Pharmacodynamics Flashcards
6/3/19
Pharmacodynamics
Study of how drugs produce their effect on the body
2 Main focuses of pharmacodynamics
1) Mechanism of action - how a drug produces its pharmacologic effects
2) Pharmacological effect - anticipated results of a drug’s actions either therapeutic or adverse
Drugs cannot create new cellular functions, they can only…
…modify existing ones
Physical/chemical mechanisms of drug actions
Some drugs produce responses by altering the cell or its environment WITHOUT interacting with cellular receptors
Receptor mechanisms of drug actions
Receptors which bind drugs usually reversibly either mimicking the action of the body’s own regulatory molecule or blocking the action of those regulatory molecules
Example of drug that mimics and drug that blocks action of norepi at the heart
Isoproteronol is similar enough to norepi, while b-blockers prevent the action
Signal transduction
Process by which a receptor binding a ligand leads to a cascade of biochemical events that results in physiological effect
4 basic mechanisms of transmembrane signaling
1) Lipid soluble ligand crosses the membrane and acts on the intracellular receptor
2) Transmembrane receptor proteins that upon binding a ligand intracellular enzymatic activity is activated
3) Ligand gated ion channels opening or closing in result of binding
4) Transmembrane receptor stimulates a G protein that generates a 2ndary messenger (often use cAMP)
Example of receptor ion channel system
GABA
Example of transmembrane receptor protein system
Insulin binding causes catalytic domain activation of glucose uptake transporters
Common 2ndary messenger G protein system
Drug -> receptor -> G protein activates -> adenylate cyclase actiavtion -> conversion of ATP to cAMP -> Kinase activation -> further phosphorylation
Common intracellular receptor system
Diffusion of hormone across cell and nuclear membrane -> bidining to a nuclear receptor ->Allows for mRNA synthesis -> protein product
Specificity in drug receptor interactions
Ability of a drug to bind to a receptor determined by the shape of the drug relative to the receptor - lock and key concept
Selectivity in drug receptor interactions
Refers to ability of drug to affect only one type of cell or tissue and produce a specific physiologic response
The less selective a drug is the more likely…
…to see unwanted or negative effects on tissues that we do not want effected
Example of drug that is less selective resulting in having multiple unintended consequences
Propranolol acts as a B blocker used to act on B1 and B2 receptors and inhibit effect of norepi on heart, but it is non specific and also has an impact on the lungs as well causing bronchoconstriction and therefore isn’t good to use in patients with asthma or COPD
Affinity
Term used to describe amount of attraction between a drug and receptor, high affinity readily binds open receptors even if conc is low, drugs iwth low affinities require a high conc. before receptrs become occupied
Efficacy
Relates to ability of drug to produce a pharmacologic response after it has interacted with a receptor
Quantifiying effect
Effect (E) is a function of the quantity of the drug receptor complex (DR) and can be expressed as E=a(DR) when a=constant for a given drug and is a partial determinant of whether an effect occurs, experimentally determined and considered a measure of a drug’s intrinsic activity (a=0 in antagonist?)
Agonist
Drug that interacts with a receptor and produces a pharmacologic response, once inserted to a suitable receptor drug acts same way normal hormone would, has affinity and efficacy
Antagonist
Drug that interacts with a receptor and produces no response, in presence of an antagonist drug, normal response reduced or completely prevented, antagonists have affinity for receptor but lack efficacy
Partial agonist
Do not evoke maximal response compared to a strong agonist, efficacy somewhere between a full agonist and full antagonist, have affinity for receptor but often do not activate receptor resulting in decreased efficacy
Partial agonist benefits
Can produce adequate effects without excessive side effects in some cases
Quantal response
All or none response to a drug and relates to the frequency with which a specified dose of a drug produces a specific response in a population, the smallest amount of drug that produces a quantal response is not the same for all members of a population
Graded dose response
As dose administered increases, pharmacologic response increases up to a point (ceiling effect, where the degree of action levels off because every receptor is bound E-max)
Potency
The dosage required to achieve a certain degree of pharmacologic effect
Chirality/sterioisomerism
Chemical structures that contain an assymetric carbon with all 4 valences utilized by different groups resulting in nonsuperimposible mirror images of each other
Determining R or S chirality
Rank the valence groups off the central carbon from highest atomic number to lowest, if it goes clockwise then it is R, if it goes counter it is S
Example of how isomers matter
Despite having the same chemical equation, the chirality of S-citalopram and R-citalopram result in S-citalopram being the most selective SSRI to have a therapeutic response while R has no clinical benefits and is not therapeutically active
Competitive antagonism
Where antagonists compete with agonists in a reversible ffashion for the same receptor site, whichever drug is in greater conc. typically has predominant effect
Noncompetitive antagonism
Relatively rare, when antagonists irrefersibly bind to receptor site therefore inhibitn gthe response to the agonist forming a strong permanent bond to receptor, no matter how much agonist is added can never acheive the same effect as with the agonist alone
Physiologic antagonism
A drug acting on a different receptor than another physiologically decreasing the effect of others
Why are physiologic antagonists less preferable to receptor specific antagonists?
Physiologic antagonists work on different receptors, they produce effects that are harder to control than the effects of a receptor specific antagonist
Antagonism by neutralization
finish it!
Therepeutic index
Describes relative safety of a drug expressed in a radion LD50/ED50
LD50
Lethal dose that will kill 50% of animals given drug
ED50
Effective dose that will produce therapeutic effect in 50% of animals given the drug
The greater the TI, the _____. The closer the TI is to 1, the ______
the safer the drug, greater potential danger to the patient
Down regulation
Desensitization - if receptors are continually stimulated as is the case with chronic use of certain drugs, their responsiveness may decrease as a result of decrease in # of receptors or changing responsiveness to existing receptors
Up regulation
Supersensitivity - prolonged decrease in stimulation of receptors can result in functional increase in receptor sensitivity, may occur with chronic use of receptor antagonist drugs, results in creased production of receptors
Why is up regulation dangerous?
If an individual suddenly stops taking a blocker, then they are hypersensitive, need to take time to ween off and have receptors return to normal levels
Pharmacodynamic tolerance
When the MEC of a drug becomes abnormally high, thought to be due to down regulation
Metabolic tolerance
Tolerance resulting from accelerated drug metabolism, brought about by the ability of some drugs to induce synthesis of drug metabolizing enzymes, does not change level of drug needed to elicit a response, increased dosage to achieve the same response not a higher one
Tachyphylaxis
Form of tolerance defined as a reduction in drug responsiveness over a very short period of time (sets it apart from others), NOT a common form of drug tolerance
Example of tachyphylaxis
Nitroglycerin response lost within 24 hours when administered transdermally, must take a break to replenish supply at night
Placebo
Preparation that is devoid of intrinsic pharmacologic activity, any response is solely the patient’s psychologic reaction and not to direct physiologic or biochemical action of the placebo itself
With all medications, some fraction of total response is a result of the…
…placebo effect
Placebo response positive and negatives
- If a patient is convinced a medication will be effective, placebo will promote recovery
- If a patient is convinced a medication will be innefective/harmful, placebo will detract from progress
