Week1 part 1 Flashcards
What is Pharmacodynamics?
What a drug does to the body
- study of the biochemical, physiologic, and molecular effects of drugs on the body; involves receptor binding
What is a receptor?
- A protein or other substance that binds to an endogenous chemical or drug
- Coupling causes chain of events leading to an effect
Nagelhout, pg. 55
What are the three common properties of a receptor?
- Sensitivity: Drug response occurs from a low concentration. Less receptors is more sensitive to a drug.
- Selectivity: Drug response produced by structurally similar chemicals. (Low selectivity means lookalike drugs can attach, high selectivity means drugs need to be identical to what the receptor wants)
- Specificity: Drug response from a given set of receptors is always the same because the cells themselves determine the response
Nagelhout, pg. 55
Name the forces (from weakest to strongest) that lead to bonds between drugs and receptors
- Van der Waals
- Hydrophobic
- Hydrogen
- Ionic
- Covalent
Nagelhout, pg. 55
True or false:
Receptors are a single type of protein to which an endogenous substance or drug may complex to transmit a signal
False
- several mechanisms/receptor types have been identified
Nagelhout, pg. 55
Name several types of receptor classifications
GABA, Opioid, Alpha, Beta, Acetylcholine, Histamine, pain-related capsaicin
Nagelhout, pg. 56
True or False
Available receptors need to be 100% saturated with drug molecules to exert the desired effect?
False
- Complete saturation of available receptors with drug molecules is not necessary for a desired tissue response to be elicited
- I.E. acetylcholine and its receptor at the neuromuscular junction (Less than 1% of the cell surface binds drug to receptor protein to achieve tissue response)
Nagelhout, pg. 56
What are the 3 main endogenous proteins? What drugs bind with them?
- Albumin: acidic drugs (contains numerous receptor sites)
- a1-Acid glycoprotein**: basic drugs
- B-globulin**: basic drugs
Current understanding of molecular pharmacology suggests that the delay recorded from initial drug administration to the onset of the tissue response is due to what 3 factors?
- Molecular orientation and attachment to the receptor
- Receptor protein conformational change
- Tissue response time
Nagelhout, pg. 56
G protein-coupled receptors (GPCR) utilize ____________ in the process of signal transduction
second messenger pathways
* e.g. cyclic adenosine monophosphate (cAMP) & cyclic guanosine monophosphate (cGMP)
Nagelhout, pg. 56
How do GCPR second messengers lead to a tissue response?
- they regulate enzymes (e.g. protein kinases, phosphatases) involved in ordered sequences or cascades of biochemical reactions
Nagelhout, pg. 56
Many drugs have similar receptor protein compositions and signal transduction processes. What leads to different drug-induced tissue responses?
The primary difference among drug receptor proteins may only be the:
* Selective binding subunits
* Ion species moving through the channel
(e.g. acetylcholine –> sodium ions, GABA –> chloride)
Nagelhout, pg. 56
Specific peptide subunits are ultimately responsible for the pharmacologic properties of what three things?
Specificity
Affinity
Potency
Nagelhout, pg. 56
What is the drug response formula?
D+R<=> (DRC) <=> TR
- Drug (D) combines with receptor (R) to form a drug receptor complex (DRC) that elicits a tissue response (TR)
- derived from law of mass action (rate of reaction proportional to concentrations of reactants)
Nagelhout, pg. 56
The _________ theory states that the magnitude of a drugs effect is proportional to ____________
- occupancy
- number of receptors occupied
(drug receptor interactions have more complexity than this, but this theory serves as a useful background for many pharmacologic concepts)
Nagelhout, pg. 56
What is Pharmacogenetics?
The study of genetically determined variations in response to drugs including –>
- Variations in how a drug is metabolized
- How drugs interact with intended and unintended targets in the body
Nagelhout, pg. 58
What is Population Variability?
- a difference in response to a single drug dosage amongst a patient population
- remember that therapeutic drug doses reflect average doses of a “normal†population of individuals
Nagelhout, pg. 58
What are some parameters that influence Population Variability?
- Age
- Sex
- Body Weight
- Body Surface Area
- Basal Metabolic Rate
- Pathologic State
- Genetic Profile
Nagelhout, pg. 58
The administration of drugs is largely determined by a mean therapeutic dose per _________ or _________ ; the mean is calculated from a previously determined average dose for the “normal” population
- kilogram of body weight
- Body surface area
Nagelhout, pg. 59
The optimal dosing approach for patients when drugs are administered by the intravenous route is _________
- by titration until the desired therapeutic response is attained
Nagelhout, pg. 59
The graded dose response characterizes the change in __________ as ____________ is increased
- measured response
- administered dose
Nagelhout, pg. 59
The graded dose response allows for the comparison of _________ of different drugs with similar MOA
- potency
Nagelhout, pg. 59
What is a quantal dose response?
- The frequency with which a given drug dose produces a desired therapeutic response in a patient population.
