Pharmacology Pharmacology Pharmacokinetics Pharmacokinetics Pharmacodynamics Pharmacodynamics
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Pharmacokinetics Pharmacokinetics •• Time Time course course of of drug drug absorption, absorption, distribution, distribution, metabolism, metabolism, excretion excretion How How the the drug drug comes comes and and goes. goes.
Pharmacokinetic Pharmacokinetic Processes Processes “LADME� is key Liberation Liberation Absorption Absorption Distribution Distribution
Metabolism Metabolism Excretion Excretion
Liberation Liberation •• ••
Applies Applies to to drugs drugs given given orally orally Components Components –– Release Release of ofdrug drug from frompill, pill, tablet, tablet, capsule capsule –– Dissolving Dissolving of of active active drug drug in in GI GI fluids fluids
Ex: Ex: Enteric Enteric coated coated aspirin aspirin slows slows absorption absorption in in stomach stomach vs vs non-coated non-coated
Absorption Absorption •• Movement Movement from from administration administration site site into into circulation circulation
Factors Factors Affecting Affecting Liberation/Absorption Liberation/Absorption •• Formulation Formulation factors factors –– Tablet Tabletdisintegration disintegration –– Inert Inertingredient ingredient// solvent solventeffects effects –– Solubility Solubility –– Drug DrugpH pH –– Concentration Concentration
•• Patient Patient factors factors –– Absorbing Absorbingsurface surface –– Blood Bloodflow flow –– Environmental EnvironmentalpH pH –– Disease Diseasestates states –– Interactions Interactionswith withfood, food, other otherdrugs drugs
Membranes Membranes and and Absorption Absorption Hydrophilic Hydrophilic Heads Heads
Lipid Bilayer Hydrophobic Hydrophobic Tails Tails
Small, uncharged
H2O, urea, CO2, O2, N2
Swoosh!
Large, uncharged
Glucose Sucrose
DENIED!
Small charged ions
H+, Na+, K+, Ca2+, Cl-, HCO3-
DENIED!
LaChatlier’s LaChatlier’s Principle Principle a.k.a. a.k.a. Mass Mass Action Action System System at at Equilibrium Equilibrium 4 Na+
+ 4 Cl_
A A reaction reaction at at equilibrium equilibrium responds responds to to stress stress in in aa way way to to best best return return to to equilibrium equilibrium
4 NaCl
4. 3. System returns responds to stress 4. System System 3.2. 1. System Stress System returns applied responds at to equilibrium! to equilibrium! to system stress 2. 1. Stress System applied at equilibrium equilibrium toto system
⇑ by 4 84 Na 4 +
System not System not at at of An example equilibrium! equilibrium! LaChatlier’s Principle
+
4 NaCl dissociate
84 Cl-
⇑ by 48 ⇓
12 84 NaCl NaCl
Ionization Ionization Acids Acids HA Bases Bases H+ + B-
++ Release/Donate H Release/Donate H
H+ + A -
Ionized Ionized form form
++ Bind/Accept H Bind/Accept H
HB
Non-ionized Non-ionized form form
Environmental Environmental pH pH and and Ionization Ionization If If we we put put an an acidic acidic drug drug in in an an environment environment with with aa lot lot of of H H++ (low (low pH) pH) what what will will this this equilibrium equilibrium do? do?
HA HA HA HA
HA
H+ + A -
++ System Equilibrium ⇑ H acid environment Non-ionized form predominates! at Equilibrium ⇑ System H from fromat acid environment Non-ionized form predominates!
A A real real live, live, actual actual clinical clinical question... question... Aspirin Aspirin isis an an acidic acidic drug. drug. In In the the stomach stomach will will itit exist exist mostly mostly in in ionized ionized or or non-ionized non-ionized form? form? NON-IONIZED Why? Why?
How How will will this this affect affect aspirin aspirin absorption? absorption? Lipid Bilayer Ionized Ionizedform form (charged) (charged)
A-
Ionized Ionizedform form (uncharged) (uncharged)
HA
HA
Moral Moral of of the the story... story... Acidic Acidic drugs drugs are are best best absorbed absorbed from from acidic acidic environments environments Basic Basic drugs drugs are are best best absorbed absorbed from from basic basic environments environments
So... So... To To ⇑⇑ absorption absorption of of an an acidic acidic drug… drug… acidify acidify the the environment environment To To ⇓⇓ absorption absorption of of an an acidic acidic drug… drug… alkalanize alkalanize the the environment... environment...
