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PH01- Pharmacodynamics and pharmacokinetics !" Pharmacodynamics and Pharmacokinetics Matthew B. Wilkinson, PhD, M4 #$%&'"()&*)"(+,$$-"$."#/0)+)&/" PH01- Enzyme kinetics 1 2 Enzyme kinetics Vmax = maximum reaction velocity for a given amount of enzyme • Proportional to enzyme concentration Michaelis-Menten plot Substrate concentration [S] (mM) Kaplan Biochemistry 2011: Figures I-8-4 FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 ME 3e: 55 PH01- Enzyme kinetics 2 3 Enzyme kinetics Michaelis constant (Km): Substrate concentration required to reach half Vmax = • High Km ! low affinity • Low Km ! high affinity Michaelis-Menten plot Substrate concentration [S] (mM) 1 affinity Kaplan Biochemistry 2011: Figures I-8-4 FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 ME 3e: 55 PH01- Enzyme kinetics 3 4 Enzyme kinetics Michaelis constant (Km): Substrate concentration required to reach half Vmax = Vmax = maximum reaction velocity for a given amount of enzyme Kaplan Biochemistry 2011: Figure: I-8-5 1 affinity • High Km ! low affinity • Low Km ! high affinity • Proportional to enzyme concentration Lineweaver-Burk plot FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 ME 3e: 55 PH01- • Resemble substrate, bind at active site • Increasing substrate concentration can overcome inhibition • Decrease potency Enzyme inhibitors 1 Competitive inhibitors Non-competitive inhibitors • Typically bind at allosteric site, not near active site • Cannot be overcome with increased substrate concentration • Decrease efficacy Enzyme Enzyme Active site Substrate Competitive inhibitor Non-competitive inhibitor 5 Enzyme inhibitors Allosteric site FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 ME 3e: 55 PH01- Enzyme inhibitors 2 Competitive Non-competitive Resemble substrate Yes No Overcome with "substrate concentration Yes No Bind active site Yes No Vmax No effect # Km " No effect Pharmacodynamics #Potency #Efficacy Graphs cross? Yes No Competitive vs. Non-competitive inhibitors 1 / (velocity) 1 / (substrate concentration) Lineweaver-Burk plot Non-competitive Competitive No inhibitor 6 Enzyme inhibitors FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 ME 3e: 55 PH01- Volume of distribution Volume of distribution, Vd = total amount of drug in body [drug]plasma Low Vd (4-8 L) Mid Vd (12-14 L) High Vd (>total body water) Vd of plasma protein bound drugs are altered in liver and kidney disease • Hepatic disease: ! synthesis of plasma proteins • Renal diseases: Plasma proteins (and bound drugs) are excreted in the urine mostly in blood mostly extracellular fluid distributed in all tissues, non-fluid compartments (fat) (liters) 7 Volume of distribution FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228 ME 3e: 166 PH01- Drug clearance Clearance (CI) = Rate of drug elimination Plasma drug concentration = Vd x ke • Clearance refers to the volume of blood totally cleared of drug per unit time • Units: • Rate of drug elimination: (mass)/(units of time) • Plasma drug concentration: (mass)/(volume of plasma) • Elimination rate constant (ke): t-1 • Renal clearance: • Clearance: • Equals glomerular filtration rate (GFR) when there is no reabsorption, secretion, or plasma protein binding • Inulin and creatinine clearance are used to estimate GFR • Protein-bound drugs are not cleared • Clearance = (free fraction) x GFR 8 Drug clearance FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228 ME 3e: 166 PH01- Drug half-life • A1$%&'"$."21/")'"'*3/4".$5"*&"*1$%&'"$."05%6")&"',/"7$08"'$"+,*&6/"78"$&/",*-." • Half-life relates to both a decrease in plasma concentration via elimination or an increase in plasma concentration via drug infusion • Steady state is reached in 4-5 half-lives with continuous infusion t1/2 = 0.7 x Vd Clearance n t1/2 [drug] 1 t1/2 2 t1/2 3 t1/2 4 t1/2 5 t1/2 50 % 75 % 87.5 % 93.75 % 96.9 % 9 Drug half-life FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228 ME 3e: 166 " PH01- Loading and maintenance doses Loading dose Bioavailability (F) • Fraction of administered drug that reaches systemic circulation • Some drugs fail to be absorbed, or are metabolized before reaching