Recorded in an all-or-nothing or yes/no fashion
Nagelhout, pg. 60
The lethal dose in 50% of the population is divided by the effective dose in 50% of the population to calculate ___________
- Therapeutic index
Nagelhout, pg. 60
Define therapeutic window
- the dosage range of a drug that provides safe, effective therapy with minimal adverse effects
Nagelhout, pg. 63
What is ED50?
- ED50 is the median effective dose at which 50% of a population responds as desired.
(Often used for comparing the potency of drugs within a class)
Nagelhout, pg. 60
The desired tissue response is observed when ________
- receptors are sufficiently occupied and activited by free drug
Nagelhout, pg. 60
What is the difference between drug affinity and drug efficacy?
- Affinity: Degree of attraction between a drug and its receptor on the cell’s surface
- Efficacy: A drug’s capacity to produce an effect (magnitude of response in relation to given dose
a high affinity does NOT equal a high efficacy (and vice versa)!
Nagelhout, pg. 61, 63
When does the receptor protein undergo a conformational change?
- When a drug combines with its receptor - Tissue response cannot occur without the structural shift
Nagelhout, pg. 61
What is the two state model of drug action?
This model describes the receptor as existing in equilibrium between either an activated or inactivated state
Constitutively active receptors can exist and are shifted towards the activated state even though no agonist or ligand is present
Drug delivery sufficient to occupy ____ of the receptors is often all that is necessary for maximum tissue response.
1% –> Drug absorption, distribution, and elimination used to be used to describe the tissue-response time course
Now it is believed that the response may be more complex
Nagelhout, pg. 61
How quickly can synthesis or destruction of receptor proteins occur?
Minutes –> Use to be believed this took much longer over a period of days.
Receptor up-regulation and down-regulation can occur during drug infusion
Nagelhout, pg. 61
What can occur if there are excessive amounts of free drug available in the body?
New receptor proteins can be synthesized in response to availability of free unbound drug
Nagelhout, pg. 61
What are the 4 types of drug antagonism?
- Pure Antagonists
- Agonist-Antagonists
- Physiologic Antagonism
- Chemical Antagonism
Nagelhout, pg. 61
What do pure antagonists do?
- can occupy the same receptor as an agonist, but do not produce a tissue response
- affinty but no intrinsic activity/efficacy
Nagelhout, pg. 61
What is the difference between competitive and noncompetitive antagonist drugs?
- competitive: weak affinity and may be displaced by an agonist - reversible
- noncompetitive: strong affinity and cannot be displaced by an agonist - irreversible (new receptors must be synthesized for agonist to bind to)
Nagelhout, pg. 61
What do agonist-antagonists drugs do?
- Have receptor protein affinity and intrinsic activity, but often only a fraction of the potency of the pure agonist
- Nalbuphine (mixed agonist-antagonist)
AKA Partial agonist
Nagelhout, pg. 61
What is physiologic antagonism?
- Involves two agonist drugs that bind to different receptors
-
These responses however generate opposing forces –>
Isoproterenol-induced vasodilation and norepinephrine-induced vasoconstriction
Nagelhout, pg. 62
What is chemical antagonism?
Occurs when a drugs action is blocked and no receptor activity is involved
Example
- Protamine
- Sugammadex
Nagelhout, pg. 62
What does receptor self regulation include?
Synthesis and degradation of the receptor
Covalent modification
Association with other regulatory proteins
Relocation within the cell
What may result from the continued stimulation of receptors/cells with an agonist?
- desensitization, refractoriness, or down-regulation
Clinical tolerance to the drug
Nagelhout, pg. 62
Receptors are subject to regulatory and homeostatic controls - modulating inputs may come from:
- Other receptors (directly or indirectly)
- Feedback regulation through self signaling outputs
What is tolerance to a drug?
Tolerance of agonists is described clinically, and increased doses are required to achieve the same effect –> Chronic agonist drugs = Down-regulation of receptors, less sensitive
Tolerance of antagonists is also described clinically, and increased doses are required to achieve the same effect –> Chronic administration of antagonists = Up-regulation, more sensitive due to chronic blockade
Both the number and sensitivity of receptors increase as a response to chronic blockade
How can you fix tolerance within a patient?
Switch the drug so a difference mechanism is being utilized
What is addition drug interaction therapy?
The combined effect of the two drugs via the same mechanism is equal to that expected by simple addition of their individual actions.
Ex –> Midazolam plus diazepam
1 + 1 = 2
What is synergism drug interaction therapy?
The combined effect of the two drugs is greater than the algebraic sum of their individual effects
Ex –> Midazolam plus propofol
1 + 1 = 3
What is potentiation drug interaction therapy?
The enhancement of the action of one drug by a second drug that has no detectable action of its own.
Ex –> Penicillin plus probenecid
1 + 0 = 3
What is antagonism drug interaction therapy?
The action of one drug opposes the action of another drug.
Ex –> Fentanyl plus naloxone
1 + 1 = 0
