DDS 6216 Dental Pharmacology Principles PDF

Colin Campbell, Ph.D. NHH, 3-130 625-8986 [email protected] DDS 6216 Dental Pharmacology...

Colin Campbell, Ph.D. NHH, 3-130 625-8986 [email protected] DDS 6216 Dental Pharmacology Principles: Pharmacokinetics 1 and 2 OBJECTIVES 1. Understand the biological, chemical and physical processes that determine how drugs are absorbed and distributed into and throughout the human body 2. Understand the biological, chemical and physical processes that determine how drugs are metabolized and/or excreted from the body 3. Understand the following basics concepts: bioavailability, volume of distribution, drug clearance, drug half-life, zero and first-order elimination, steady state drug concentration, and loading doses No Relevant Financial Interests Any mention of drugs by their brand names is for educational purposes only and should not be considered an endorsement for any specific product Pharmaco-dynamics Farmakos dunamis -The study of the biochemical and physiological effects of xenobiotics on living systems. ‘The effect of drugs on the body’ Pharmaco-kinetics Farmakos kineo-The study of the biological, physical and chemical processes that are responsible for changes observed in xenobiotic concentration in the blood over time following administration. ‘The effect of the body on drugs’ Absorption 1. drugs in aqueous solution 2. drugs and lipid bilayers Distribution 1. body compartments 2. specialized capillary beds 3. routes of drug administration ‘ADME’ Metabolism 1. Phase I metabolism 2. Phase II metabolism Excretion EXCRETION 1. Renal 2. Biliary 3. ‘Other’ Absorption-process of xenobiotic gaining entry into body-not relevant when drugs are delivered parenterally. Understand the factors that influence xenobiotic absorption. Lipid partition coefficient (LPC)= conc. Drug (Octanol phase)/ conc. Drug (Aqueous phase) Some refer to this as lipid/water partition coefficient DRUG DRUG Doctanol Octanol Agitate/equilibrate Octanol Water Water Dwater Drugs with higher LPC preferentially accumulate in the octanol phase compared to drugs with lower LPC. Drugs with higher LPC typically cross biological membranes more efficiently than drugs with lower LPC-WHY?  Drugs and lipid bilayers Cell membrane is chemically similar to the octanol phase in previous slide-drugs that preferentially accumulate in octanol phase are likely to have enhanced solubility in the plasma membrane relative to drugs that preferentially accumulate in aqueous phase Aqueous phase (Cell exterior) Organic phase (Cell membrane) Aqueous phase (Cell interior) Drugs that are able to partition between aqueous and organic phase (and back again) are more able to cross biological membranes.  Influence of pH on drug absorption For weak acids and weak bases, the nonionized form of the molecule is typically much more efficiently absorbed across membranes.  Drugs and lipid bilayers Passive diffusion versus carrier mediated transport Passive diffusion: can’t be saturated, can’t be competed. Favors small, un-charged molecules with relatively high LPC. Driven by concentration gradient Carrier mediated (Facilitated diffusion and active transport): can be saturated, can be competed. Individual carrier molecules exhibit selectivity, i.e. preference for one or more molecules over others Facilitated diffusion is energy-independent, i.e. driven by concentration gradient Passive Facilitated Active Diffusion Diffusion Transport Active transport is energy-dependent, can move molecules against conc. gradient Absorption, distribution, and excretion can occur via carrier mediated, and non- carrier mediated processes. Understand role of transporters; essential difference between carrier and non-carrier mediated transport. Schematic representation of biological transport molecules. Clinical Significance: broad tissue distribution of these molecules influences drug absorption, distribution and excretion. Giacomini KM (2010) Nature Reviews Drug Discovery  Drug Distribution-Compartments Intravascular space (~5%) Intracellular space (~40%) Primary Interstitial space (~15%) Other: adipose, bones/teeth, keratinized tissue Why is distribution therapeutically important? 1.Drugs typically administered at sites distant from their site of action, 2.Drugs can accumulate differentially in different compartments. Drug Distribution-Compartments Why is distribution therapeutically important? 1.Drugs typically administered at sites distant from their site of action, 2.Drugs can accumulate differentially in different compartments.  Drug Distribution: Effect of protein binding Plasma Tissue Bound Drug Bound Drug Free Drug Free Drug Clinical significance: For many important therapeutics a significant fraction of drug is bound to proteins, not freely soluble. Clinical significance: distribution of THC in various compartments, not metabolism or excretion is responsible for duration of action. (Note transient, elevated accumulation in brain shortly after administration.) Schematic depiction of cellular architecture at/surrounding CNS capillary bed. Clinical significance: blood-borne xenobiotics must cross multiple cellular membrane To gain access to brain. Blood Brain Barrier. Front. Pharmacol., 15 November 2013 | doi: 10.3389/fphar.2013.00140  Routes of Drug Administration Enteral – Oral (bioavailability, first pass effect, variable absorption) – Sub-lingual (avoids first pass effect-limited by LPC) – Rectal (avoids first pass effect, other benefits/costs) Parenteral – Intravenous (Intravascular) – Intramuscular – Subcutaneous – Other Inhalation Transdermal Be familiar with major routes of administration and relative pros/cons associated with each  Drug Metabolism ‘Biotransformation’ ‘Detoxification’-Ethanol Decrease biological half-life Prodrug activation Procarcinogen activation Increase biological half-life Complexity Drug-Drug Interactions Genetic Polymorphisms Clinical significance: extensive modification of xenobiotics can hav distinctly different (and unanticipated) effects on clinical outcomes Phase I metabolism: Cytochrome P450 Multigene family (N=57 in H. sapiens) Genes classified within families and subfamilies 12 Families; most drugs metabolized by members of families 1-3 NADPH-dependent monooxygenase enzymes Oxidize endogenous and xenobiotic organic molecules All members contain heme co-factor group CYP2D6 Family Sub-Family Individual gene member  Relative percentage of drugs metabolized via Phase I enzymes CYP-cytochrome P450, ADH, alcohol dehydrogenase, ALDH, aldehyde dehydrogenase, NQO1 DT diaphorase, DPD, dihydropyrimidine dehydrogenase Clinical significance: 1. Inter-individual variation in activity levels of these proteins can lead to variable drug outcomes, 2. Co-administration of two drugs that are each metabolized by the same CYP can have unanticipated adverse effects.