circulation Maintenance dose • Large initial dose given to fill up Vd • Can increase plasma concentration in less than 4-5 half-lives LD = Vd x Cp F MD = Cl x Cp F • Given to maintain constant blood plasma levels • Lowered if hepatic/renal function is impaired F = 1 for IV infusion Cp blood plasma conc. Cl clearance F bioavailability 10 Loading and maintenance doses FA 2012: 259.2 • FA 2011: 233.1 • FA 2010: 229 ME 3e: 167 PH01- Drug elimination Zero order elimination First order elimination • Constant amount of drug eliminated with time • Phenytoin, aspirin, ethanol • Constant fraction of drug eliminated with time • Most drugs follow first-order kinetics 100 mg ! 90 mg ! 80 mg ! 70 mg ! ! 100 mg ! 50 mg ! 25 mg ! 12.5 mg ! ! 11 Drug elimination FA 2012: 260.1 • FA 2011: 233.2 • FA 2010: 229 ME 3e: 166 PH01- Renal excretion • Both ionized (I) and nonionized (N) forms are filtered • Only non-ionized forms are actively secreted or reabsorbed • Ionized forms of drug are “trapped” in filtrate • Drugs that are weak acids: • Barbiturates, methotrexate, aspirin, • Drugs that are weak bases: • Amphetamines Kaplan Pharmacology 2011: Figure I-1-3 12 Renal excretion 􀀴􀁆􀁄􀁕􀁊􀁐􀁏􀀃􀀪 􀀃􀁏􀀃􀀃􀀨􀁆􀁏􀁆􀁓􀁂􀁍􀀃􀀱􀁓􀁊􀁏􀁄􀁊􀁑􀁍􀁆􀁔 PERMEATION • Drug permeation is dependent on: – Solubility. Ability to diffuse through lipid bilayers (lipid solubility) most drugs; however, water solubility can influence permeation phases. – Concentration gradient. Diffusion down a concentration gradient—unionized drug forms contribute to the concentration gradient. – Surface area and vascularity. Important with regard to absorption the systemic circulation. The larger the surface area and the the better is the absorption of the drug. • Ionization – Many drugs are weak acids or weak bases and can exist in either ionized forms in an equilibrium, depending on the pH of the the pKa (the pH at which the molecule is 50% ionized and – Only the nonionized (uncharged) form of a drug crosses biomembranes. – The ionized form is better renally excreted because it is water Weak Acid R–COOH R–COO– + (crosses membranes) (better cleared) Weak Base R–NH+ 3 R–NH2 + H+ (better cleared) (crosses membranes) 80 Form weak base In A Nutshell For Weak Acids and Weak Bases Ionized = Water soluble Nonionized = Lipid soluble Clinical Correlate Gut bacteria metabolize lactulose to lactic acid, Draft Not for Distribution 􀀴􀁆􀁄􀁕􀁊􀁐􀁏􀀃􀀪 􀀃􀁏􀀃􀀃􀀨􀁆􀁏􀁆􀁓􀁂􀁍􀀃􀀱􀁓􀁊􀁏􀁄􀁊􀁑􀁍􀁆􀁔 PERMEATION • Drug permeation is dependent on: – Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs; however, water solubility can influence permeation through aqueous phases. – Concentration gradient. Diffusion down a concentration gradient—only free, unionized drug forms contribute to the concentration gradient. – Surface area and vascularity. Important with regard to absorption of drugs into the systemic circulation. The larger the surface area and the greater the vascularity, the better is the absorption of the drug. • Ionization – Many drugs are weak acids or weak bases and can exist in either nonionized or ionized forms in an equilibrium, depending on the pH of the environment and the pKa (the pH at which the molecule is 50% ionized and 50% nonionized) – Only the nonionized (uncharged) form of a drug crosses biomembranes. – The ionized form is better renally excreted because it is water soluble. Weak Acid R–COOH R–COO– + H+ (crosses membranes) (better cleared) Weak Base R–NH+ 3 R–NH2 + H+ (better cleared) (crosses membranes) 80 60 Nonionized Form Renal Clearance weak base In A Nutshell For Weak Acids and Weak Bases Ionized = Water soluble Nonionized = Lipid soluble Clinical Correlate Gut bacteria metabolize lactulose to lactic acid, acidifying the fecal masses and Draft Not for Distribution 􀀴􀁆􀁄􀁕􀁊􀁐􀁏􀀃􀀪 􀀃􀁏􀀃􀀃􀀨􀁆􀁏􀁆􀁓􀁂􀁍􀀃􀀱􀁓􀁊􀁏􀁄􀁊􀁑􀁍􀁆􀁔 PERMEATION • Drug permeation is dependent on: – Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs; however, water solubility can influence permeation through aqueous phases. – Concentration gradient. Diffusion down a concentration gradient—only free, unionized drug forms contribute to the concentration gradient. – Surface area and vascularity. Important with regard to absorption of drugs into the systemic circulation. The larger the surface