Pharmacology Principles PDF

PHARMACOLOGY BASIC PRINCIPLES OF PHARMACOLOGY DEFINITIONS  Pharmacology – study of drugs  Drugs – articles used in diagnosis, prevention, treatment, mitigation of diseases o Classifications of Drugs:  Diagnostic agents  Ex...

PHARMACOLOGY BASIC PRINCIPLES OF PHARMACOLOGY DEFINITIONS  Pharmacology – study of drugs  Drugs – articles used in diagnosis, prevention, treatment, mitigation of diseases o Classifications of Drugs:  Diagnostic agents  Ex: Edrophonium (Tensilon®)  diagnosis of myasthenia gravis; differentiates myasthenic from cholinergic crisis  Radiopharmaceuticals  Technetium 99m sestamibi for MI  Insulin  performance of Insulin Tolerance Test to determine reserves of growth hormone  Replenishers  Given to supplement lacking endogenous substances  Ex: Cyanocobalamin  mgt of pernicious anemia (B12 deficiency)  Insulin  for insulin-requiring DM  Functional Modifiers  Alter normal physiologic function or pathologic processes  Biggest class of drugs  Ex: Analgesics  alter pain perception  Antipyretic  alter effects of endogenous pyrogens  Chemotherapeutic Agents  Agents used to kill or inhibit growth or multiplication of cells (or nucleic acids) that are considered as foreign to the body  Ex: anti-infectives, antineoplastics  Branches of Pharmacology o Pharmacodynamics (PD)  What the drug does to the body  Study of the biochemical and physiologic effects of drugs in biological systems, and the mechanisms by which these effects are produced o Pharmacokinetics (PK)  What the body does to the drug  Study of the processes a drug undergoes as it reaches and leaves the biological site of action o Pharmacotherapeutics  Study of the rational use of drugs in the management of diseases PRINCIPLES OF PHARMACODYNAMICS  Protein – the chemical nature of the biologic site of action o Biological site of action = target site of action = target protein = receptors  Mechanisms of Drug Action o Receptor – mediated  Receptor – cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within the cells  Receptor locations:  TYPES OF RECEPTORS:  GPCR (G Protein-coupled Receptor) o 7-transmembrane spanning receptor o Metabotropic: effects due to metabolites (or secondary messengers) o Involved in signal transduction o Most common receptor o Called “G protein” because it is associated with GDP  Ion Channels o Voltage-gated  Governed by changes in membrane potential (ex: inside membrane is more or less positive or negative)  Na channels: M gate (outside), H gate (inside)  3 conformations of Na channels:  Open – both gates are open  Inactive – M gate is open, H gate is closed  Close – H gate is open, M gate is closed o Ligand-gated  Aka ionotropic receptors  Causes change in configuration of the gate to open → allow movement of certain molecules and ions o Kinases and Catalytic Receptors  Characterized by receptors that exists as monomers o Enzymes  Examples:  RIMA → reversible inhibitor of MAO A o Transporters  Aka carriers o Structural Proteins and Other Molecules  o Nuclear Receptors o Non receptor – mediated  Examples:  Direct chemical interaction – acid neutralizers (e.g. antacids), chelating agents  Colligative mechanism/mass effect – osmotic diuretics o Colligative – properties of solution dependent on number of particles in solution  Counterfeit incorporation – purine-pyrimidine analogues (e.g. 5-FU)  Characteristic of Drug-Receptor Interaction o DEFINITIONS:  Affinity – ability to bind to a receptor or target protein; ligand activity  Intrinsic activity – ability to generate a series of biochemical events leading to an effect after receptor binding  Constitutive/Constitutional activity – ability to generate a series of biochemical events leading to receptor effects even in the absence of a ligand o Receptor Binding Sites o Agonists, Inverse