Week 1: Pharmacodynamics Flashcards

1
Q

Pharmacodynamics vs. Pharmacokinetics

A

Dynamics - what the Drug Does to the body Kinetics - what the body does to the drug

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2
Q

Working Definition of a Receptor (2 parts)

A

Working Definition: 1. BINDING site for drugs/endogenous substances 2. TRANSDUCES binding into BIOLOGICAL RESPONSE

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3
Q

Four Types of Drug Specificity

A
  1. Biological - types of tissue have different effects 2. Chemical - changing drug potency changes effects & stereospecificity changes effects 3. Selective Antagonism - specific antagonists may inhibit one agonist over another even if both activate identical pathways 4. Molecular Biology - cloning/sequencing/expression of receptors can be modified - leading to receptor subtype specificity
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4
Q

Enzyme Kinematics Changes for Competitive, Uncompetitive, Noncompetitive Inhibitors

A

Competitive - Increase Km, No change Vmax Noncompetitive - No change Km, Decrease Vmax Uncompetitive - Decrease Km, Decrease Vmax

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5
Q

Definition of EC50, Kd, Efficacy, Potency

A

EC50 - concentration of agonist that produces half-maximal biological response Kd - concentration of agonist that binds to half of all receptors - represents thermodynamic driving force (low Kd, easier to bind, low deltaG, more favorable rxn) Efficacy: ability of a drug to produce maximal biological response (~Vmax) Potency = 1/EC50 (highly potent drug has low effective concentration) FOR DRUG BINDING: Kd = EC50 FOR BIOLOGICAL REPONSE: Kd ~= EC50

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6
Q

Competitive Antagonist

A
  1. binds to orthosteric site (agonist binding site) 2. Complementary shape to receptor agonist for tighter fit 3. Overcome by increasing [agonist] 4. Decreases potency (Increases EC50) 5. No change to efficacy (max response) dose-response curve parallel shift to the right
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7
Q

Noncompetitive Antagonist

A
  1. binds irreversibly to orthosteric site, or binds to allosteric site and prevents activation 2. Reduces the number of available receptors without affecting agonist binding at others 3. Decreases efficacy (lower max response) 4. No Change to potency (EC50 constant)
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8
Q

Uncompetitive Antagonist

A
  1. allosteric binding to only activated receptors 2. low effect at low [agonist] due to small amount of activated channels 3. Decreases efficacy (lower max response) 4. Increases potency (lower EC50)
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9
Q

Full Agonist

A

produces maximal biological response in both quiescent and constitutively active systems

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10
Q

Partial Agonist

A
  1. Binds to same site as full agonist but gives partial response in both quiescent and constitutively active systems 2. Acts as competitive antagonist for the full agonist
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11
Q

Inverse Agonist

A
  1. produces no effect on quiescent systems; acts as a competitive antagonist on quiescent systems 2. reduces activity of constitutively active receptors (turns them off - useful in cancers and viral infections)
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12
Q

Spare Receptors

A

Why EC50 ~= Kd for biological response, because there are more receptors than necessary to achieve maximal response 1. at low doses of antagonist, noncompetitive behaves identical to competitive because reducing the number of receptors does not reduce max response (no change in efficacy) 2. Delineate between noncompetitive and competitive by increasing [antagonists], eventually noncompetitive will have an effect

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13
Q

4 types of cooperativity and 2 models of cooperativity

A
  1. Cooperative binding - binding of 1 mLc increases binding of another (Hb O2) 2. Independent binding, but requires >1 mLc to activate (MOST CHANNEL RECEPTORS) 3. Cooperative relationship between binding and response - multiple active states possible depending on what is bound 4. Receptors exist as subunits A. constrained model - all subunits are inactivated or activated together - 2 states exist in equilibrium, and agonist binding LeChatlier shifts equilibrium toward active state B. Sequentially Activated model - different ligands induce specific conformational shapes - full agonists open the channel widest, partial agonists open channel less widely
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14
Q

Quantal-Dose Response Curve

A

quantifies all-or-none responses (pregnancies, deaths, seizures, etc.), typically a cumulative curve, used to identify therapeutic index

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15
Q

ED50, LD50, TI

A

ED50 - median effective dose - 50% of population gets desired effect at dosage LD50 - median lethal dose - 50% of population dies at dosage TI - Toxic ED50 / Beneficial ED50: measure of drug safety Wide TI - safer drug

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16
Q

Electrical & Molecular Basis for Resting Membrane Potential

A

Balance between 1. Concentration Gradient (chemical potential) 2. Electrostatic Forces (electrical potential)

