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NPLEX Combination Review Concepts in Pharmacology, Pharmacognosy and Nutrition Paul S. Anderson, ND Medical Board Review Services Copyright MBRS 4-Day Review Synopsis: • *With the exception of the introductory section, each organ system will be integrated in the manner the cases will likely come on the Board Exams: ========================================== GENERAL SCHEDULE: • Day 1 – Introduction through Pulmonology / Hematology • Day 2 – Hematology through Neurology • Day 3 – Emergency Medicine through Dermatology / Gastro • Day 4 – Gastro through GYN Pharmacodynamics and Pharmacokinetics They are reactions between the body, the drug and possibly other substances that can potentially affect the availability and usefulness of the drug administered. Pharmacology of Interactions: • Pharmacokinetic Reactions – Absorption – Distribution • Additive to or Displacing from Albumen • Cellular Effects – Distribution / Receptor Activity – Metabolism – Elimination • Pharmacodynamic Reactions – Antagonist – Synergist / Additive / Agonist Interactions: Absorption • pH Alteration – Drugs that require ionization (Antifungal, Minerals) suffer in higher pH gastric environments. • Direct Blockade – Binding / Chelating agents • GI Motility Alteration – Increased motility = Increased absorption – Decreased motility = Decreased absorption – (To a point). Interactions: Distribution • Albumen Effects – Most drugs / Hormones are transported on albumens – The “Free” portion (unbound) is the bio-available portion – Substances that increase binding DECREASE availability of drug to tissues – Substances that decrease binding INCREASE availability of drug to tissues • Cellular Effects – Distribution / Receptor activity • Actions by one substance on another substance at the receptor level. • May include displacement from cellular binding site • May include receptor blockade • May include enzyme modification (common with poisons) Interactions: Metabolism • Induction Errors – Substances that INDUCE hepatic metabolism REDUCE plasma availability of the drug • Inhibition Errors – Substances that SLOW hepatic metabolism INCREASE plasma availability of the drug • Substrate Errors – Some substances supply substrate for the hepatic detoxification pathways – These substances induce metabolism, REDUCING plasma availability Hepatic Detoxification Pathways: PHASE-1 (Cytochrome P450) Pathways: Generally render Non-polar (Lipid Soluble) substances Polar Reactions: Oxidation, Reduction, Hydrolysis, Hydration… Co-factors / Substrates: B2,3,6,12,Folate, GSH, AA’s… This process NATURALLY creates peroxide and superoxide free radicals! PHASE-2 (Conjugation) Pathways: Take intermediary (more-polar) P450 metabolites and conjugate them with Amino Acids. EXCRETION: BILE SERUM URINE LIVER DETOXIFICATION PATHWAYS Fat – Soluble Compounds Phase-1 CYP450 (-OH added) Phase-2 Water – Soluble compounds Enzymatic Conjugation Excreted derivatives Glycine Hippurates Glutathione Mercapturates Glucuronic Acid Glucuronides Natural creation of Hydroxyl and Superoxide Radicals leading to Lipid Peroxidation. Interactions: Elimination • Kidney Clearance Issues: – Reduced GFR can result in Increased plasma levels of RENALLY CLEARED DRUGS. – Increased GFR will cause lower effect of chronically prescribed drugs, due to increased excretion. Calculated GFR GFR Changes and drug elimination considerations: • Healthy Kidneys: 60 or higher • Stage 1 Chronic Kidney Disease (CKD): – 90 or higher with HTN, Proteinuria, AbN Ki anatomy • Stage 2 Chronic Kidney Disease (CKD): – 60-89 with the above • Stage 3 Chronic Kidney Disease (CKD): – 30-59 • Stage 4 Chronic Kidney Disease (CKD): – 15-29 • Stage 5 – 15 or less / Dialysis The Bottom Line: • Use caution applying typical dosing for substances in patients with any pathologic alteration in the physiologic parameters of drug