4/17/2016. General Principles. Pharmacologic Principles. Dose-Response Curve. Threshold. Ceiling BASICS

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1 Pharmacologic Principles i.e., totally geeky nerdy boring yucky but important stuff Bart Johnson, DDS MS General Principles Basics Receptor Theory Absorption Distribution Redistribution Metabolism Elimination BASICS Dose-Response Curve Threshold Ceiling Threshold Ceiling Giving too little drug will not elicit a clinical response Need to start with a sufficient amount This can vary from patient to patient After a certain dose, giving more drug is worthless, or dangerous Benefit is no greater, but side effects increase Stay below maximums to be safe 1

2 Agonists Full: Can produce ceiling/maximal effects Partial: Cannot produce ceiling/ maximal effects Less intrinsic efficacy Agonist-Antagonist Occurs when a partial agonist displaces a full agonist Antagonizes the full effect Antagonists Competitive Binds at same active site as the agonist No intrinsic activity Can be out-competed by adding more agonist Antagonists Noncompetitive Binds nearby and alters the receptor so the agonist cannot bind - or Irreversibly binds to the active site Potency Classically: Denotes receptor affinity Potency Sedatives: More likely a measure of lipid solubility 2

3 Receptors Ligands bind the receptors RECEPTOR THEORY Receptors Conformational change occurs Twists, loops, cuts, splices, warps, bends Dimerizes Translocates Kicks off repressors Binds activators Receptors Then magically something else happens Receptor Interaction Questions Does initial drug binding increase additional drug binding? Receptor Interaction Questions Tissue variability: Does the same receptor act the same in different tissues? Does the ligand sit and stay? Does it bind/ unbind/ bind again? Does speed matter? How much variability is there among individuals? 3

4 Oral ABSORPTION The inside of your gut is still outside your body Oral Slowest (assume minutes) Requires planning Safest Least likelihood of allergic reaction Flat drug absorption profile Need patient compliance / ability Oral Least predictable Hepatic first pass effect Rate of gastric emptying Better absorbed in acid? Keep drug in stomach = Take with food Better absorbed in neutral ph? Move drug quickly through stomach and into intestine = Take with water and no food IM Capillary absorption Governed by: Lipid/water solubility Particle size Ionization Deltoids/Quads best Tongue not so good IM Do not give insoluble drugs or dextrose Diazepam crystallizes Dextrose pulls water out of cells Mild control over rate of absorption Can increase rate by exercise / heat Can decrease rate by ice / tourniquet Practically, this is rarely done Highest incidence of allergic reactions 4

5 IV Considered the gold standard Bypasses gut and hepatic first pass issues Can titrate!! Greatest control Little danger Line serves as emergency access Subcutaneous (SQ) Best for < 2 ml volume Similar to absorption in resting muscle Epi is our only typical SQ drug in dentistry Transmucosal Sublingual Intranasal (Rectal) DISTRIBUTION Avoids gut and hepatic first pass issues Fairly high rate of absorption Where can drugs go? All sedative agents must go into the bloodstream for transport to the brain Considerations: Water solubility Carrier proteins Plasma protein binding Plasma Proteins Albumin Fibrinogen Immunoglobulins (IgG, IgM, etc.) Provides oncotic pressure = thickens the blood 5

6 The Albumin Bus Albumin sponges up free drug Bound drug is unavailable = ineffective Only the unbound drug gives the effect The Albumin Bus Many sedative medications are highly plasma protein bound Example: Midazolam = 97% PPB 97% useless 3% sedates The IMPORTANT Concept: Changes in the bus system greatly affect clinical outcomes Three main changes occur: How many riders want seats How many buses are available Other drugs competing for seats Changes to PP Binding Doses First dose mostly fills seats Second dose gives more free (active) drug GO LOWER ON SECOND DOSES!! Changes to PP Binding Physiologic changes to albumin content Disease Cancer Emaciation Liver disease Any of the protein wasting syndromes Age Anyone > 60 y/o may have reduced albumin Changes to PP Binding Other drugs Already occupy seats on the bus Your first dose = more potent Displace bound drug Increased relative dose Other drugs may displace your sedative or Your sedative may displace other drugs! 6

7 Pharmacologic Phish REDISTRIBUTION Imagine 3 interconnected aquariums Left and Center connect via large tube Center and Right connect via a small tube Fish can be added to and removed from the center aquarium only Pharmacologic Phish Let s add Phish Pharmacologic Phish Within seconds to minutes Pharmacologic Phish In minutes to tens of minutes Pharmacologic Phish Over minutes to hours 7