Distribution Distribution •• •• •• ••
Rate Rate of of perfusion perfusion Plasma Plasma protein protein (albumin) (albumin) binding binding Accumulation Accumulation in in tissues tissues Ability Ability to to cross cross membranes membranes –– Blood-brain Blood-brain barrier barrier –– Placental Placental barrier barrier
Plasma Plasma Protein Protein Binding Binding warfarin warfarin (Coumadin) (Coumadin) isis highly highly protein protein bound bound (99%). (99%). Aspirin Aspirin binds binds to to the the same same site site on on serum serum proteins proteins as as does does Coumadin. Coumadin. If If aa patient patient on on Coumadin Coumadin also also takes takes aspirin, aspirin, what what will will happen? happen? 1) 1) Why? Why? The available Coumadin will 2) do 2) Why Why do we we care? care? increase.
Blood-Brain Blood-Brain Barrier Barrier The The blood blood brain brain barrier barrier consists consists of of cell cell tightly tightly packed packed around around the the capillaries capillaries of of the the CNS. CNS. What What characteristics characteristics must must aa drug drug possess possess to to easily easily cross cross this this barrier? barrier? Non-protein bound, non-ionized, Why? Why? and highly lipid soluble
Metabolism Metabolism (Biotransformation) (Biotransformation) •• Two Two effects effects –– Transformation Transformation to to less less active activemetabolite metabolite –– Enhancement Enhancement of of solubility solubility
•• ••
Liver Liver == primary primary site site Liver Liver disease disease –– Slows Slows metabolism metabolism –– Prolongs Prolongs effects effects
Hepatic Hepatic ‘First-Pass’ ‘First-Pass’ Metabolism Metabolism •• •• ••
••
Affects Affects orally orally administered administered drugs drugs Metabolism Metabolism of of drug drug by by liver liver before before drug drug reaches reaches systemic systemic circulation circulation Drug Drug absorbed absorbed into into portal portal circulation, circulation, must must pass pass through through liver liver to to reach reach systemic systemic circulation circulation May May reduce reduce availability availability of of drug drug
Elimination Elimination •• Kidneys Kidneys == primary primary site site –– Mechanisms Mechanisms dependent dependent upon: upon: •• Passive Passiveglomerular glomerularfiltration filtration •• Active Activetubular tubulartransport transport
–– Partial Partial reabsorption reabsorption –– Hemodialysis Hemodialysis
•• Renal Renal disease disease –– Slows Slows excretion excretion –– Prolongs Prolongs effects effects
Active Active Tubular Tubular Transport Transport Probenecid Probenecid isis moved moved into into the the urine urine by by the the same same transport transport pump pump that that moves moves many many antibiotics. antibiotics. Why Why isis probenecid probenecid sometimes sometimes given given as as an an adjunct adjunct to to antibiotic antibiotic therapy? therapy? It competes with the antibiotic at the pump and slows its excretion.
Urine Urine pH pH and and Elimination Elimination A A patient patient has has overdosed overdosed on on phenobartital. phenobartital. Phenobarbital Phenobarbital isis an an acid. acid. If If we we ‘alkalinalize’ ‘alkalinalize’ the the urine urine by by giving giving bicarbonate bicarbonate what what will will happen happen to to the the phenobarbital phenobarbital molecules molecules as as they they are are filtered filtered through through the the renal renal tubules? tubules? They will ionize...
How How will will this this affect affect phenobarbital phenobarbital reabsorption reabsorption by by the the kidney? kidney? Non-ionized
HA
Ionized
H+ + A -
Decreased Decreased reabsorption reabsorption Increased Increased elimination elimination
Elimination Elimination •• Other Other sources sources –– Feces Feces –– Exhaled Exhaled air air –– Breast Breast milk milk –– Sweat Sweat
Biological ) Biological Half-life Half-life (t(t 1/2 1/2) •• Amount Amount of of time time to to eliminate eliminate 1/2 1/2 of of total total drug drug amount amount •• Shorter Shorter tt 1/21/2 may may need need more more frequent frequent doses doses •• Hepatic Hepatic disease disease may may increase increase tt1/21/2
AA drug drug has has aa half half life life of of 10 10 seconds. seconds. You You give give aa patient patient aa dose dose of of 6mg. 6mg. After After 30 30 seconds seconds how how much much of of the the drug drug remains? remains? Time Time
Amount Amount
00 sec sec
66 mg mg
10 10 sec sec
33 mg mg
20 20 sec sec
1.5 1.5 mg mg
30 30 sec sec
0.75 0.75 mg mg
Administration Administration Routes Routes •• Intravenous Intravenous –– Fastest, Fastest, Most Most dangerous dangerous
•• Endotracheal Endotracheal –– Lidocaine, Lidocaine, atropine, atropine, narcan, narcan, epinephrine epinephrine
•• Inhalation Inhalation –– Bronchodilators Bronchodilators via via nebulizers nebulizers
•• Transmucosal Transmucosal –– Rectal Rectal or or sublingual sublingual
Administration Administration Routes Routes •• Intramuscular Intramuscular –– Depends Depends on on perfusion perfusion quality quality
•• Subcutaneous Subcutaneous –– Depends Depends on on perfusion perfusion quality quality
•• Oral Oral –– Slow, Slow, unpredictable unpredictable –– Little Little prehospital prehospital use use
Pharmacodynamics Pharmacodynamics •• The The biochemical biochemical and and physiologic physiologic mechanisms mechanisms of of drug drug action action What What the the drug drug does does when when itit gets gets there. there.