metabolism: – Kidney disease – Liver disease – GI disease – Any patient over 65 Interactions: Antagonist • Antagonistic Pharmacologic Properties – Must have opposite actions of drugs at same time – Different sites of action in the body – Drugs of equal strength (of action) will have uniform antagonism – Unequal antagonism will favor the stronger acting drug. Interactions: Synergist / Additive / Agonist • Additive effects of drugs • May have: – Common receptor activity • I.e. Alcohol and Benzodiazepines – Synergistic receptor activity • I.e. H-1 Blockers and Skeletal Muscle Relaxants Half Life • The biological half-life of a substance is the time required for half of that substance to be removed from an organism by either a physical or a chemical process. • Biological half-life is an important pharmacokinetic parameter and is usually denoted by the abbreviation t-1/2. Half Life and Elimination • First-order elimination Fast. This process is usually a first-order logarithmic process - that is, a constant proportion of the agent is eliminated per unit time. • Michaelis – Menten (and Hill) – Saturable quality of Enzyme reactions: – Estimating the speed of enzymatic reaction based on [substrate.] – Once the enzyme system is saturated (by substrate) the kinetics (eA) change (First order to Zero order elimination.) • Zero-order elimination Slow. There are circumstances where the half-life varies with the concentration of the drug. – For example, Aspirin, Phenytoin and Ethanol may be consumed in sufficient quantity to saturate the metabolic enzymes in the liver, and so is eliminated from the body at an approximately constant rate (zero-order elimination). Half Life and Elimination • First-order elimination Fast. This process is usually a first-order logarithmic process - that is, a constant proportion (percent) of the agent is eliminated per unit time. Michaelis – Menten (and Hill) Saturable quality of Enzyme reactions: Estimating the speed of enzymatic reaction based on [substrate.] Once the enzyme system is saturated (by substrate) the kinetics (eA) change (First order to Zero order elimination.) Shows drug in and drug out over time, initially as first order. Once the enzymatic elimination pathways are saturated the kinetics of elimination (and build-up) in the body change to zero order, often causing overdose. Vmax Maximum elimination under MM kinetics: Half Life and Elimination • In practice, this means that it takes just over 4.7 times the half-life for a drug's serum concentration to reach steady state after regular dosing is started, stopped, or the dose changed. – “The 5X rule” • So, for example, digoxin has a half-life (or t½) of 24-36 hours; this means that a change in the dose will take the best part of a week to take full effect. • For this reason, drugs with a long half-life (e.g. amiodarone, elimination t½ of about 90 days) are usually started with a loading dose to achieve their desired clinical effect more quickly. Sample Rx – Narcotic (C-II) Sample Rx – General DRUG INTERACTIONS / SIDE EFFECTS Increase plasma drug level Decrease plasma drug levels Increase plasma drug levels Increase plasma drug levels DRUG INTERACTIONS / SIDE EFFECTS - 2 DRUG INTERACTIONS / SIDE EFFECTS - 3 Gent., Tobra., and Streptomycin Antidepressants should not be combined due to possible additive effects, but often are now prescribed in combination. DRUG INTERACTIONS / SIDE EFFECTS - 4 DRUG INTERACTIONS / SIDE EFFECTS - 5 • Physiologic Actions Prefix recognition: – Cholinergic: • Muscarinic • Nicotinic jct. – Adren___ • Beta 1&2 • Alpha 1&2 Acetylcholine receptor. Found at postsynaptic parasympathetic locations Autonomic ganglia. Adrenal medulla. Neuromuscular “Adrenal acting” (Epi. N.E.) acting receptor: Cardio-pulmonary postsynaptic sympathetic GI, Vascular, CNS presynaptic sympathetic • Suffix recognition: – __mimetic: Mimics / acts like the physiologic