Agonists, Antagonists  Full Agonists – produce the maximal clinical effects expected with receptor interaction  Partial Agonists  Produce less than the maximal clinical effects expected with receptor interaction  Produce some of the anticipated effects with receptor interaction and inhibit other effects attributed to receptor interaction (a.k.a. mixed agonist-antagonist activity)   Clinical Antagonists – drugs that produce clinical effects that are opposite of another drug or of the endogenous agonist; includes antagonists and inverse agonists  Classification of Antagonists: o Based on mechanism of antagonist action  Pharmacologic – opposite effects produced by binding to the same receptor  Physiologic/Functional – produces opposite effects by binding to a different receptor o Based on ability to surmount antagonist effect o Based on reversibility of drug-receptor interaction o Allosteric Modulators  Dose-Response Relationship o Relationship between concentration/dose and effect  Hill Equation  Hill - Langmuir Equation  Dose Response Graph  Graded Dose-Response Graph o Parameters:  o Applications:  Quantal Dose-Response Graph o All or none PRINCIPLES OF PHARMACOKINETICS  PROCESSES: o Transport processes o Liberation o Absorption o Distribution True pharmacokinetic processes; DISPOSITION o Metabolism ELIMINATION o Excretion  TRANSPORT PROCESS - Mechanisms of drug movement across the cell membrane o Basic requirement for drugs to undergo transport: must be in aqueous solution o Passive transport  Involves movement across a bilipid barrier  Dominant; slow transport process  No need for ATP  Movement along concentration gradient  Governed by Fick’s Law of Diffusion  Diffusion coefficient (D) o Property of drug dependent on particle size and lipophilicity o ↑ diffusion coefficient = ↑ rate of transport  Surface area of membrane (A) o The greater the surface area, the faster the rate o lung > small intestines > stomach  Thickness (h) – inversely related to the diffusion coefficient  Parameters that increase diffusion coefficient:  Smaller particle size o Increases surface area contact with cell membrane o Application: micronization to improve bioavailability of rifampicin  Greater lipophilicity o Less degree of ionization of dissociation into charged molecules/ions  Weakly acidic drug in an acidic environment (lower pH)  Weakly basic drug in a less acidic environment (basic or higher pH) environment o Higher lipid-water partition coefficient  Experimental procedure: solubility in an octanol-water system  Lipid-water partition coefficient: ratio of solubility in lipid (octanol) to solubility in water o Carrier – mediated transport  Specificity/Selectivity o Carrier recognizes only certain molecular configuration/conformation o Ex: L-DOPA vs Dopamine  Subject to competition o Molecules with similar configuration/confirmation will compete for the same carrier o Ex: L-DOPA vs 3-O-methyl-DOPA  Saturability – limited number of carriers  Active Transport (Uphill transport)  ATP – dependent  Movement against concentration gradient (at least one)  Fast transport  Facilitated Transport (Downhill transport)  ATP – independent  Movement along concentration gradient  o Convective transport  Movement through water-filled pores o Ion pair transport o Pinocytosis  Involves the use of vesicles; a form of endocytosis  Key properties:  ATP-driven  Transport of large lipids in micelle form o Micelle – oil globules that are stabilized by surfactants  Bile acids/bile salt  most important surfactant in the body  Ex: Vit ADEK, griseofulvin  LIBERATION o Release of drug from the drug product o Drug must be in aqueous solution – required for most transport processes (except pinocytosis)  Solid dosage forms  disintegration  dissolution  Liquid non-solutions  dissolution o Governed by Noyes Whitney