Lecture 4-5 Pharmacodynamics Flashcards
What is the component of a cell to which a drug binds to initiate the chain of events that leads to a biological response
Receptor
Most receptors are ___, some are ___
Proteins, nucleic acids
For most drugs the duration of action is directly related to the __ the drug is bound to the receptor
Time
As the drug is cleared from the blood stream its action will be ___
Terminated
What are some drugs that are exceptions to the relationship between time bound to receptor and action
Corticosteroids, MAO inhibitors, omperazole, aspirin, DFP
How do corticosteroids persist for several weeks after the drug has been cleared from the body
Act on nuclear receptors and alter the expression of genes
How does the effect of MAO inhibitors, omeprazole, aspirin and DFP persist for a long period of time even without lots of free drug in the plasma
Irreversibly bind to and inhibit enzymes and their effects
What are the 5 drug-receptor interactions
- Electrostatic interactions
- Hydrogen bonds
- Van der waals
- Hydrophobic interactions
- Covalent binding
Which drug-receptor interactions have low energy bonds and therefore break easily
Electrostatic interactions, hydrogen bonds, van der waals, hydrophobic interaction
Which drug-receptor interactions have high energy bonds and therefore are irreversible
Covalent binding
Why type of receptors regulate gene expression
Intracellular receptors
How do intracellular receptors work/interact with hormone or drug
Hormone or drug crosses the plasma membrane, stimulates intracellular receptor.
Then stimulates gene transcription
Effect on intracellular receptors occurs after ___ period and ____over time
Lag period and persists over time
What some examples of molecules/hormones that can act on intracellular recpetors
Corticosteroids, mineralcorticoids, sex steroids, Vitamin D, and thyroid hormone
Can steroid hormones that act on intracellular receptors be stored
No, except for thyroid hormone
Why can’t steroid hormones be stored
They must be very lipid soluble to cross plasma membrane and interact with intracellular receptor and considering storage vesicles are made of lipids they would just diffuse out
How do allosterically regulated transmembrane proteins work
Ligand binds causing receptors to associate, stimulating tyrosine kinase, phosphorylating receptors and other downstream proteins
What enzymes can be used in allosterically regulated trans membrane signaling
Tyrosine kinase, serine kinase, guanylyl cyclase
What are some molecules that can active protein tyrosine kinases
Insulin, epidermal growth factor and platelet derived growth factor
How do ligand gated ion channels work
Binding of neurotransmitter or drug opens the channel, causing influx of ions either depolarizing or hyperpolarizing the cell
Do nicotine acetylcholine receptors excite/depolarize or inhibit/hyperpolarize
Excite/depolarize
Do GABA-a receptors inhibit/hyperpolarize or excite/depolarize
Inhibit/hyperpolarize
What ion channel opens when ACh binds
Na+
What channel is always open at NMJ and why
K+ to establish membrane potential
Acetylcholine acts on what receptor to influx what ion
Acts on nicotinic receptor and influxes Na+
What receptor does GABA act on and what ion channel does it open
Acts on GABA-A receptor and opens Cl- channels
What receptor do benzodiazepines act on and what ion channel does it open
Acts on GABA-A receptor and opens Cl- channels
What ions does glutamate act on
Ca2+ and Na+
Why are benzodiazepines less toxic than phenobarbital
Benzos need to act on GABA-A receptor to open Cl- channels, meanwhile phenobarbital opens Cl- channels by itself so very limited therapeutic range
Describe the basic mechanism of GPCR’s
Molecule binds, activates Gq, Gs, or Gi subunits and acts on phospholipase C
Stimulation of G-proteins ___ the response to binding of agonist to the receptor
Amplifies
Do receptors linked to Gs stimulate or inhibit cAMP
Stimulate
Do receptors linked to Gi inhibit or stimulate formation of cAMP
Inhibit
What is the downstream signaling when an agonist activates a GPCR
Gs—> AC—> cAMP—> phosphorylation of various proteins
What breaks down cAMP
PDE
What happens if you phosphorylation K+ channels
Close channels and decrease membrane potential—> depolarization
What would happen if you phosphorylated Ca2+ channels
Open
What receptors does epinephrine act on through Gs GPCR
B1 and B2
What receptor does NE act on through Gs GPCR
B1
What receptor does isoproterenol act on via Gs GPCR
B1 and B2
What receptor does Dobutamine act on in Gs GPCR
B1
What receptor does histamine act on via Gs GPCR
H2
Does FSH and ACTH act through Gs or Gi pathway
Gs
What receptor does NE act on via Gi GPCR
Alpha-2
