Pharmacodynamics Flashcards
Pharmacodynamics
the study of the relationship of drug concentrations to drug effects
D+R=>DR
biological effect correlates to amount of DR
Receptor
Proteins on the surface or within cell that recognize and bind w/ specific molecules that act as chemical signals
-bind ligands
Ligands
- drugs
- endogenous signalling molecules (ie hormones and neurotransmitters)
How do drugs elicit their effects-undesirable or desirable?
By mimicking or blocking the actions of hormones and neurotransmitters
Agonist
-drug binds to receptor and causes same effect as endogenous substance
Antagonist
- drug binds to receptor but doesn’t produce a response
- inhibitory effect since it prevents endogenous binding
Kd
- equilibrium dissociation constant
- drug conc. at which 1/2 of Bmax is achieved
- measure of the affinity of DR
- constant-not altered by conc of drug or receptor number
- smalle kd= higher affinity
Emax
-the max response achieved by the drug
ED50
- the drug dose at which 50% of Emax is achieved
- POTENCY
Graded Dose Response Curve
-infinite number of intermediate states
eg vessel dilation, bp change, heart rate change
Quantal dose response curves
- all or none
eg. death, pregnancy, cure, pain relief, effect of given magnitude
Under what circumstances are quantal dose response curves particularly useful?
- to describe pop response to drugs
- based on plotting cumulative frequency distribution of responders against the log drug dose
Potency
- ED50
- related to the amount of agonist needed to produce an effect of a given magnitude
Efficacy
Emax
-related to the max effect that can be achieved w/ a particular agonist
Full agonist
- high potency, max efficacy
- reduced potency, max efficacy
Partial agonist
- high potency, reduced efficacy
- reduced potency, reduced efficacy
- have a lower functional impact on the receptor
Max. efficacy is defined by the max. effect achieved with ?
the endogenous R agonist
Constitutive Receptor Activation
- agonist binding induces conformational change in the receptor from inactive to active
- agonists stabilize the active state
- spont. dissociation of agonist returns receptor to inactive state
- conformational change to active state can also occur spot in the absence of agonist
- -> constitutive receptor activation
Inverse Agonist
- stabilizes the inactive state
- destabilizes the active state
- constitutive receptor activation
Draw diagram demonstrating experimental apparatus to measure constitutive receptor activity
Pharmacodynamics
What is the effect of agonists on receptors with constitutive activity?
-has an independent impact upon receptor activity
What is the effect of antagonists on receptors with constitutive activity?
-impacts receptor activity only in the presence of agonist (lacks efficacy)
What is the effect of inverse agonists on receptors with constitutive activity?
- has an independent impact upon receptor activity
- produces an effect opposite to agonist
Chemical Antagonism
Direct interaction of 2 substances in solution such that the effect of one or both is lost
Example of Chemical Antagonism
- protamine (acidic anticoagulant) and heparin (basic anticoagulant)
- loss of activity of both drugs
Physiological Antagonism
Indirect interaction of 2 substances with opposing physiological actions
Example of Physiological Antagonism
- histamine, lowers bp through vasodilation (H1 R)
- epinephrine raises bp through vasoconstriction (alpha1 adrenergic R)
Pharmacological Antagonism
- bind to receptors but do not activate signal transduction mechanisms
- biological effects from blocking ability of agonist to bind/activate R
Example of Pharmacological Antagonism
cimetidine blocks binding of histamine to H2 R resulting in lower gastric acid secretion
Competitive Antagonists
-bind reversibly to the receptor
-inhibition can be overcome by increasing agonist conc
AFFECTS AGONIST POTENCY
Non-competitive Antagonists
- bind irreversibly (e.g. covalently) to the R or reversibly/irreversibly to a site on the receptor different from agonist (allosteric)
- inhibition cannot be overcome by increasing agonist conc
- AFFECTS AGONIST EFFICACY
Draw the dose response curve for agonist in the presence of competitive antagonist
Pharmacodynamics
Draw the dose response curve for agonist in the presence of non competitive antagonist
Pharmacodynamics
ED50 of antagonists
- the antagonist dose at which 50% of Emax is achieved
- aka potency, ID50, IC50
Emax of antagonists
- max biological effect achieved by the antagonist
- NOT a measure of efficacy
T or F: majority of endogenous receptor ligands are full agonists
True
T or F: endogenous inverse agonists are common
False-rare
What is an example of an endogenous inverse agonist?