area and the greater the vascularity, the better is the absorption of the drug. • Ionization – Many drugs are weak acids or weak bases and can exist in either nonionized or ionized forms in an equilibrium, depending on the pH of the environment and the pKa (the pH at which the molecule is 50% ionized and 50% nonionized) – Only the nonionized (uncharged) form of a drug crosses biomembranes. – The ionized form is better renally excreted because it is water soluble. Weak Acid R–COOH R–COO– + H+ (crosses membranes) (better cleared) Weak Base R–NH+ 3 R–NH2 + H+ (better cleared) (crosses membranes) 80 Form Renal weak base Nutshell Weak Acids and Weak Ionized = Water soluble Nonionized = Lipid soluble Clinical Correlate bacteria metabolize lactulose to lactic acid, Draft Not for Distribution 􀀴􀁆􀁄􀁕􀁊􀁐􀁏􀀃􀀪 􀀃􀁏􀀃􀀃􀀨􀁆􀁏􀁆􀁓􀁂􀁍􀀃􀀱􀁓􀁊􀁏􀁄􀁊􀁑􀁍􀁆􀁔 PERMEATION • Drug permeation is dependent on: – Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs; however, water solubility can influence permeation through aqueous phases. – Concentration gradient. Diffusion down a concentration gradient—only free, unionized drug forms contribute to the concentration gradient. – Surface area and vascularity. Important with regard to absorption of drugs into the systemic circulation. The larger the surface area and the greater the vascularity, the better is the absorption of the drug. • Ionization – Many drugs are weak acids or weak bases and can exist in either nonionized or ionized forms in an equilibrium, depending on the pH of the environment and the pKa (the pH at which the molecule is 50% ionized and 50% nonionized) – Only the nonionized (uncharged) form of a drug crosses biomembranes. – The ionized form is better renally excreted because it is water soluble. Weak Acid R–COOH R–COO– + H+ (crosses membranes) (better cleared) Weak Base R–NH+ 3 R–NH2 + H+ (better cleared) (crosses membranes) 80 Form Renal Clearance weak base In A Nutshell For Weak Acids and Weak Bases Ionized = Water soluble Nonionized = Lipid soluble Clinical Correlate Gut bacteria metabolize lactulose to lactic acid, Draft Not 9 9 :" ;" :" ;" Weak Acid" 􀀴􀁆􀁄􀁕􀁊􀁐􀁏􀀃􀀪 􀀃􀁏􀀃􀀃􀀨􀁆􀁏􀁆􀁓􀁂􀁍􀀃􀀱􀁓􀁊􀁏􀁄􀁊􀁑􀁍􀁆􀁔 PERMEATION • Drug permeation is dependent on: – Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs; however, water solubility can influence permeation through aqueous phases. – Concentration gradient. Diffusion down a concentration gradient—only free, unionized drug forms contribute to the concentration gradient. – Surface area and vascularity. Important with regard to absorption of drugs into the systemic circulation. The larger the surface area and the greater the vascularity, the better is the absorption of the drug. • Ionization – Many drugs are weak acids or weak bases and can exist in either nonionized or ionized forms in an equilibrium, depending on the pH of the environment and the pKa (the pH at which the molecule is 50% ionized and 50% nonionized) – Only the nonionized (uncharged) form of a drug crosses biomembranes. – The ionized form is better renally excreted because it is water soluble. Weak Acid R–COOH R–COO– + H+ (crosses membranes) (better cleared) Weak Base R–R–NH2 + H+ (better crosses membranes) 80 Form Renal weak base In A Nutshell For Weak Acids and Weak Bases Ionized = Water soluble Nonionized = Lipid soluble Clinical Correlate Gut bacteria metabolize lactulose to lactic acid, Draft Not for Distribution FA 2012: 260.2 • FA 2011: 233.3 • FA 2010: 229 ME 3e: 166 PH01- Biotransformation 1 • Occurs in the liver • Conversion of lipid soluble drugs into water soluble metabolites " # renal excretion • Two forms of drug metabolism: Phase 1 and 2 Phase I: • Three mechanisms of metabolization: Oxydation, reduction, and hydrolysis • Cytochrome P450 enzymes: • Located in smooth endoplasmic reticulum of the liver (to lesser extent GI, lungs, kidneys • Require O2 and NADP • Mechanisms of cytochrome P450 enzyme metabolism: • Reduction • Oxidation • Hydroxylation and dealkylation 13 Biotransformation FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4 ME 3e: 167 PH01- Cytochrome P-450 interactions Inducers Inhibitors Quinidine HIV protease inhibitors Barbiturates Isoniazid (INH) St. John’s wort Sulfonamides Phenytoin