17
Q

Equilibrium Potential (Equation) & Key Ion Equilibrium Potentials

A

Nernst Equation: membrane voltage where there is zero net ion flow Na: IC - 12mM; EC - 145 mM; E - +66mV K: IC - 140mM; EC - 4mM; E - -95mV Cl: IC - 10mM; EC - 110mM; E - -64mV Ca: IC - 0.0001mM; EC - 2.5mM; E - +135mV

18
Q

What determines resting membrane potential

A
  1. Ion Transports create ion gradients (Na-K ATPase: 3Na out, 2K in - requires 1 ATP) 2. Leak Channels control ion permeability (Na leak depolarizes; K leak hyperpolarizes and dominates, bringing Vrest close to Ek; Cl leak contributes least but used as buffer for any big changes)
19
Q

3 Types of Graded Potentials

A

Transient change in Vm by NTs that open up ion channels - inputs are summed together 1. EPSP: excitatory, depolarizing 2. EPP: where motor neuron interfaces skeletal muscle, always depolarizing 3. IPSP: inhibitory, hyperpolarizing

20
Q

Skeletal/Neuronal Action Potential (Steps & Propagation)

A

Steps: 1. synaptic signals sum to depolarize region of membrane above Vthresh 2. Opening of V-gated Na channels - rapid depolarization toward ENa 3. Rapid inactivation of Na channels (major reason for refractory period) 4. Delayed activation of V-gated K channels (repolarization & hyperpolarization toward Ek) 5. K channels close, Na channels go from inactivated to close, Na-K ATPase & leak channels restore Vrest Propagation: APs jump from Nodes of Ranvier across myelin sheaths of axons

21
Q

Two types of Refractory Periods in Neuronal & Skeletal AP

A
  1. Absolute - impossible to trigger 2nd AP when Na channels are inactivated 2. Relative - 2nd AP requires stronger stimulus, when Vm hyperpolarized, incomplete Na channel recovery, residual active K channels
22
Q

Cardiac Action Potential (Steps)

A

Phase 0: initiation - localized change in Vm activates V-gated Na channels for rapid depolarization Phase 1: Na channels inactivate, activation of fast V-gated K channels (outward repolarization), V-gated L-type Ca channels activate Phase 2: Plateau phase - depolarizing L-type Ca & residual Na channels & emerging repolarizing K channels Phase 3: K channel repolarization dominates net flow Phase 4: inward rectifying K current helps repolarize cardiac myocytes back to Vrest

23
Q

Causes of Long QT Syndrome

A
  1. Ion imbalance 2. Ventricles depolarize too long due to extended APs - occurs in K channel blocker drugs
24
Q

Experiments 1. What happens to AP when you decrease EC Na concentration? 2. What happens to AP when you increase EC K concentration?

A
  1. Smaller AP peak and less steep depolarization due to less Na influx 2. Hyperexcitability due to depolarizing Vrest by changing K Nernst Potential
25
Q

Epithelial Cells (Definition, Properties, Directions of Transport, Types, Key Features)

A
  1. monolayer sheets, 1st barrier to enter, final barrier to leave (intestine lining, renal tubules, intrahepatic biliary) 2. tight junctions - cell adhesion domain in epithelial sheets (segregates membrane into apical-lumen and basal-interstitium side, creates asymmetric division, enabling unidirectional flow with unique domain transporters) 3. Absorption (from apical to basolateral); Secretion (from basolateral to apical); Cellular (through epithelial cell); Paracellular (between cells) 4. Leaky (low resistance to flow, no TM potential, bulk movement flow - small intestine + PT); Tight (high resistance to flow, TM potential - colon + CD) 5. Microvilli on apical side expand surface area which increase absorption on apical side
26
Q

Endothelial Cells (Definition, Types)

A
  1. Lines Blood Vessels + Capillaries 2. Continuous: little space b/w cells (BBB - also has glial architecture and tight junctions to further reduce transport) 3. Fenestrated: holes in cells due to cytoplasmic branching (most organs for leaky fluid movement) 4. Sinusoidal: large intercellular gaps, very leaky (spleen + bone marrow where whole cells need to move)
27
Q

Passive Diffusion (Types, Methods)

A
  1. Lipid soluble drugs diffuse freely (rate depends on concentration and lipid solubility coefficient) 2. Aqueous diffusion - through fenestrations and paracellular junctions - very slow 3. AQPs - family of water channels through lipid bilayer 4. pH-dependence: diffuse in non-ionized form
28
Q

Henderson-Hasselbach Equation (Acids v. Bases, Trapping)

A

pKa - pH = log([protonated]/[non-protonated]); Acids: protonated = anionic form Bases: protonated = cationic form Trapping occurs when one side of membrane has different pH than the other when environment pH is lower than drug pKa, the excess protons react with drug so majority is protonated