4. Pharmacodynamics Flashcards
- Define agonist (full, partial, inverse), antagonist (competitive, non competitive), affinity, intrinsic activity and efficacy (objective)
Answer later
- Know the types and relative strengths of the bonding forces involved in drug-receptor interactions (objective)
Answer later
- Understand the relationship between the amount of drug-receptor complex, the Kd, and concentrations of the receptor and the drug (objective)
Answer later
- Understand receptor desensitization and receptor down-regulation (objective)
Answer later
- Be able to use sigmoid concentration-response (or dose-response) curves to compare drugs (objective)
Answer later
- Be able to use linear (probit) dose-response curves to compare ED50, TD50 and clinical responses (objective)
Answer later
- Understand therapeutic index and margin of safety (objective)
Answer later
Pharmacodynamics (levels)
1. Molecular level: Drug-Receptor Interactions 2. Cellular and Tissue Physiology Level: Graded Dose-Response Curves 3.Clinical Therapeutics Level: Quantal Dose-Response Curves
- Molecular Level: Drug-Receptor Interactions (history)
1690, John Locke
1897, Paul Ehrlich, drug receptor concept, similar to lock and key (“side-chain” on cells bound toxins, chains could be released into blood where they could act as antitoxins or antibodies)
1905, John Langley, termed receptive substance (nicotine and curare on skeletal muscle), idea that drugs elicit inhibitory response
Receptor (definition)
Structure that recognizes endogenous or exogenous compounds (ligands) with high selectivity
Binding of appropriate ligand to receptor initiates/terminates a physiologic process
Not all drug actions mediated by receptors
Neutralization of stomach acid with a base (antacid)
Osmotic diuretic action of mannitol
Agonist
Drug that mimics the effects of the endogenous ligand for a receptor
Antagonist
Drug which does not have intrinsic activity, but which interferes with the binding of the endogenous ligand (or agonist) to a receptor
Bonding Forces (list from weakest to strongest)
Van der Walls (weakest) Hydrophobic Hydrogen Ionic Covalent (strongest)
Affinity (affinity of a receptor for a particular drug is determined by)
- Number of interacting sites
2. The types of forces that are involved in the binding interactions
Equation Describing Reversible Drug-Receptor Interaction (Reaction 1)
[D]+[R] forward arrow [DR]
k1 is on arrow
[DR] forward arrow [D]+[R]
k2 is on arrow
Reaction is double arrow/reversible
Equations describing the dissociation constant (Kd); note that the Kd called the “affinity” constant
Kd=k2/k1
=rate of DR dissociation/rate of DR association
=”off” rate/”on” rate
When [DR]=0.5[Rtotal] then Kd=[D]
Thus, Kd is concentration of drug which one-half of total # of receptors are bound by drug. Kd units of moles liter-1
Affinity (Kd)
Kd of a drug for a receptor is the concentration of drug that occupies half of the total number of available receptors [Rt]
Lower the molar concentration value of Kd for a given drug, the higher drug’s affinity for the receptor
DR=(([Rt])([D]))/((Kd)+([D]))
Like Michaelis-Menten equation
Rt=receptor total
Drug Receptor Binding [DR] vs Drug Concentration [D] Graph
Upward slope until it plateaus.
Halfway mark in slope is Rt (1/2 DR) and Kd
Drug Bound/Drug Free [DR]/[D] vs Drug-Receptor Binding [DR] Graph
Kd=-1 slope
Downward slope with x intercept at Rt
*Just to compare things linearly (Kd is slope)
Other graph shows data points but with a curve going downwards (example there exists receptor subtypes)
Raymond Ahlquist (1914-1983)
Concept of receptor subtypes
1948, proposed existence of alpha and beta subtypes of adrenergic receptors
Decreasing Response to Drugs with Sustained Exposure
Receptor Desensitization:
Time-Seconds to Minutes
Mechanism-Receptor Phosphorylation
Effect-Decreased Affinity
Receptor Down-Regulation:
Time-Hours to Days
Mechanism-Receptor Turnover
Effect-Decreased Receptor Number
- Cellular and Tissue Physiology Level: Graded Dose-Response Curves (miscellaneous)
Efficacy- clinical response
y= intrinsic activity in tissue or lab
[DR] forward arrow with y to Re (response)
Re=y[DR]
Re=[y([Rt])([D])] / [(Kd)+([D])]
Michaelis-Menten version for response
% response (Re) vs Drug Concentration [D] Graph
Hyperbolic curve (upward until plateau) Now just compared response to drug concentration instead of receptors
Then graph of sigmoid curve (just log of drug concentration): Kd is the point where 50% response
Comparing Re vs Log Drug Concentration Curves
Sigmoid curves
Kd is way to compare drugs
Sigmoid curve to the left has higher affinity then one on the right
Effect of a positive allosteric modulator on an agonist log drug-response curve (Diazepam example)
With diazepam, the sigmoid curve shifts to the left (high affinity)
Gamma Amino Butyric Acid (GABA)
Agonist
Drug that can elicit response after interaction with receptor has intrinsic activity greater than zero (y>0)
Full agonist (graph)
Every receptor you bind, get some level of response, y=1. %response and receptor binding curves overlap
Partial Agonist (graph)
In case of opioids, you don’t want to give them full agonist (addiction, respiratory arrest…)
Y=0.5
Receptor binding is normal curve, % response curve is shifted to the right with a lower max plateau (lower drug receptor binding)
Spare Receptors (graph)
Rate limiting step can be downstream of receptor binding, doesn’t need to bind to all of the receptors to get a full response.