Equation o Immediate vs Modified-Release Dosage Forms  ABSORPTION o Definitions:  Pharmacokinetic – rate and extent of drug entry into the systemic circulation  Physiologic – rate and extent of disappearance of the drug from the site of administration or absorption o Factors affecting absorption: o Gastric emptying time o Measuring absorption  Bioavailability – measure of rate and extent of drug entry into the systemic circulation  Can be through blood measurement and urine measurement  Minimum number of subjects/participants required for bioavailability studies: 6  Bioequivalence  Measure of similarity in bioavailability of a generic drug product to that of the innovator or reference drug product  Measures 90% confidence interval about the ratios of AUC, Cmax, and Tmax  Acceptable 90% confidence interval: 80 – 125% (extended to 75 – 133% for Cmax)  Minimum number of subjects/participants required for bioequivalence studies: o 12 – immediate release o 20 – controlled release  Can be done on drug products that are pharmaceutical equivalents or pharmaceutical alternative o Pharmaceutical equivalents – contain same drug in the same salt/ester/complex, same dosage form, same dose, same quality o Pharmaceutical alternatives – contain the same drug but may have different salt/ester/complex, different dosage forms but can be measured in equivalent doses  Which drug products it is necessary?   Therapeutic Equivalence  If they are pharmaceutical equivalent and can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling; “switching/substitution”  FDA Criteria: o Approved as safe and effective o Pharmaceutical equivalent o Bioequivalent o Adequately labeled o Manufactured in compliance with cGMP regulations  DISTRIBUTION o The process of drug movement from the systemic circulation to the different body compartments (organs/tissues) o Objectives:  Most biological sites of action are outside the systemic circulation  Distribution allows drug to reach the biological site of action o Distribution Parameters:  Protein binding  Drugs exist in 2 forms in the systemic circulation: bound drug and unbound drug (free drug)  Blood proteins involved: o Albumin (nonselective but preferentially binds to weak acid) o Alpha 1 acid glycoprotein (nonselective but preferentially binds to weak base) o Globulin (structurally selective; binds to hormones)  Examples of drugs with high protein binding: diazepam, digitoxin, indomethacin, tolbutamide, warfarin, midazolam  Relevance: o Limit access to compartments o Longer duration o Drug displacement  most likely to happen to px with problems with drug clearance (renal or hepatic dysfunction)  Volume of Distribution  Hypothetical volume of body fluid necessary to dissolve a given dose or amount of drug to a concentration equal to that of the plasma  Relevance: o Estimating loading doses o Predicting fluid compartment of distribution  Drugs with HIGH Vd: atropine, chloroquine, digoxin, fluoxetine, imipramine, TCA, beta blockers  Drugs with LOW Vd: chlorpropamide, furosemide, tolbutamide, valproic acid, warfarin  METABOLISM o Biotransformation – chemical change o First pass effect/First pass metabolism – initial metabolism a drug undergoes before reaching the systemic circulation o Goals: metabolites that are  Less active/inactive  Less toxic/nontoxic  Polar and easily excreted o Exceptions:  Prodrug  active  Active  active  Nontoxic  toxic  o PHASES OF DRUG METABOLISM  Phase I: Functionalization Phase  Addition or unmasking of a functional group  Reactions: hydrolysis, oxidation, reduction  Phase II: Conjugation/Synthetic Phase  Addition of polar conjugate  Reactions: glucuronidation, acetylation, glycine conjugation, etc o Enzyme Inhibition – Induction o Genetic Polymorphism  Genetic differences in the expression of enzymes  Categories based on enzyme