What receptor does Epinephrine act on via Gi GPCR
Alpha-2
What receptor does dexmedetomidine act on via Gi GPCR
Alpha-2
What receptor does acetylcholine act on in Gi GPCR
M2
What receptor does morphine act on in Gi GPCR
Mu, kappa, delta
What receptor does serotonin act on via Gi GPCR
5-HT1
Describe the steps in poylphosphoinositide signaling
- Agonist binds GPCR
- Gq activates PLC
- PLC hydrolyzes IP3 and DAG
- IP3 releases Ca2+ from intracellular stores
- DAG stimulates protein kinase C
- IP3 is dephosphorylated
- DAG is broken down
- Ca2+ is pumped out
What is the result of IP3 releases Ca2+
Ca2+ will bind calmodulin and activate myosin in smooth muscle leading to smooth muscle contraction
What neurotransmitters can stimulate GQ formation of IP3 and DAG
Acetylcholine, norepinephrine, epinephrine, phenylephrine, and serotonin
What receptor does acetylcholine act on in GQ stimulation of IP3/DAG
Muscarinic M1 and M3
What receptor does NE and epinephrine act on in GQ stimulated formation of IP3 and DAG
Alpha1
What receptor does phenylephrine act on in GQ stimulated formation of IP3/DAG
Alpha1
What receptor does serotonin act on in GQ stimulated formation of IP3/DAG
5-HT1c
What are some examples of drugs that interact with body components that have non-receptor mediated effects on the body
Antacids and osmotic agents (mannitol, laxatives)
Heparin can bind to what in order to inactive
Protamine
Is a drug-receptor interaction reversible or irreversible
Usually reversible
The response to a drug is directly related to the # of
Receptors occupied
The response to a drug is maximal when….
All available receptor sites are occupied or bound to the drug and further addition of the drug does not produce an additional response
What can we determine from dose response curves
EC50- 50% effective concentration
When can a graded dose response curve be used
When measuring in response to 1 unit is given
Ex: give increasing doses of NE and measure vasoconstriction
Maximal effect is equivalent to
Efficacy
Are more potent drugs on the left or right side of response curves
Left
When can you use quantal dose response curves
Measuring a population
What does a quantal dose response curve related
Dosages of the drug to the frequency with which a designated response will occur within a population
Does a graded or quantal dose response curve have an “all or none” response
Quantal
How is the quantal dose response curve displayed in graph
Frequency distribution
What are quantal dose response curves used to determine
Therapeutic ratio
How do quantal dose response curves determine therapeutic ratio
Give increasing doses of drug and measure ED50 to determine effective dose in 50% and LD50 to determine lethal in 50%
What is the therapeutic ratio equation
Therapeutic index= (LD50)/(ED50)
where on this graph would indicated therapeutic dose and why
B because it is the beginning of overlap with greatest therapeutic response and lowest lethal response
What is affinity
Measures binding of drug to receptor
What is Kd
Concentration needed to produce half maximal binding
What is potency
Dose required to produce a given effect
What is EC50
Dose required for half maximal effect
What is efficacy
Degree of biological response produced by binding of a particular drug to the receptor, not related to potency
What is intrinsic activity
Synonymous with efficacy, ability of a drug to initiate a response
Do antagonists, agonists or partial agonists have affinity and intrinsic activity
Agonists
Do antagonists, agonists, or partial agonists have affinity but no intrinsic activity
Antagonists
Do antagonists, agonists or partial agonists have affinity but lower intrinsic activity
Partial agonists
Compare the potency and efficacy (intrinsic activity) of Drug X and Y and are these full or partial agonists
These are full agonists as they reach 100% effect but drug Y needs higher concentration. Therefore Drug Y and X have the same efficacy but drug Y is less potent
compare and contrast drug X and Drug Y on their potency and efficacy (intrinsic activity) and are these full or partial agonists
These are partial agonists as they don’t reach 100% effect. Drug Y doesn’t even reach 50% so can’t compare ED/LD and Drug Y is less potent and has less efficacy
What is an agonist
Binds the receptor and initiates a response, causes a maximum shift of receptors to the activated state
What is an antagonist
Binds to the receptor, but does not initiate a response, will block response to agonist
What is a partial agonist
Binds to the receptor and causes a response, response is lower than produced by full agonist, may block the response to the full agonist
T or F: partial agonists can also function as antagonists