%response curve is shifted to the left with same max plateau
Receptor Antagonist
Drug that can bind to receptor but has y=0.
Occupies receptor but does not elicit response
Agonist and Competitive Antagonist Graph
Agonist + competitive antagonist sigmoid curve shifted to the right of just agonist curve: competes and overcomes agonist, binding to the same site.
Need more agonist to overcome bound antagonist for same response as just against with agonist alone.
Agonist and Noncompetitive Antagonist Graph
Agonist with noncompetitive antagonist sigmoid curve shifted to the right (same Kd) and lower max plateau than agonist sigmoid curve: inactive portion of receptors bound by antagonist, changes maximal response (lowers)
Therapeutic Examples of Noncompetitive Antagonist
Phenoxybenzamine: binds a-adrenergic receptors; blocks catecholamine-induced vasoconstriction, used to treat pheochromocytoma (tumor of adrenal medulla)
Aspirin: irreversibly acetylates cyclooxygenase; block prostaglandin synthesis
Losartan and Candesartan: act as both comp and noncomp antagonists at angiotensin type 1 receptors; maintains endothelial function in patients with non-insulin-dependent diabetes mellitus
Penicillins: covalently bind bacterial transpeptidases, involved in cell wall synthesis
Other Forms of Antagonism
Physiological
Therapeutic Windows (at some point get a decreased response)
Inverse Agonist
Receptor doesn’t need to be bound to have a response.
Binding of inverse agonist to a receptor that has constitutive (basal/ligand independent) activity results in inhibition of agonist-independent activity
Long term treatment with inverse agonist may lead to receptor up-regulation
Concept of agonist-directed trafficking of receptor signaling
Some receptors (GPCRs) have been shown to couple to more than one signal transduction pathway (more than one G-protein)
- Clinical Therapeutics Level: Quantal Dose-Response Curves
ED50=effective dose in 50% population (half people that show response at certain dose) # of responders vs Log Drug Dose Graph: Bell configuration (curve)
Comparing different drug bell curves (# of responders vs Log of drug dose graph)
Width of bell curve is inter patient variability. (Higher amplitude=smaller bell curve width)
Slide 51
A and C have similar variability, but takes less of A than C amount of drug for ED50 response
Same ED50 dose for B as A, but less variability in B than A.
Comparing different drug sigmoid curves (cumulative percent of population responding vs log drug dose graph)
Drug A and B E50 is the same dose (potency)
Drug C sigmoid curve is to the left of A and B and is thus less potent
Plateaus of each sigmoid curve is the efficacy of the drugs
Probit Scale vs. Log Drug Dose (conversion of sigmoid curves to linear curves; comparing new drugs A and B)
Drug A desired line, Drug A toxic line, Drug B desired line, Drug B toxic line (left to right, Drug B lines are more steep than A lines)
Drug A lines are flatter, thus if you draw 100% point of desired drug A line down, large percentage (60%) of people will have toxic side effects.
Drug B desired line drawn down has less people with toxic side effects
TI for A greater than TI for B
Therapeutic Index
TI=TD50/ED50
TD-toxic dose
ED-effective dose
Higher TI is better and implies safety generally
Margin of Safety
Margin of Safety=TD1/ED99
Summary Chart
1.Drug-Receptor Binding Reactions:
Affinity (Kd); Receptor Number (Rt)
2.Graded Biochemical Physiological Responses:
Affinity/potency; maximal response (REmax); intrinsic activity y (agonist, antagonist)
3. Quantal Responses:
Potency(ED50); Efficacy; biological variation; therapeutic index