Cimetidine Rifampin Ketoconazole Griseofulvin Grapefruit juice Carbamazepine Omeprazole Chronic alcohol use Chloramphenicol Glucocorticoids Marcolides Ritonavir 14 Cytochrome P-450 interactions FA2012 273 • FA 2011: 245.2 • FA 2010: 241.2 ME 3e: 167 PH01- Biotransformation 2 Phase I Metabolism • Leads to polar, water-soluble metabolites • Non-cytochrome P450 enzyme metabolism • Mechanisms of metabolism: • Hydrolysis: Addition of H20 to drugs to assist metabolism • Esterase • Amiidase • Monoamine oxidase: Metabolizes amines • Endogenous amines: Dopamine, norepinephrine, serotonin • Exogenous amines: Tyramine • Alcohol metabolism 15 Biotransformation FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4 ME 3e: 167 PH01- Biotransformation 3 Phase II Metabolism • Conjugation of functional groups to a drug • Converts polar molecules to inactive molecules " # renal excretion • Mechanisms of metabolism: • Acetylation • Glucuronidation • Sulfation • Methylation • Glutathione conjugation 16 Biotransformation FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4 ME 3e: 167 PH01- Potency vs. efficacy 1 Potency: measure of how much drug required to give desired effect typically expressed as EC50 - concentration that gives 50% of max. response Efficacy: maximal effect that a drug can produce Kaplan Pharmacology 2011: Figure I-2-2 B = full agonist A = partial agonist (low efficacy) with high potency C = partial agonist with low potency 17 Potency vs. efficacy FA 2012: 261.1 • FA 2011: 233.5 • FA 2010: 229 ME 3e: 168 PH01- Potency vs. efficacy 2 log [drug] % Response log [drug] % Response Competitive Antagonists Non-competitive Antagonists Efficacy Potency Potency: # Efficacy: no effect Potency: no effect Efficacy: # Partial Agonist Acts at same site as agonist, but lower efficacy Can have higher or lower potency than agonist Full agonist <" =" Partial agonist >" 18 Potency vs. efficacy FA 2012: 261.2 • FA 2011: 234.1 • FA 2010: 230 ME 3e: 168 PH01- Physiologic antagonists Substrate that produces opposite effect of an agonist, but acts through different receptor/pathway Example: Bronchoconstriction Bronchodilation Muscarinic Agonist "-adrenergic Agonist 19 Physiologic antagonists FA 2012: n/a • FA 2011: 234.2 • FA 2010: n/a ME 3e: n/a PH01- Therapeutic index Measure of drug safety. Higher therapeutic index indicates safer drug. TI = median dose that produces toxic or lethal effect median dose required to produce therapeutic effect = LD50 ED50 LD - lethal dose ED - effective dose Kaplan Pharmacology 2011: Figure I-2-5 20 Therapeutic index FA 2012: 261.3 • FA 2011: 234.3 • FA 2010: 230 ME 3e: 168 PH02- Sympathetic and parasympathetic nervous systems 1 Sympathetic and Parasympathetic Nervous Systems Matthew B. Wilkinson, PhD, M4 !"#$%&'($)(&'*+"",&"-&!./(*($.& PH02- Autonomic nervous system Kaplan Pharmacology 2011: Figure II-1-1 * 2 Autonomic nervous system Parasympathetic Sympathetic * Thoracolumbar , Sympathetic fibers release dopamine to activate renal vascular smooth muscle via D1 receptors! FA 2012: 262.1 • FA 2011: 235.1 • FA 2010: 231 ME 3e: 186 PH02- Acetylcholine receptors Nicotinic ACh receptors (nAChRs) Muscarinic ACh receptors (mAChRs) Ligand-gated Na+/K+ channels NN: autonomic Nm: somatic muscular (neuromuscular junction) G protein-coupled receptor M1 M2 M3 M4 M5 Autonomic Nervous System CNS 3 Acetylcholine receptors FA 2012: 262.2 • FA 2011: 235.2 • FA 2010: 231 ME 3e: 189 PH02- G protein-coupled receptor 0)1,)$&2+)34)*","56&7899:&;(5#3.&<=7=>& Gs / Gi Gq 4 G protein-coupled receptor FA 2012: 263.1 • FA 2011: 236.1 • FA 2010: 232 ME 3e: 169 PH02- GPCR physiology Class Receptor Functions q !1 vascular smooth muscle contraction, pupillary dilation (mydriasis), intestinal and bladder sphincter contraction i !2 !sympathetic release, !insulin release s "1 "heart rate and contractility, "renin release s "2 vasodilation, bronchodilation, !uterine tone q M1 CNS, gastric parietal cells i M2 !heart rate, !atrial contractility q M3 stimulates glandular secretions (sweat, gastric acid), "gut peristalsis, pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accommodation) s D1 renal vascular smooth muscle relaxation i D2 !sympathetic release