Drug Drug Mechanisms Mechanisms •• ••
Receptor Receptor interactions interactions Non-receptor Non-receptor mechanisms mechanisms
Receptor Receptor Interactions Interactions Lock and key mechanism
Agonist
Receptor
Agonist-Receptor Interaction
Receptor Receptor Interactions Interactions Induced Fit
Receptor
Perfect Fit!
Receptor Receptor Interactions Interactions Competitive Inhibition
Antagonist
Receptor
DENIED!
Antagonist-Receptor Complex
Receptor Receptor Interactions Interactions Non-competitive Inhibition
Agonist
Antagonist
Receptor
DENIED!
‘Inhibited’-Receptor
Non-receptor Non-receptor Mechanisms Mechanisms •• Actions Actions on on Enzymes Enzymes –– Enzymes Enzymes == Biological Biological catalysts catalysts •• Speed Speedchemical chemicalreactions reactions •• Are Arenot notchanged changedthemselves themselves
–– Drugs Drugs altering altering enzyme enzyme activity activity alter alter processes processes catalyzed catalyzed by by the the enzymes enzymes –– Examples Examples •• Cholinesterase Cholinesteraseinhibitors inhibitors •• Monoamine Monoamineoxidase oxidaseinhibitors inhibitors
Non-receptor Non-receptor Mechanisms Mechanisms •• Changing Changing Physical Physical Properties Properties –– Mannitol Mannitol –– Changes Changes osmotic osmotic balance balance across across membranes membranes –– Causes Causes urine urine production production (osmotic (osmotic diuresis) diuresis)
Non-receptor Non-receptor Mechanisms Mechanisms •• Changing Changing Cell Cell Membrane Membrane Permeability Permeability –– Lidocaine Lidocaine •• Blocks Blockssodium sodiumchannels channels
–– Verapamil, Verapamil, nefedipine nefedipine •• Block Blockcalcium calciumchannels channels
–– Bretylium Bretylium •• Blocks Blockspotassium potassiumchannels channels
–– Adenosine Adenosine •• Opens Openspotassium potassiumchannels channels
Non-receptor Non-receptor Mechanisms Mechanisms •• Combining Combining With With Other Other Chemicals Chemicals –– Antacids Antacids –– Antiseptic Antiseptic effects effects of of alcohol, alcohol, phenol phenol –– Chelation Chelation of of heavy heavy metals metals
Non-receptor Non-receptor Mechanisms Mechanisms •• Anti-metabolites Anti-metabolites –– Enter Enter biochemical biochemical reactions reactions in inplace place of ofnormal normal substrate substrate “competitors” “competitors” –– Result Result in in biologically biologically inactive inactive product product –– Examples Examples •• Some Someanti-neoplastics anti-neoplastics •• Some Someanti-infectives anti-infectives
Drug Drug Response Response Relationships Relationships •• ••
Time Time Response Response Dose Dose Response Response
Time Time Response Response Relationships Relationships Maximal (Peak) Effect
Effect/ Response
Latency
Duration of Response
Time
Time Time Response Response Relationships Relationships
IV
IM
SC
Effect/ Response
Time
Dose Dose Response Response Relationships Relationships •• Potency Potency –– Absolute Absolute amount amount of of drug drug required required to to produce produce an an effect effect –– More More potent potent drug drug isis the the one one that that requires requires lower lower dose dose to to cause cause same same effect effect
Potency Potency A
B Therapeutic Effect
Effect
A! Why? A! Why? Dose Which drug is more potent?