expression:  Common enzyme systems subject to polymorphism  EXCRETION o Elimination: metabolism and excretion  Excretion – loss of the drug from the body  Site: kidneys (major), biliary, lungs, sweat/secretions, mammary  Prerequisite: drugs must be polar or water soluble  Renal excretion involves glomerular filtration +/- tubular secretion AUTONOMIC PHARMACOLOGY ANATOMY AND PHYSIOLOGY OF THE ANS  ORGANIZATION OF THE NERVOUS SYSTEM o Afferent (sensory) neurons – effector to CNS o Efferent (motor) neurons – CNS to effector o Interneuron – integrate information that flows between afferent and efferent ANS SNS Anatomy 2 – neuron setup 1 – neuron setup Ganglia Present Absent Effector organs Smooth muscles, glands Skeletal muscles Function Involuntary / independent / automatic / vegetative Voluntary o Ganglion – aggregation neurons’ cell bodies located in the PNS  SYNAPTIC NEUROTRANSMISSION o Explains the mechanism of impulse transport across the synapse o Presynapse  Synthesis, storage, and release of neurotransmitters (through exocytosis)  Have enzymes for metabolism  Autoreceptors – receptors found presynaptically o Synapse  Have enzymes for metabolism o Post-synapse  Majority of receptors are present  Have enzymes for metabolism  AUTONOMIC NERVOUS SYSTEM o Composed of effector/motor neurons, has ganglia, controls involuntary functions and has 3 major subdivisions:  Sympathetic NS  Parasympathetic NS  Enteric NS – a semiautonomous part of the ANS located in the GI tract, with specific functions for the control of this organ system SYMPATHETIC PARASYMPATHETIC Thoracolumbar Craniosacral Origin / Roots of Fibers T1 – T12; L1 – L5 CN 9, 10, 7, 3; S2 – S4 Short preganglionic Long preganglionic Length of Neurons Long postganglionic Short postganglionic Location of Ganglion Near the spinal cord Near the effector organs Preganglion: ACh Neurotransmitters Pre/Postganglion: ACh Postganglion: NE (principal NT), Epi, DA Receptors (ganglion) Nicotinic receptor (NN) Nicotinic receptor (NN) Receptors (effector) Adrenergic receptors (, ) Muscarinic (majority), nicotinic SYMPATHETIC DRUGS  Receptors (Adrenoceptors)  Sympathomimetics o Classifications:  Based on Chemistry  Catecholamines o Compounds that possess a catechol nucleus (a benzenediol) and an ethylamine side chain o Properties of natural catecholamines as drugs:  High potency at adrenoceptors  Higher affinity at beta receptors than alpha receptors o Low dose  beta effect o Higher dose  alpha effect  Poor penetration in the CNS  Metabolized by MAO and COMT  Undergoes extensive first pass effect therefore no oral preparations available  Degradation products of metabolism of catecholamines: o NE, Epi: 3 – methoxy – 4 – hydroxymandelic acid (vanillylmandelic acid) o DA: homovanillic acid o Examples:  Natural catecholamines: NE, Epi, DA  Synthetic catecholamines: Isoproterenol  o BIOSYNTHESIS:  Tyrosine hydroxylase – rate-limiting enzyme  Storage of DA through VMAT is needed to avoid premature metabolism by enzymes of the presynaptic cleft (e.g. MAO)  Termination processes: diffusion, metabolism (MAO, COMT), reuptake (Uptake 1  NET, DAT)  Reuptake inhibitors: Cocaine, TCA, Reboxetine (antidepressant)  Non-catecholamines o Characteristics:  No catechols  Not metabolized by MAO and COMT  Longer half-lives  Administered orally o Examples:  Phenylephrine  Methoxamine  Ephedrine  Amphetamine  Based on Mechanism of Action  Direct – acting o NONSELECTIVE  Epinephrine  Binds to 1, 1, 2  1st line tx for anaphylactic shock, anaphylaxis and anaphylactoid reaction o Anaphylactic SHOCK  hypotension  Epi helps in increasing BP of px (alpha 1 innervation) o Also causes difficulty in breathing  Epi helps in bronchodilation (beta 2 innervation)  Cardiac stimulant, local vasoconstrictor (with lidocaine)  For glaucoma (Dipivefrin)  Norepinephrine  