q H1 "sinus and bronchial mucus production, bronchiole constriction, itching/pain s H2 "gastric acid secretion q V1 vascular smooth muscle contraction s V2 "water reabsorption in collecting tubules of kidneys 5 GPCR physiology FA 2012: 263.1 • FA 2011: 236.1 • FA 2010: 232 ME 3e: 187 PH02- Cholinergic nerve terminal Kaplan Pharmacology 2011: Figure II-2-1 Hemicholinium Botulinum Vesamicol Toxin 6 Cholinergic nerve terminal FA 2012: 264.1 • FA 2011: 237.1 • FA 2010: 233 ME 3e: 189 PH02- Metyrosine Reserpine Guanethidine Amphetamines Cocaine TCAs Amphetamines Adrenergic nerve terminal Kaplan Pharmacology 2011: Figure II-3-1 7 Adrenergic nerve terminal FA 2012: 264.1 • FA 2011: 237.1 • FA 2010: 233 ME 3e: 192 PH02- Cholinomimetics Cholinomimetic Drugs (parasympathomimetics) Bethanechol Muscarinic agonist. Longer acting than ACh (resistant to esterase). Treatment of ileus and urinary retention (Bowels and Bladder) Carbachol Muscarinic/nicotinic agonist. Applied to eye to cause contraction of ciliary muscle, relief of open-angle glaucoma. Also constricts pupil Pilocarpine Muscarinic agonist. Stimulates tears, sweat, saliva. Constricts pupil and ciliary muscle. Also used for acute glaucoma Methacholine Muscarinic agonist. Causes bronchoconstriction when inhaled. Used for asthma challenge test 8 Cholinomimetics FA 2012: 265.1 • FA 2011: 238.1 • FA 2010: 234 ME 3e: 189 PH02- Anticholinesterases Anticholinesterases (indirect cholinomimetics) Neostigmine Quaternary amine (no entry into CNS). Treatment of ileus, urinary retention, and myasthenia gravis. Post-operative reversal of neuromuscular junction blockade Pyridostigmine Quaternary amine. Treatment of myasthenia gravis Edrophonium Very short acting (10-20 mins.) Diagnosis of myasthenia gravis Physostigmine Tertiary amine (can enter CNS). Treatment of glaucoma. Antidote for atropine toxicity Echothiophate Treatment of glaucoma 9 Anticholinesterases FA 2012: 265.1 • FA 2011: 238.1 • FA 2010: 234 ME 3e: 190 PH02- Cholinesterase inhibitor poisoning 10 Cholinesterase inhibitor poisoning Cholinesterase inhibitor poisoning (high systemic acetylcholine) Symptoms: Diarrhea Urination Miosis Bronchoconstriction Bradycardia Excitation (skeletal muscle and CNS) Lacrimation Salivation Sweating Treatment: Atropine (muscarinic antagonist) Pralidoxime a.k.a 2PAM (regenerates cholinesterase) FA 2012: 265.2 • FA 2011: 238.2 • FA 2010: 234 ME 3e: 191 PH02- Muscarinic receptor antagonists 11 Muscarinic receptor antagonists Classic example: Atropine • Tertiary amine ! can enter the CNS • Effects: the opposite of DUMBBELSS • ! Epithelial secretions • Mydriasis, cycloplegia • Hyperthermia • Vasodilation Muscarinic receptor antagonists: • Tachycardia • Sedation • Urinary retention • Constipation 50 Pharmacologic effects • Atropine effects in order of increasing dose are: – Decreased secretions (salivary, bronchiolar, sweat) – Mydriasis and cycloplegia – Hyperthermia (with resulting vasodilation) – Tachycardia – Sedation – Urinary retention and constipation – Behavioral excitation and hallucinations • Other classes of drugs with antimuscarinic pharmacology: – Antihistamines – Tricyclic antidepressants – Antipsychotics – Quinidine – Amantadine – Meperidine • Treatment of acute intoxication: – Symptomatic ± physostigmine Table II-2-6. Clinical Uses and/or Characteristics of M Blockers Drug Clinical Uses and/or Characteristics Atropine Antispasmodic, antisecretory, management of AChE inhibitor OD, antidiarrheal, ophthalmology (but long action) Tropicamide Ophthalmology (topical) Ipratropium Asthma and COPD (inhalational)—no CNS entry, no change in mucus viscosity Scopolamine Used in motion sickness, causes sedation and short-term memory block Benztropine, Lipid-soluble (CNS entry) used in parkinsonism and in acute trihexyphenidyl extrapyramidal symptoms induced by antipsychotics NICOTINIC RECEPTOR ANTAGONISTS Ganglion Blocking Agents • Drugs: hexamethonium and mecamylamine • Reduce the predominant autonomic tone (see Table II-2-7) • Prevent baroreceptor reflex changes in heart rate (see Figure II-2-4) • Most are no longer available clinically because of toxicities (rarely, mecamylamine in hypertension) Bridge to