Yes- because they will compete for binding sites with a full agonist
Is morphine an agonist, antagonist or partial agonist
Agonist
Is naloxone an agonist, antagonist or partial agonist
Antagonist
Is buprenophine an agonist, antagonist or partial agonist
Partial agonist
What are the 4 different ways a drug can function as an antagonist
- Competitive binding
- Non-competitive binding
- Functional/physiological
- Chemical
What does a competitive antagonist do
Compete for receptor binding with agonist
What is the intrinsic activity and efficacy of a competitive antagonist
Zero
How do competitive antagonist impact affinity
Decrease
How do competitive antagonists shift dose response curve
To the right in a parallel fashion
Do competitive antagonists affect the maximum response produced
No
What is non-competitive antagonists do
Bind irreversibly to the receptor so agonist can’t bind or bind to secondary site so agonist can’t act
How do non-competitive antagonists impact maximum response
Decrease
How do non-competitive antagonists impact EC50
May or may not change
What is functional/physiological antagonism
Antagonist acts through a different receptor or mechanism to alter a physiological response, less specific and harder to control
What is an example of functional/physiological antagonism
Anaphylaxis causes histamine release which acts on H1 receptors and decrease BP and to counteract give epinephrine to vasoconstrict and increase BP
**both act to increase BP but do not act in the same mechanism
What is a chemical antagonist
Antagonist neutralizes drug or compound chemically
What is an example of a chemical antagonist
Heparin neutralized by protamine
___ agonists produce a response but with lower efficacy than full agonists
Partial
What is tolerance
After chronic administration of many drugs effect of the drug decreases
Pharmacokinetic tolerance
Drug induces its own metabolism and may increase metabolism of another drug (via P450)
Barbiturates undergo ___ tolerance
Pharmacokinetic
Pharmacodynamic tolerance
Usually due to a receptor down or up regulation
Beta receptor agonists or antagonists and opioids undergo ___ tolerance
Pharmacodynamic
How do beta blockers chemically induce super sensitivity or hyperactivity
Induce bradycardia and decrease BP but if you abruptly stop beta blocker it will result in increase BP and HR because new receptors are not being inhibited anymore
How can surgically induced denervation cause super sensitivity or hyperactivity
Increase NMJ and give stimulators agent and will cause big effect
How do antagonist increase super sensitivity or hyperactivity
Upregulate receptors to drugs
How does a deficiency of degrading enzymes increase supersensitivity or hyperactivity
Increase lifespan of drug action
What kind of physiologic synergism do NSAIDs provide
Additive or summation
What type of physiological synergism do antihypertensives cause
Synergism
What type of physiologic synergism do cholinesterase inhibitors do
Potentiation
How can one drug elicit multiple responses
Due to presence of multiple receptors being activated at different dose levels
Drugs are ____ but rarely ___
Selective but rarely specific
What are some examples of drugs that can act on multiple receptors and cause adverse effects
- Phenothiazines
- Antihistamines
- CNS depressants
What is a dose dependent toxicity
If an adverse reaction is mediated by the same receptor-effector mechanism
What are some common dose-dependent toxicities
- Excessive hypotension
- Arrhythmias
- Hypoglycemia
- Hemorrhage
What organ specific toxicity does aminoglycosides cause
Renal and ototoxicity
What organ specific toxicity does acetaminophen cause
Hepatotoxicity
What organ specific toxicity does chloramphenicol cause
Aplastic anemia
What organ specific toxicity does tetracycline cause
Retardation of bone growth
What form of antagonism does the following graph show
Competitive- in order for drug A to have same efficacy in the presence of increasing concentrations of drug B it must also increase concentration to reach the same efficacy
What type of antagonism does the following graph show
Competitive- acetylcholine by itself can be administered at a lower dose to reach maximum efficacy but when administered with atropine the dose of acetylcholine must be increased to reach same efficacy
What type of antagonism is this graph showing
Non-competitive- bind irreversibly so adding dibenamine to epinephrine will inhibit epinephrine from reaching maximum efficacy even if you increase the dose of epi
What type of antagonism is the graph showing
non-competitive because drug A in presence of non-competitive inhibitor drug B will never be able to reach maximum efficacy despite increasing dose of drug A