Binds to 1, 1  1st line for septic shock  Alternative management for cardiogenic shock; for acute heart failure  Dopamine  Binds to 1, 2, D1  Stimulates them in dose-dependent manner o At low therapeutic doses  stimulates renal dopamine o At high doses  stimulates cardiac 1 o At higher doses  stimulates to 1  Tx of acute severe heart failure and hypotensive shock  Toxicity:  Digital necrosis  Ventricular tachyarrhythmias  o SELECTIVE  1 Agonists  Phenylephrine, Methoxamine, Propyhexedrine, Tetrahydrozoline, Oxymetazoline, Nafazoline, Midodrine  Uses: nasal and ophthalmic decongestants; for hypotension  Toxicity: o Rhinitis medicamentosa o Hypertension o Urinary retention  2 Agonists  Clonidine, Methyldopa, Guanfacine, Guanabenz o Centrally-acting o Antihypertensive  Apraclonidine, Brimonidine o Anti-glaucoma   Agonists  Isoproterenol (Isoprenaline) o Nonselective o Alternative mgt for heart failure  Dobutamine o 1 – selective; Cardiac stimulant o Diagnostic agent for pharmacologic stress test o 1st line for cardiogenic shock; for mgt of heart failure  Salbutamol/Albuterol, Terbutaline, Metaproterenol, Pirbuterol (SABA); Salmeterol, Formoterol, Bambuterol, Indacaterol (LABA) o 2 – selective o Bronchodilators  Ritodrine, Isoxuprine o Tocolytics  Mirabegron o 3 – selective o Relief of sx of overreactive bladder  Dopamine Agonists  Fenoldopam o Alternative tx for hypertensive crisis  Indirect – acting o Releasers  Enhance exocytosis of NE  Tyramine, Amphetamine, Methamphetamine  Phenmetrazine  Anorexiant  Methylphenidate  1st line for ADHD  Modafinil  For narcolepsy o Reuptake Inhibitors  Cocaine  Local anesthetic; only local anesthetic that causes vasoconstriction  Atomoxetine  Mgt of ADHD  Sibutramine  Obesity  Mixed – acting o Causes activation of adrenergic receptors by both direct binding, as well as release of stored NE from presynaptic terminals o Ephedrine  For narcolepsy o Pseudoephedrine (Sudafed®)  Used as a decongestant o Mephentermine, Metaraminol  For hypotension o Phenylpropanolamine  For nasal congestion  Sympatholytics o Are antagonists at adrenoceptors prevent or reverse the actions of:  Endogenously released NE or Epi  Exogenously administered sympathomimetic agents o Classifications:  Direct – acting  Alpha Blockers o Effects: vasodilation, relief of urinary retention o NONSELECTIVE  Phenoxybenzamine  1, 2 – nonselective, irreversible  For presurgical tx of pheochromocytoma  Used for px with mastocytosis (H blockade)  Used for mgt of carcinoid tumor (5-HT blockade)  Phentolamine  1, 2 – nonselective, reversible  For tx of pheochromocytoma (during surgery)  Mgt of Raynaud syndrome  Accidental local infiltration of alpha agonists and sympathomimetic poisoning  Mgt of erectile dysfunction (administered locally) o SELECTIVE  Prazosin, Doxazosin, Terazosin, Tamsulosin, Alfuzosin  1 – selective, reversible  Mgt of hypertension (prazosin, doxazosin, terazosin)  Mgt of benign prostatic hyperplasia/BPH (tamsulosin, alfuzosin)  Yohimbine  2 – selective, reversible  Found in some dietary supplements  Used in veterinary medicine to reverse sedative effects of alpha-2 agonist such as Xylazine o Toxicity:  Reflex tachycardia  Orthostatic hypotension  Nausea and vomiting   Beta Blockers o Effects: negative dromotropism (lesser conduction velocity), negative inotropism (lesser force), negative chronotropism (lesser rate) o NONSELECTIVE  Nadolol, Sotalol, Timolol, Propranolol o SELECTIVE  1 Agonists (Cardioselective)  Metoprolol, Atenolol, Bisoprolol, Acebutolol, Betaxolol, Esmolol, Celiprolol o WITH INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA)  Pindolol, Carteolol, Celiprolol, Labetalol, Acebutolol, Penbutolol  Have the ability not only to block but also to weakly stimulate beta 1 and beta 2 receptors  diminished effect on cardiac rate and