Physiology ANS Dominance For effector tissues with dual innervation, PANS is dominant. These include the SA and AV nodes of the heart, the pupil, GI and GU muscles, and sphincters. SANS is dominant only in terms of vascular tone and thermoregulatory sweat glands. Draft Not for Distribution Kaplan Pharmacology 2010: Table II-2-6 FA 2012: 266.1 • FA 2011: 239.2 • FA 2010: 235 ME 3e: 190 PH02- Nicotinic antagonists 12 Nicotinic antagonists Hexamethonium (nicotinic antagonist) Used to prevent vagal reflexes due to sympathetic stimulation Example: can be used to prevent reflex bradycardia caused by increased blood pressure due to increased norepinephrine Excess hexamethonium can cause orthostatic hypotension, blurred vision, constipation FA 2012: n/a • FA 2011: 239.3 • FA 2010: 235 ME 3e: 189 PH02- Direct sympathomimetics 1 13 Direct sympathomimetics Epinephrine: • Function: • !," agonist • Low doses selective for "1 receptors • Clinical usage: • Treatment for anaphylaxis, open-angle glaucoma, asthma, hypotension • Prolongs the effect of local anesthesia • Adverse effects: • "systolic blood pressure + !diastolic blood pressure = widened pulse pressure Norepinephrine: • Function: • Mainly !-receptor agonist, but has some "-receptor activity • Clinical usage: • Treatment of hypotension • Adverse effects: • Splanchnic vasoconstriction and !renal perfusion • "systolic blood pressure + "diastolic blood pressure = little/no change in pulse pressure • Reflexive decrease in heart rate FA 2012: 266.3 • FA 2011: 240.1 • FA 2010: 236 ME 3e: 193 PH02- Direct sympathomimetics 2 Isoproterenol "1 "2 agonist. Treatment for AV conduction block. !diastolic BP (this effect induces a reflexive "heart rate) Dopamine D1 = D2 > " > ! agonist. Inotropic and chronotropic. Treatment for shock, especially with heart failure Dobutamine "1> "2 agonist. Inotropic. Treatment of heart failure. Used in cardiac stress test Ritodrine "2 agonist. Reduces premature uterine contractions Metaproterenol Albuterol Salmeterol Terbutaline Selective "2 agonists ("2>"1). Treatment of asthma Acute: metaproterenol and albuterol Long-acting: salmeterol Direct sympathomimetics 14 Direct sympathomimetics FA 2012: 266.3 • FA 2011: 240.1 • FA 2010: 236 ME 3e: 193 PH02- Indirect sympathomimetics Amphetamine Induces catecholamine release from terminals. Treatment for narcolepsy, obesity, and ADHD. Ephedrine Induces catecholamine release. Treatment for nasal congestion, urinary incontinence, hypotension. Cocaine Inhibits reuptake of catecholamines. Vasoconstriction, local anesthetic. Tyramine Similar mechanism to amphetamines, cleared by MAO (MAO inhibitors can cause hypertension, especially with tyramine-rich foods such as wine and cheese). Indirect sympathomimetics 15 Indirect sympathomimetics FA 2012: 267.1 • FA 2011: 240.1 • FA 2010: 236 ME 3e: 194 PH02- Sympathoplegics Clonidine: • Agonists of central !2-adrenergic receptors which decreases sympathetic outflow !-methyldopa: • Used to treat hypertension by decreasing sympathetic tone 16 Sympathoplegics FA 2012: 267.2 • FA 2011: 241.1 • FA 2010: 237 ME 3e: 193 PH02- Alpha-blockers Non-selective (!1 and !2) !1-selective !2-selective Phenoxybenzamine (irreversible) Phentolamine (reversible) Treatment of pheochromocytoma. Also used to treat Raynaud’s syndrome Prazosin Terazosin Doxazosin (longest acting) Treatment of hypertension, urinary retention (BPH). May cause orthostatic hypotension (usually taken at bedtime) Mirtazapine Treatment of depression. Can cause sedation, increased serum cholesterol, and increased appetite 17 Alpha-blockers FA 2012: 268.1 • FA 2011: 241.2 • FA 2010: 237 ME 3e: 193 PH02- Beta-blockers 1 Non-selective ("1 and "2) "1-selective Partial "-agonists Pindolol Acebutolol Metoprolol Atenolol Betaxolol Esmolol (very short acting) Propranolol (migraines) Timolol (glaucoma) Nadolol Pindolol Mixed ! and " blockers Carvedilol Labetalol 18 Beta-blockers FA 2012: 269.1 • FA 2011: 242.1 • FA 2010: 238 ME 3e: 193 PH02- Beta-blockers 2 Treatments for: 19 Beta-blockers Side effects: • Exacerbation of asthma • Impotence • Bradycardia • AV blockade • Sedation • Decreased glucagon secretion FA 2012: 269.1 • FA 2011: 242.1 • FA 2010: 238 ME 3e: 193 PH03- Sympathetic and parasympathetic nervous systems 1 Toxicology and Adverse Reaction Matthew B. Wilkinson, PhD, M4 !"