Agouti Related peptide (AGRP)
- reduces constitutive R activity of melanocortin R
- increases food intake and reduces energy expenditure
T or F: Endogenous pure antagonists are rare
True
What is an example of an endogenous pure antagonist?
Kynurenic acid
- NMDA receptor antagonist
- physiological role unclear but may play a role in neurotransmission and neuropathologies
? is a full agonist that mimics epinephrine at cardiac Beta1R
Isoproterenol
? is a partial agonist that mimics endogenous endorphins at u opiod R
-buprenorphine
Why is buprenorphine safer than morphine
-reduced risk with of respiratory depression with overdose
Superagonists
> 100% Emax
-uncommon in clinical practice
Drug Desensitization
-effect of a drug often diminishes when given continuously or repeatedly
Receptor Mediated Desensitization (2)
- loss of receptor fxn
- reduction of receptor number
How does loss of receptor function cause desensitization?
- rapid desensitization due to change in receptor conformation
- usually due to feedback of cellular effects of agonist
How does reduction of receptor number cause desensitization?
- slower, long term desensitization due to change in receptor number
- usually due to feedback of cellular effects of agonist
What is an example of desensitization caused by loss of receptor function?
Phosphorylation of specific amino acids in GPCRs blocks coupling to G proteins
What is an example of desensitization caused by reduction of receptor number?
-Phosphorylation of specific aa’s in GPCRs causes removal from cell surface
What are the 3 types of non receptor mediated desensitization?
- reduction of receptor coupled signalling components
- increased metabolic degradation
- biological adaptation
How does reduction of receptor coupled signalling cause desensitization?
-depletion of signaling molecules required for biological response
What is an example of reduction of receptor coupled signalling desensitization?
-prolonged stimulation of G-protein coupled receptors can lead to depletion of intracellular secondary messengers
ie cellular stores of ATP depleted by prolonged cAMP production
How does increased metabolic degradation cause desensitization?
- increase in the rate of metabolism and/or elimination of drug
- lowers plasma drug concentrations
What is an example of desensitization caused by increased metabolic degradation?
-barbiturates induce the expression of metabolic enzymes that degrade these drugs
How does increased physiological adaptation cause desensitization?
- reduction or amelioration of drug effects due to opposing homeostatic response
- very few well characterized mechanisms
What are the 3 adverse drug effects?
- side effects
- toxic reaction
- allergic reaction
Side Effect
- dose dependent
- not directly related to desired effect of drug
- action of drug at other sites to produce undesirable effects
Toxic Reaction
- dose dependent
- directly related to desired effect of drug
- excessive action of drug at intended target site
Allergic Reaction
- not dose dependent
- not related to desired effect of drug
- immunologic response to drug (largely unpredictable)
What is the desirable therapeutic effect of cyclosporine?
- promotes survival of transplanted organs
- magnitude of effect is dose dependent
What are the toxic effects of cyclosporine?
- increased susceptibility to infection
- consequence of intended pharmacological action (immunosuppression)
- dose dependent
What are the side effects of cyclosporine?
- kidney damage
- not related to intended pharmacological activity
- dose dependent
What are the allergic effects of cyclosporine?
- rash, hives, itching, breathing difficulties
- not related to intended pharmacological activity
- not dose dependent
T or F: the nature of the drug determines toxicity
False-the amount determines toxicity
Therapeutic Index
-a measure of drug safety
-dose required for a toxic/ adverse drug effect vs that required for beneficial effect
TI=Toxic ED50/Beneficial ED50
-larger TI indicates a clinically safer drug
Therapeutic Window-Relationship to blood levels
-considers a range of blood concentrations assoc. with toxic effects, therapeutic benefit or lack of effect within a pop.
Therapeutic Window-Relationship to dose
-considers the range of dosages assoc. with toxic effects, therapeutic benefit or lack of effect within a pop.