Dose Dose Response Response Relationships Relationships •• Threshold Threshold (minimal) (minimal) dose dose –– Least Least amount amount needed needed to to produce produce desired desired effects effects
•• Maximum Maximum effect effect –– Greatest Greatest response response produced produced regardless regardless of of dose dose used used
Dose Response Relationships B A Therapeutic Effect
Effect
Dose Which drug has the lower threshold dose? Which has the greater maximum effect?
A A BB
Dose Dose Response Response Relationships Relationships •• Loading Loading dose dose –– Bolus Bolus of of drug drug given given initially initially to to rapidly rapidly reach reach therapeutic therapeutic levels levels
•• Maintenance Maintenance dose dose –– Lower Lower dose dose of of drug drug given given continuously continuously or or at at regular regular intervals intervals to to maintain maintain therapeutic therapeutic levels levels
Therapeutic Therapeutic Index Index •• •• •• ••
Drug’s Drug’s safety safety margin margin Must Must be be >1 >1 for for drug drug to to be be usable usable Digitalis Digitalis has has aa TI TI of of 22 Penicillin Penicillin has has TI TI of of >100 >100
LD50 TI = ED50
Therapeutic Therapeutic Index Index Why Why don’t don’t we we use use aa drug drug with with aa TI TI <1? <1?
ED50 ED50 << LD50 LD50 == Very Very Bad! Bad!
Factors Factors Altering Altering Drug Drug Responses Responses •• Age Age –– Pediatric Pediatric or or geriatric geriatric –– Immature Immature or or decreased decreased hepatic, hepatic, renal renal function function
•• Weight Weight –– Big Big patients patients “spread” “spread” drug drug over over larger larger volume volume
•• Gender Gender –– Difference Difference in in sizes sizes –– Difference Difference in in fat/water fat/water distribution distribution
Factors Factors Altering Altering Drug Drug Responses Responses •• Environment Environment –– Heat Heat or or cold cold –– Presence Presence or or real real or or perceived perceived threats threats
•• ••
Fever Fever Shock Shock
Factors Factors Altering Altering Drug Drug Responses Responses •• Pathology Pathology –– Drug Drug may may aggravate aggravate underlying underlying pathology pathology –– Hepatic Hepatic disease disease may may slow slow drug drug metabolism metabolism –– Renal Renal disease disease may may slow slow drug drug elimination elimination –– Acid/base Acid/base abnormalities abnormalities may may change change drug drug absorption absorption or or elimination elimination
Influencing Influencing factors factors •• Genetic Genetic effects effects –– Lack Lack of of specific specific enzymes enzymes –– Lower Lower metabolic metabolic rate rate
•• Psychological Psychological factors factors –– Placebo Placebo effect effect
Pediatric Pediatric Patients Patients •• ••
Higher Higher proportion proportion of of water water Lower Lower plasma plasma protein protein levels levels –– More More available available drug drug
•• Immature Immature liver/kidneys liver/kidneys –– Liver Liver often often metabolizes metabolizes more more slowly slowly –– Kidneys Kidneys may may excrete excrete more more slowly slowly
Geriatric Geriatric Patients Patients •• •• •• ••
Chronic Chronic disease disease states states Decreased Decreased plasma plasma protein protein binding binding Slower Slower metabolism metabolism Slower Slower excretion excretion
•• ••
Dietary Dietary deficiencies deficiencies Use Use of of multiple multiple medications medications •• Lack Lack of of compliance compliance
Web Web Resources Resources •• Basic Basic Pharmacokinetics Pharmacokinetics on on the the Web Web –– http://pharmacy.creighton.edu/pha443/pdf/Defa http://pharmacy.creighton.edu/pha443/pdf/Defa ult.asp ult.asp
•• Merk Merk Manual: Manual: Overview Overview of of Drugs Drugs –– http://www.merck.com/pubs/mmanual_home/se http://www.merck.com/pubs/mmanual_home/se c2/5.htm c2/5.htm
Web Web Resources Resources •• Merk Merk Manual: Manual: Factors Factors Affecting Affecting Drug Drug Response Response –– http://www.merck.com/pubs/mmanual_home/se http://www.merck.com/pubs/mmanual_home/se c2/8.htm c2/8.htm
•• Merk Merk Manual: Manual: Pharmacodynamics Pharmacodynamics –– http://www.merck.com/pubs/mmanual_home/se http://www.merck.com/pubs/mmanual_home/se c2/7.htm c2/7.htm
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