substance. • I.e. Sympathomimetic substances – __lytic substance. Blocks the action of the physiologic • I.e. Parasympatholytic substances • Receptor activity: – Agonist: – Antagonist: Stimulates that receptor to action. Blocks that receptor from action. Autonomic Nervous System Activity: • Sympathetic N.S. • Parasympathetic N.S. – Generally stimulating – GI & GU Tract Depressing • Sympathomimetic – Drug (i.e. Epinephrine) that acts at one or more sympathetic receptor site. – Actions of the drug mimic sympathetic activity to the extent that receptors are activated • Sympatholytic – Drug (i.e. Reserpine) that blocks or otherwise decreases catecholamines. Thus increasing some parasympathetic tone. – Generally relaxing – GI & GU Tract Stimulating • Parsympathomimetic – Drug (i.e. Pilocarpine) that acts at one or more parasympathetic receptor site. – Actions of the drug mimic parasympathetic activity to the extent that receptors are activated • Parasympatholytic – Drug (i.e. Atropine) that blocks one or more parasympathetic receptor sites. – Actions of the drug effectively block parasympathetic activity and thus increase some sympathetic tone. Excitable Membrane Physiology The resting membrane potential is predicated on the ionic balance between the ICF and the ECF. Changes in those ion concentrations create AP generation and cellular activation. ICF ECF [Na] [K] [K] [Na] [Mg] [Ca] [Mg] [Ca] Cl(Cl- influx hyperpolarizes the cell, inactivating it.) CHEMICAL COMPOSITION OF ECF –vs- ICF E.C.F. I.C.F. Na 142 mEq/L 10 mEq/L K 4 “ 140 “ Ca 2.4 “ 0.0001 “ Mg 1.2 “ 68 “ Cl 103 “ 4 “ HCO3- 28 “ 1 “ pH 7.4 7.0 CHOLINERGIC (ACh) RECEPTORS THE ACETYLCHOLINE (ACh) CHANNEL (A Ligand Gated Ion Chanel) Acetylcholine • Multiple sites of action in the body – Acts as a neurotransmitter (PNS / CNS) – Acts as a hormone (Cornea) • Peripherally acts at the neuromuscular junction, and elsewhere via Nicotinic and Muscarinic receptors • Centrally seems to be involved in memory and other neurological counter regulation Acetylcholine Metabolism SERINE Pyruvate Phosphatidylethanolamine SAMe Betaine [Folate / B3 / B6] SAMh Phosphatidylcholine Acetate [B2 / B5 / B6] Acetyl-CoA Choline [Choline Acetylase] Acetylcholine (ACh) Diet [Acetylcholine esterase] Choline Acetate ADRENERGIC (Epi. / NE) RECEPTORS Plant Medicine Prototypes - 1 • Rauwolfia serpentina – Acts by decreasing activity of neuronal storage vessicles. • CNS: Decreases Catecholamines • PNS: Decrease Norepinephrine and Serotonin • Digitalis lanata (leaf) – Decreases aberrant SA to AV conduction • Positive Inotrope and Dromotrope – Blockade of Na/K ATPase pump (Increases intracellular Ca. results in elongated plateau on cardiac AP) – Improves atrial dysfunction • Chincona (bark) – Two primary chincona alkaloids: – Mild to moderate anticholinergic effects, direct toxic effects. • Quinine (Anti spasmodic [noctournal leg cramps], antipyretic, Ameobacide) • Quinidine (Antiarrhythmic) • Atropa belladonna – Acetylcholine antagonist (Parasympatholytic) • Muscarinic receptor blocade (Post-synaptic parasympathetic) • Slows digestion, decreases secretions, dilates pupils… Plant Medicine Prototypes - 2 • Calabar (bean) – Physostigmine • Reversible inhibition of Acetylcholine Esterase • Increases Acetylcholine levels (Parasympathomimetic) – Increases secretions, digestion, constricts pupils… • Pylocarpus mycrophyllus / jaborandi – Pilocarpine • Cholinergic (Parasympathomimetic) • Used as eye drop in glaucoma treatment • Erythroxylon coca – Cocaine • Dilates pupils • Anesthetic to mucous membranes • Increases Dopamine (reuptake inhibition) especially active in the nucleus accumbuns / pleasure centers. Plant Medicine Prototypes - 3 • Eschscolizia californicum – California poppy • Used in pain control tincture formulas etc. • Papaver somniferum – Opium, Codeine, Morphine… • The “Opiates” – Analgesic pain medications, centrally