8 Pharmacologic Phish Key Points Adding more Phish Drugs move to highly vascular spaces first Brain Heart Lungs Liver Key Points Over time, they move to lightly vascular spaces and get trapped Adipose Muscle cells Key Points Clinical recovery occurs more due to redistribution than metabolism/excretion Drugs are in the body much longer than we see Need for after-care May get rebound effect Key Points First doses are filling reservoirs Second doses are only replacing lost phish = Second doses need to be much smaller! METABOLISM / EXCRETION 8

9 drug plasma concentration 4/17/2016 T ½ Half-life is a measure of how long the body takes to eliminate half the drug Alpha T ½ : Clinical Effect Beta T ½ : True elimination Comparison Redistribution (a -T ½ ) Metabolism/excretion (b -T ½ ) Cmax 5 T ½ s are considered necessary to have full recovery 100% - 50% - 25% - 12% - 6% - 3% Tmax drug administration time Metabolism Cytochrome P450 system Oxidative metabolism Converts lipophilic substances to be more hydrophilic or amphipathic Metabolism May have active metabolites Diazepam / Oxazepam / Temazepam Occurs in Liver and BV endothelium Excretion Moved to bowel via bile Removed to urine via kidneys Excreted to atmosphere via lungs PHARMACOKINETICS 9

10 General Concept O Lipophilia, Lipophilia! Wherefore art thou, Lipophilia? Gotta cross lipid fences Lipid Membranes Exist all over the body Blood-Brain Barrier is lipid All cells have a lipid membrane Nuclei have lipid membranes To get a drug into the brain cells, MUST cross lipid structures Crossing Lipid Barriers Passive Diffusion Lipophilic move fastest Non-ionic Lipid chains Ring structures Hydrophilic move slowest Ionic Polar groups Crossing Lipid Barriers Completely lipophilic drugs go into the membrane but fail to come out Lipid trapping Renders drug useless Crossing Lipid Barriers Channels Small molecules move fastest Large molecules move slowest 10

11 Crossing Lipid Barriers Why does this matter? Carriers Active Requires Energy Passive So much of the Personality of each sedative agent is linked to understanding its relative lipophilia vs. hydrophilia When you know this, you can make better clinical choices! Lipophilic vs. Hydrophilic Onset time: Lipophilic = Fast Hydrophilic = Slow Lipophilic vs. Hydrophilic Duration of Effect: Lipophilic = Short duration Hydrophilic = Long duration Alters when you give the drug prior to your dental treatment Impacts how long the drug will clinically be effective Do you want a short acting drug? Do you want one that will last? Lipophilic vs. Hydrophilic Tissue Irritation: Lipophilic = More irritation when injected Hydrophilic = Less irritation when injected Alters how the manufacturer packages the drugs May affect your decision-making Lipophilic vs. Hydrophilic Side Effects: Lipophilic = Less side effects (Zips right into brain) Hydrophilic = More side effects (Hangs out in the periphery, finds other fun things to do) In reality, not usually a problem with sedatives 11

12 Lipophilic vs. Hydrophilic Ideal Drugs Combine Hydrophilia with Lipophilia! Yes, these drugs exist REVIEW OF PREGNANCY RISK CATEGORIES Category A: Controlled studies performed in pregnant women No risk in first trimester No risk in later trimesters Possibility of fetal harm appears remote Examples: Levothyroxine Folic Acid Vitamin B Category B: Animal studies show no evidence of fetal risk, but no human controlled studies have been performed -or- Animal studies show an adverse effect, but it is not confirmed in pregnant women during the first or later trimesters Examples: Acetaminophen Lidocaine Penicillin VK Clindamycin 12

13 Category C: Animal studies show a teratogenic or embryocidal effect, but no human controlled studies have been performed -or- Studies in pregnant women or animals are not available Examples: Zolpidem Ibuprofen Articaine Morphine Aspirin Drugs should only be given if benefit justifies the fetal risk Category D: Positive evidence of fetal risk, but benefits may make drug acceptable despite risks May be used in life-threatening situations or serious disease Examples: Midazolam Diazepam Lorazepam Alprazolam Category X: Data clearly shows fetal abnormalities and the risk of using the drug in pregnant women clearly outweighs any possible benefit. Examples: Retinoic Acid Thalidomide Triazolam The drug is contraindicated in any woman who is or may become pregnant. 13

14 Understand your drugs! SUMMARY These totally geeky nerdy boring yucky but important points make a big difference! Make decisions keeping them in mind Your patients will be safer Your outcomes will be better Your personal risk to your practice will be lower We ll discuss specific examples in the upcoming lectures THANK YOU! 14