#$%&'($)(&'*+"",&"-&!./(*($.& PH03- Antidotes 1 Drug Antidote Acetaminophen N-acetylcysteine Salicylates Sodium bicarbonate to alkalinize urine, dialysis Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 2 ME 3e: 172 PH03- Antidotes 2 Drug Antidote Anticholinesterases Organophosphates (insecticides) Atropine, 2-PAM (pralidoxime) Anticholinergics Physostigmine 3 Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 ME 3e: 172 PH03- Antidotes 3 Drug Antidote !-blockers Glucagon to increase inotropy and chronotropy of heart Digitalis Anti-digitalis Fab fragments. Normalize serum electrolytes, especially K+, then lidocaine, magnesium 4 Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 ME 3e: 172 PH03- Antidotes 4 Drug Antidote Iron Deferoxamine (de-Fe-roxamine) Lead Ca-EDTA (chelator), dimercaprol, succimer, penicillamine Arsenic, mercury, gold Dimercaprol, succimer Copper, arsenic, gold Penicillamine 5 Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 ME 3e: 171 PH03- Antidotes 5 Drug Antidote Cyanide Nitrite, hydroxocobalamin, thiosulfate Methemoglobin Methylene blue, vitamin C Carbon monoxide 100% O2 (hyperbaric chamber) 6 Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 ME 3e: 172 PH03- Antidotes 6 Drug Antidote Methanol, ethylene glycol Ethanol, fomepizol Opioids Naloxone, naltrexone Benzodiazepines Flumazenil Tricyclic antidepressants (TCAs) NaHCO3 (intravenous alkalinization), adjunctively treat for seizure, hyperthermia, and arrhythmia 7 Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 ME 3e: 172 PH03- Antidotes 7 Drug Antidote Heparin Protamine Warfarin (coumadin) Vitamin K, fresh frozen plasma (restore factors II, VII, IX, X, and Proteins C, S) tPA, streptokinase Aminocaproic acid Theophylline !-blocker 8 Antidotes FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 ME 3e: 172 PH03- Adverse effects: cardiovascular reactions Side effect Causal agent Atropine-like (anti-cholinergic) symptoms TCAs, anti-histamines Dilated cardiomyopathy Doxorubicin, daunorubicin Coronary vasospasm Cocaine, sumatriptan Cutaneous flushing Vancomycin, Adenosine, Niacin, Ca-channel blockers (VANC) Torsades de pointes Class III (sotalol) and Class IA (quinidine) antiarrythmics, cisapride (update: removed from the US market because of arrhythmias) Treat with magnesium Dilated cardiomyopathy Dr. Edwin P. Ewing, Jr., commons.wikimedia.org Used with permission. 9 Cardiovascular reactions FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240 ME 3e: 170 PH03- Adverse effects: hematologic reactions Side effect Causal agent Agranulocytosis Clozapine, carbamazepine, colchicine, propylthiouracil, dapsone, methimazole Aplastic anemia Chloramphenicol, benzene, NSAIDs, felbamate Hemolytic anemia (Coombs-positive) Methyldopa Gray baby syndrome Chloramphenicol G6PD-deficient hemolytic anemia Isoniazid (INH), sulfa drugs, aspirin, ibuprofen, nitrofurantoin, primaquin Megaloblastic anemia (hypersegmented neutrophils) Methotrexate, sulfa drugs, phenytoin Thrombosis Oral contraceptives (higher risk with smoking) Hypersegmented Neutrophils Bobjgalindo, commons.wikimedia.org Used with permission. 10 Hematologic reactions FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240 ME 3e: 170 PH03- Adverse effects: respiratory reactions Side effect Causal agent Cough ACE-inhibitors (use angiotensin-receptor blockers instead) Pulmonary fibrosis Bleomycin, amiodarone, busulfan 11 Respiratory reactions FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240 ME 3e: 170 PH03- Adverse effects: GI reactions Side effect Causal agent Hepatitis Isoniazid (INH) Cholestatic hepatitis Macrolide antibiotics (azithromycin, clarithromycin) Hepatic necrosis Halothane, valproic acid, acetaminophen, Amanita phalloides (mushroom) Pseudomembranous colitis Clindamycin, ampicillin, cephalosporins Pancreatitis Azathioprine, sulfonamides, valproic acid, methyldopa, furosemide, corticosteroids, sulindac, tetracycline, didanosine, estrogens, 6-mercaptopurine, pentamidine, 5-aminosalicyclic acid compounds, octreotide Pseudomembranous colitis, endoscopy Bijan Zendeh, commons.wikimedia.org Used with permission. 