acting – Also block parasympathetic activity – Papaverine • Papaver alkaloid – Used for angina (vasodilatation) • Claviceps purpurea (Ergot – Rye or Wheat fungus) – Primarily vasoconstrictive agents (Ergonovine, DHE …) • Post partum / abortive hemorrhage – Also Bromocriptine (Dopamine agonist) and LSD family. Glutathione The Glutathione Redox Cycle and Peroxide H2O2 2 GSH (Red) Glut. Peroxidase [Se] GSSG (Ox) 2 H2O NADP+ [B2-FAD] Glut. Reductase NADPH+H HMP Shunt LIPID METABOLISM AND CARNITINE PROTEINS: Amine Transfer B6 and Transaminase Reactions VITAMINS-1 • WATER SOLUBLE – B-1, B-2, B-3, B-5, B-6, B-12 –C – FOLACIN – BIOTIN • FAT SOLUBLE –A –D –E –K VITAMINS-2 VITAMIN FUNCTION DEFICIENCY A D E K Part of RHODOPSIN / VISION GI (Incr. Calcium absorption) Antioxidant CARBOXYLATION (of glutamate) / Calcium “chelation” with glutamate. NIGHT BLINDNESS Rickets / Osteomalacia Ataxia Factor 2/7/9/10 bleeding disorders B-1 B-2 B-3 B-5 B-6 B-12 ALDEHYDE transfer / DECARBOXYLATION H+ Transfer / FMN – FAD (Flavins) H+ Transfer / NAD – NADP ACYL Group Transfer / Co-A AMINO Group transfer / De-& Trans “aminations” BERIBERI CHEILOSIS / GLOSSITIS VIT-C BIOTIN H+ Transfer / Hydroxylation of Lysine CARBOXYLATION FOLATE METHYL Transfer METHYL Transfer / Methionine Synth. Proline& PELLEGRA (Dementia/Diarrhea/Dermatitis) Burning Feet / HA / Nausea Microcytosis / Neuropathy Macrocytosis / Pernicious Anemia / Neuropathy SCURVY Seborrheic Dermatitis, Nervous disorders, Bound by Avidin (in egg white) Macrocytosis / Glossitis / Colitis VITAMINS-3 • B-1 (THIAMIN) Thiamin pyrophosphate - active – Beri-beri. Oxidative decarboxylation – Wheat germ, fish, meat, eggs, milk, cereals, green veggies. – Cardiac and neurological effects. • B-2 (RIBOFLAVIN) – FMN (flavinoidmononucleotide), FAD (flavinadeninedinucleotide) – Fish, meat, eggs, milk, greens. – Angular stomatitis, glossitis, seborrhea, anemia • B-3 (NIACIN / NIACINAMIDE) – – – – Pellagra. NAD / NADH formation. Part of the GTF. Used in Dehydrogenase reactions. Aka. Nicotinic acid / Nicotinamide. Wheat germ, fish, liver, peanuts. VITAMINS-4 • B-5 (Pantothenic acid) – Ubiquitous in foods. – Deficiency not common. Part of Acetyl~S~CoA. (CoA) • B-6 (Pyridoxine) Pyridoxal-5-Phosphate (active) – Magnesium is a cofactor. Used for amino acid metabolism. – Cereals, fish, meat, eggs, greens. – Anemia, dermatitis, neurological deficits (peripheral) • B-12 (Cyanocobolamin) – – – – – Meat, dairy, fermented foods. (Bacterial action) Intrinsic Factor facilitates absorption. Pernicious anemia. Macrocytic (megaloblastic) anemia. Activates the conversion of Homocystiene to Methionine Terminal Ileum absorption VITAMINS-5 : B12 & FOLATE THF (TetraHydroFolate) is active in methyl group transfer. The CH3 transfer helps DNA in new cell production. B12 frees FOLATE from its bound form (N-5-CH3-THF) to its coenzyme form (THF). It does this via a CH3 release in the following reaction: CH3 N-5-METHYL-THF THF METHIONINE HOMOCYSTIENE CH3 VITAMINS-6 • C (ASCORBATE) – Fruit / Vegetables – Reducing agent (antioxidant). Large amounts convert to oxalate. Hydroxylation Reaction cofactor. (Bile, Proline, Dopamine) – Collagen integrity, immune function. • FOLATE – Converted to the active form (Tetrahydrofolate – THF) by B12. Required for nucleotide synthesis. Methyl donor. – Cereals, liver, fruit, greens. – Macrocytic anemia, like B-12, without the neurologic deficits. • BIOTIN – – – – Many foods, produced by intestinal bacteria. Dermatitis. Carries CO2 in carboxylase reactions Avidin (from raw eggs) will bind Biotin. Oxidation of Ascorbic Acid Ascorbyl Radical Ascorbate [ASC*] [ASC] Dehydroascorbic Acid [DHA] LDL Oxidation: The LDL has the potential to carry an incredible load of free radical. Anti-Oxidant effects of Vitamins E, C, GSH and the RBC - Lipid – Plasma Interaction RBC Plasma LDL Reduced Glutathione ASC Toco R Oxidized Glutathione ASC R