptors
-Tyrosine kinase
-cytokind receptors - Ion Channels
- G protein-coupled receptors
Types of transmembrane signaling receptors
memorize table 2-1 in ppt
often induces accelerated endocytosis of receptors from cell surface
lead to down regulation
ligand-binding
will not immediately relieve symptoms but effects decrease slowly after administration
Glucocorticoids
Mechanism of activation of the epidermal growth factor (EGF) receptor
-tyrosine kinase
- have extracellular hormone binding domain and cytoplasmic domain (proteintyrosine, serine, guanylyl)
-noncovalent
-inhibitors:
1. Extracell: monoconal antibodies (trastuzumab, cetuximab)
2. cytoplasmic: permeant small molecule (gefitinib, erlotinib)
-limited by downregulation bcs of accelerated endocytosis
-respond to heterogenous group of peptide ligands
-include growth factor, erythropoietin, interferon
- usedps JAK instead, noncovalentky bonded to STAT
Cytokine receptors
-often mimic or block natural agonists
- natural ligands are ACH, serotonin, GABA, gkutamate
The nicotinic acetylcholine (ACh) receptor -ion channel
regulated by phosphorylation and endocytosis
ligand gated
do not bind neurotransmitters directly, but controlled by membrane potential
bind to a site of receptor dif. from the charged amino acids
Voltage gated
antiarrythmic
reduce BP w/o antagonizing any known endogenous transmitter
verampamil
allosteric modulators for CFTR
Lumacaftor- deliver to PM
Ivacaftir- channel conductance
-note: ion channel
-uses 2nd messagers (camp, calcium ion phosphoinositides)
-produces the phenomenon of spare receptors
G protein coupled receptors
-largest receptor family
-has 7transmembrane/serpentine
-receptor tail contains serine and threonine
-N (amino): extraceullar
-C (carboxyl): intracellular
GPCRs
accelerates endocytosis
leades to disensitization of GPCRs
B-arrestin
are thought to occupy the orthosteric ligand binding site, and differ on receptor conformation
Functionally/selective agonist biased-
well established 2nd messengers
Cyclic Adenosine Monophosphate (cAMP) Phosphoinositides and Calcium
Cyclic Guanosine Monophosphate
cAMP-mediated responses
- mobilization of stored energy
- conservation of water by the kidney
- Ca2= homeostasis
- increased rate and contractile force of the heart muscke
- adrenal and sex steroids
- smooth muscle
mobilization of stored energy
breakdown kf carbs in liber, TG3 in fat cells by B adrenomimipetic catecholamines
water coservation by kidney
vasopressin
calcium homeostasis regulated by
parathyroid hormones
increased rate and contractile force of heart muscle
β adrenomimetic catecholamines
Regulation of the production of adrenal and sex steroids
in reponse to corticotropin or follicule- stimulating hormone
Read on The Ca2+ phosphoinosited signaling pathway, cAMP second messenger pathway, and cGMP pathways.
which is faster?
cAMP
stays on the transmembrane and activates Pk-C, dephosphorylated, deacylated to yield arachidonic acid
DAG
relase CA2+ into the cytoplasma
IP3
splits PIP2 into DAG and IP3
PLC
phosphoinositide-specific phospholipase C
Inyerplay among signaling mechanism
- Isolation of signaling mechanisms – e.g. calcium signaling in te heart
- Reversible phosphorylation in almost all 2nd messengers
differing substance specifities
Flexible regulation
Her2 breast Ca
Trastuzumab
inhibitor of cytoplasmic tyrosine kinase
treat cylonous leukemia
abl (CML)
imatinib
related to NO and relaxation of muscle
cGMP
related to cintracting muscle
IP3 and Ca2+ pathway
relax muscle
cAMP
stimulate glucose release
IP3, Ca2+ and cAMP
fast
nicotinic
slow
muscarinic
reduce HR w/o preventing SNS from causing vasoconstriction
propanolol
acts as antagonist for estrigen in other tissues but an agonist in bones.
inc. bone density and treat bone cancer
tamoxiten
long term increase in receptor number, may occur when receptor activation is blocked for prolonged periods by pharmacologic antagonists or by denervation.
upregulation
Long-term reductions in receptor number, may occur in response to
continuous exposure to agonists
Downregulation
A graph of the increasing response to increasing drug concentration or dose
Graded dose response curve
A graph of the increasing fraction of a population that shows a specified response at progressively increasing doses
Quantal dose response curve
relates the dose of a drug required to produce a desired effect to that which produces an undesired effect
“the dose that will heal over the dose that will kill”
therapeutic index
the range between the minimum toxic dose and the minimum therapeutic dose
Therapeutic window
unusual; one that is infrequently observed in most patients, usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms (e.g. allergic reactions)
isiosyncratic response
intensity of effect of a given dose of drug is diminished or increased compared with the effect seen in most individuals
Hyporeactive/Hyperreactive response
allergic or other immunologic responses to drugs
Hypersensitivity
responsiveness usually decreases as a consequence of continued drug administratio
tolerance
responsiveness diminishes rapidly after administration of a drug
tachyphylaxis
Mechanisms contributing to variation in drug responsiveness
- Alteration in concentration of drug that reaches the receptor
- Variation in concentration of an endogenous receptor ligand
- Alterations in number or function of receptors
- Changes in components of response distal to the receptor
study of genetic factors determining drug response
Pharmacogenetics
the use of gene sequencing or expression profile data to tailor therapies specific to an individual patient is called
Personalized or precision medicine
term used by Pharmaceutical advertisements and prescribers implying that the effect in question is insignificant or occurs via a pathway that is to one side of the principal action of the drug; implications are frequently erroneous
side effect
Beneficial and toxic effects mediated by the same receptor-effector mechanism
(pharmacologic effect – e.g. insulin & hypoglycemia)
In the case of insulin therapy for diabetes, the challenge is to achieve glycemic control (lowering blood sugar) without inducing hypoglycemia (excessively low blood sugar).
Beneficial and toxic effects mediated by identical receptors but in different tissues or by different effector Pathways (e.g. glucocorticoids)
promoting glucose production in the liver, which can be beneficial during times of stress when the body requires additional energy.
Chronic use of glucocorticoids can lead to the loss of bone density, increasing the risk of osteoporosis and fractures.
Beneficial and toxic effects mediated by different types of receptors (e.g. opioids)
Opioid drugs, like morphine or oxycodone, are commonly used to relieve pain. Their beneficial effects are mainly mediated by binding to specific opioid receptors in the central nervous system.
One of the most significant and potentially life-threatening toxic effects of opioids is respiratory depression. This occurs when opioid drugs bind to opioid receptors in the brainstem,