12 GI reactions FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240 ME 3e: 170 PH03- Adverse effects: reproductive/endocrine reactions Side effect Causal agent Adrenocortical insufficiency Glucocorticoid withdrawal, etomidate Gynecomastia Spironolactone, digitalis, cimetidine, alcohol, estrogens, ketoconazole Hot flashes Tamoxifen, clomiphene Hypothyroidism Lithium, amiodarone 13 Reproductive/endocrine reactions FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240 ME 3e: 170 PH03- Adverse effects: musculoskeletal/connective tissue reactions Side effect Causal agent Gingival hyperplasia Phenytoin Gout Furosemide, thiazides Osteoporosis Corticosteroids, heparin Photosensitivity Sulfonamides, Amiodarone, Tetracyclines, Fluoroquinolones Rash (Stevens-Johnson syndrome) Sulfa drugs, penicillin, carbamazepine, allopurinol Lupus-like syndrome Hydralazine, INH, procainamide, phenytoin Tendon rupture Fluoroquinolones Stevens-Johnson syndrome Dr. Thomas Habif, commons.wikimedia.org Used with permission. 14 Musculoskeletal/connective tissue reactions FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241 ME 3e: 170 PH03- Adverse effects: renal/GU reactions Side effect Causal agent Fanconi’s syndrome Expired tetracycline Interstitial nephritis Methicillin, NSAIDs Hemorrhagic cystitis Cyclophosphamide 15 Renal/GU reactions FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241 ME 3e: 170 PH03- Adverse effects: neurologic reactions Side effect Causal agent Cinchonism Quinidine, quinine Diabetes insipidus Lithium, demeclocycline Seizures Bupropion, imipenem/cilastatin, INH Parkinson-like syndrome Haloperidol, chlorpromazine, reserpine, metoclopramide Tardive dyskinesia Typical antipsychotics 16 Neurologic reactions FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241 ME 3e: 170 PH03- Adverse effects: multi-organ reactions Side effect Causal agent Disulfiram-like reaction Metronidazole, procarbazine, sulfonylureas, cephalosporins Nephrotoxicity / neurotoxicity Polymxyins Nephrotoxicity / ototoxicity Aminoglycosides, vancomycin, loop diuretics, cisplatin 17 Multi-organ reactions FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241 ME 3e: 170 PH03- Cytochrome P-450 interactions Inducers Inhibitors Quinidine HIV protease inhibitors Barbiturates Isoniazid (INH) St. John’s wort Sulfonamides Phenytoin Cimetidine Rifampin Ketoconazole Griseofulvin Grapefruit juice Carbamazepine Omeprazole Chronic alcohol use Chloramphenicol Glucocorticoids Marcolides 18 Cytochrome P-450 interactions FA 2012: 273.1 • FA 2011: 245.2 • FA 2010: 241 ME 3e: 167 PH03- Alcohol metabolism Kaplan Pharmacology 2011: Figure IV-2-1 19 Alcohol metabolism Treatment (both): Ethanol, Fomepizole, or in severe cases, dialysis! FA 2012: n/a • FA 2011: 246.1 • FA 2010: 242 ME 3e: 13 PH03- Sulfa drugs • Any drugs that contain a sulfonamide group • Allergies to these drugs are common Edgar181, commons.wikimedia.org Used with permission Symptoms: Sulfonamide group • Pruritic rash • Fever • Stevens-Johnson syndrome • Hemolytic anemia • Thrombocytopenia • Agranulocytosis • Urticaria (hives) Drugs: • Sulfonamide antibiotics • TMP-SMX • Acetazolamide • Furosemide • Thiazides • Sulfasalazine • Celecoxib • Probenecid 20 Sulfa drugs FA 2012: 273.2 • FA 2011: 246.2 • FA 2010: 242 ME 3e: n/a PH03- Common drug name endings -afil erectile dysfunction drugs -ane inhalational anesthetics -azepam benzodiazepines -azine phenothiazine -azole antifungals -barbital barbiturates -caine local anesthetics -cillin penicillins -cycline antibiotics, protein synthesis inhibitors -etine SSRIs -ipramine tricyclic antidepressants -navir protease inhibitors -olol ! antagonist -operidol butyrophenone (neuroleptic) -oxin cardiac glycoside (inotropic) -phylline methylxanthines -pril ACE inhibitor -terol !2 agonist -tidine H2 antagonist -triptan 5-HT1B/1D agonists (migraine) -triptyline TCAs -tropin pituitary hormone -sartan angiotensin receptor blockers -zolam benzodiazepine -zosin "1 antagonist 21 Common drug name endings FA 2012: 274.1 • FA 2011: 247.1 • FA 2010: 243 ME 3e: n/a

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