DHA LDL + R = “oxidized LDL” Toco GLUTATHIONE • A TRIPEPTIDE (thiol glutathione [GSH]) • Poor oral absorption • Cofactor for antioxidant enzymes – Mitochondrial protection from endogenous oxygen radicals – High electron donating capacity, coupled with its high intercellular concentration give it extreme reducing power. • Two forms: – Reduced (the antioxidant) and Oxidized • Production: – Step 1: {[methionine cysteine] + glutamate}GGCS enz gamma-glutamylcysteine – Step 2 : {gamma-glutamylcysteine+glycine–GSH enz GSH – Glutathione is preserved by Ascorbate Glutathione The Glutathione Redox Cycle and Peroxide H2O2 2 GSH (Red) Glut. Peroxidase [Se] GSSG (Ox) 2 H2O NADP+ [B2-FAD] Glut. Reductase NADPH+H HMP Shunt VITAMIN - K Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K-dependent proteins. Normally synthesized by bacteria in the gut. Newborns are deficient. The key vitamin K-dependent proteins include: 1. Coagulation proteins: factors II (prothrombin), VII, IX and X 2. Anticoagulation proteins: proteins C, S and Z 3. Others: bone proteins osteocalcin and matrix-Gla protein, and certain ribosomal proteins VITAMIN - E Vitamin E a-Tocopherol Vitamin E is a mixture of several related compounds known as tocopherols. The a-tocopherol molecule is the most potent of the tocopherols. Vitamin E is absorbed from the intestines packaged in chylomicrons. The liver can export vitamin E in VLDLs. Due to its lipophilic nature, vitamin E accumulates in cellular membranes, fat deposits and other circulating lipoproteins. The major site of vitamin E storage is in adipose tissue. The major function of vitamin E is to act as a natural antioxidant by scavenging free radicals and molecular oxygen. In particular vitamin E is important for preventing peroxidation of polyunsaturated membrane fatty acids. The vitamins E and C are interrelated in their antioxidant capabilities. Active a-tocopherol can be regenerated by interaction with vitamin C following scavenge of a peroxy free radical. Alternatively, a-tocopherol can scavenge two peroxy free radicals and then be conjugated to glucuronate for excretion in the bile. VITAMIN - A Vitamin A Use RBP (Retinol Binding Protein) VITAMIN - D MACROMINERALS MACROMINERALS MACROMINERALS • Magnesium Mg++ MACROMINERALS MACROMINERALS MICROMINERALS MICROMINERALS MICROMINERALS MICROMINERALS MICROMINERALS OTHER NUTRIENTS - FLAVINOIDS • Phenols are universal in plant material • Flavinoids are polyphenolic compounds – Act as antioxidant to foods in storage – Protect Ascorbate and Tocopherol from oxidative decomposition during digestion – Have various levels of activity after absorption, based on the form taken in the plasma. • Some forms stabilize mast cells – (anti histaminic) – Hesperidin, Quercetin, Rutin… OTHER NUTRIENTS – Co-Q-10 • Aka. Ubiquinone – Dose for Cardio Effect 75 mg + – Absorption is better with fat intake (either in the supplement or taken with dietary fats) • Powerful antioxidant – Helps in the preservation of Vitamin E – Found in Fish and other Meats (low quantity) • Body ability to synthesize drops after 30 • Formed in the Cholesterol / HMG pathway – Decreased by the “statin” class of drugs OTHER NUTRIENTS – ALPHA-Lipoic-acid • Cofactor for mitochondrial energy reactions • Substrate production for Krebs cycle – Catalyses the metabolism of the branch chain AA’s • Leucine, Isoleucine, Valine – Supports glycine cleavage which supports 5-10-Methyl Tetrahydrofolate production • Used in nucleic acid synthesis • Antioxidant capabilities – Complexes with arsenic as an antioxidant – Regenerates other antioxidants (C,E,Q10, GSH) – Repairs oxidative damage • Inhibits the enzyme elastase which degrades pulmonary elastin in COPD • Metal ion chelation ?? (in vitro only?) Some charts and figures come from the Case Files series, Particularly Case Files in Emergency Medicine and Case files in Internal Medicine. Lang Publishing.