cardiac output  Can be beneficial in patients who cannot tolerate other beta blockers due to preexisting bradycardia or heart block o WITH MEMBRANE – STABILIZING ACTION  Propranolol, Pindolol, Acebutolol, Labetalol, Metoprolol o WITH ALPHA – 1 BLOCKING ACTION  Carvedilol, Labetalol o ENHANCES NITRIC OXIDE  Nebivolol  Most cardioselective blocker o Uses:  1st line agents for px with history of post-MI  Mgt of chronic stable angina pectoris (by lowering myocardial oxygen demand)  Mgt of CHF (bisoprolol, metoprolol succinate, carvedilol, nebivolol)  Arrhythmia (Class II)  Sympathetic symptoms of hyperthyroidism (propranolol)  inhibits peripheral conversion of T4 to T3  Prophylaxis of migraine; for stage fright (propranolol)  Glaucoma (timolol, betaxolol) o Toxicity:  Augmentation of hypoglycemia  Lipidemia  Bradycardia; AV block  Bronchoconstriction  Peripherally – acting (Adrenergic Neuronal Blockers)  Reserpine o Inhibits storage of DA o Toxicity: CNS depression, extrapyramidal symptoms  Bretylium, Guanadrel, Guanethedine o Inhibits release of NE o Causes pharmacologic sympathectomy (guanethedine) PARASYMPATHETIC DRUGS  Acetylcholine o Locations: Preganglionic fibers, Postganglionic fibers, CNS, skeletal muscles, stomach o Biosynthesis:  Hemicholinium – research drug; inhibits transport of choline to the nerve terminal  Vesamicol – inhibits transpot of ACh into its vesicles for storage by VAT  Botulinum toxin – cleaves SNAP25 disrupting the fusion of vesicles preventing ACh release  Receptors  Parasympathomimetics o Classifications:  Direct – acting  Mimic the effects of ACh by binding to either muscarinic or nicotinic receptors  Choline Esters o NONSELECTIVE  Acetylcholine  Primary transmitter at cholinergic nerve endings (preganglionic ANS, postganglionic parasympathetic, postganglionic sympathetic cholinergic fibers to thermoregulatory sweat glands and some other organs, and somatic neuromuscular end plates)  It is rapidly inactivated by cholinesterases  Carbachol  Structurally similar to ACh, thus effectively mimics effects of ACh  Not very susceptible to acetylcholinesterases therefore has long duration of action  Sometimes used only locally as miotic during eye surgery and for tx of glaucoma  Methacholine  Used for pulmonary challenge test  diagnosis of bronchial asthma o M – SELECTIVE  Bethanechol (Urecholine)  Mgt of urinary retention  Post-op abdominal distention and gastric atony  Alkaloids o NONSELECTIVE  Arecoline o M – SELECTIVE  Muscarine  Pilocarpine  Mgt of glaucoma by increasing aqueous outflow o N – SELECTIVE  Nicotine, Lobeline, Varenicline  Mgt of smoking cessation  Indirect – acting (Cholinesterase inhibitors/Anticholinesterases)  Binds to acetylcholinesterase enzyme which catalyzes breakdown of ACh  resulting to buildup of ACh in the synaptic cleft and corresponding effect  REVERSIBLE INHIBITORS o Aminoalcohol  Edrophonium (Tensilon®)  Very short duration of action  ~ 10 – 20 minutes  Typically restricted to diagnosis of myasthenia gravis  Also used for NMB reversal o Carbamates  Physostigmine (Eserine)  Neostigmine  Its structure is more polar therefore, it does not absorb well from the GI tract and does not enter the CNS  Used for tx of myasthenia gravis; post-op ileus and urinary retention  Used to reverse effects of anesthesia from nondepolarizing NMB  Pyridostigmine  Longest – acting  DOC for myasthenia gravis  Ambenonium, Demecarium  IRREVERSIBLE INHIBITORS o Organophosphates  Echothiophate  Therapeutic use is restricted to tx of open-angle glaucoma only, however, it is rarely used at all due to its s/e profile  Malathion, Parathion o Nerve Gases  Sarin, Tabun, Soman o CNS – ACTING  Tacrine, Donepezil, Galantamine, Rivastigmine  Uses: o Glaucoma (physostigmine, demecarium, echothiophate) o GI and urinary tract atony (physostigmine, demecarium, echothiophate) o Myasthenia gravis  An autoimmune disease caused by antibodies that block ACh receptors  Characterized by progressive muscle weakness, drooping of eyelids, respiratory paralysis  Diagnostic agent: Edrophonium (Tensilon test)  Therapeutic agent: Pyridostigmine, Ambenonium, Neostigmine o Alzheimer’s disease (tacrine, donepezil, galantamine, rivastigmine)  Toxicity: o DUMBBELSS (diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, sweating, salivation)  Treatment:  Atropine (primary tx)  Pralidoxime, Diacetylmonoxime (cholinesterase reactivators)  Parasympatholytics o Classifications:  Antimuscarinics (Anticholinergics)  Block primarily muscarinic receptors thus causing inhibition of muscarinic functions  Atropine o Prototype o Actions: Inhibits gastric secretion, tachycardia, inhibits secretions (dry mouth, anhidrosis, cutaneous vasodilation, erythema), mydriasis, cycloplegia, bronchodilation, ileus, urinary retention, CNS effects (acute psychosis, confusion, agitation, disorientation) o Uses:  Symptomatic bradycardia  Antidote of cholinomimetic poisoning  Given with diphenoxylate to minimize addiction with diphenoxylate  Scopolamine o Centrally-acting o Mgt of motion sickness and post-op N & V  Benztropine, Biperiden, Trihexyphenidyl o Centrally – acting o Mgt of EPS and Parkinsonism  Homatropine, Anistropine, Cyclopentolate o Mydriatics, cycloplegics  Ipratropium, Tiotropium, Oxytropium, Aclidinium, Umeclidinium o Bronchodilators o Given with LABAs for additive effect o Mgt of bronchial asthma and COPD IPRATROPIUM TIOTROPIUM Short – acting (4 – 6 hrs) Long – acting (24 hrs) Once – a – day dosing Typically requires up to 4x daily dosing Less effective for asthma; more effective for COPD  Pirenzepine, Telenzepine o Act on the gastric gland o Peptic ulcer disease  Darifenacin, Fesoterodine, Solifenacin, Tolterodine o MOA: Like atropine, but modest selectivity for M3 receptors o For urinary urgency and incontinence  Methscopolamine, Glycopyrrolate, Hyoscine, Dicycloverine, Oxybutinin, Scopolamine o Act on GIT and urinary bladder o Mgt of hypermotility disorders and urinary incontinence  Toxicity: o Hyperthermia or atropine fever (“hot as a pistol”) o Reduced/stopped sweating, salivation, lacrimation (“dry as a bone”) o CNS toxicity (“mad as a hatter”) o Dilation of the cutaneous vessels of the arms, head, neck, and trunk/atropine flush (“red as a beet”)i o Tachycardia o Acute angle closure glaucoma o Urinary retention especially in men with prostatic hyperplasia o Constipation o Blurring of vision  Antinicotinics  GANGLIONIC BLOCKERS o NN blockers o Prevent ACh at neuromuscular junction  prevent triggering of skeletal muscle contractions o Hexamethonium, Trimethaphan, Mecamylamine  Vasodilation and anticholinergic  NEUROMUSCULAR BLOCKERS o NM blockers o Skeletal muscle relaxants; used for spastic disorders o Anesthetic adjuncts o Classification:  DEPOLARIZING NMB  Act as acetylcholine receptor agonists  Mimic the ACh however they are much more resistant to degradation by AChE and therefore produce persistent depolarization  Succinylcholine o Antinicotinic agonist o Irreversibly activates NM receptors  Phase I Block (prolonged depolarization): transient fasciculations  flaccid paralysis  Phase II Block (repolarization and desensitization) o Use: facilitate sequence endotracheal intubation in critically ill patients (during emergency setting) o Toxicity:  Respiratory paralysis (Tx: edrophonium, neostigmine)  Malignant hyperthermia (Tx: dantrolene)  Myalgia, myositis, rhabdomyolysis  NONDEPOLARIZING NMB  Competitive antagonists  Bind to ACh receptors but they do not induce ion channel opening  prevent depolarization of the muscle cells  inhibit muscle contraction  Once administered, these agents paralyze small, fast, contracting muscles first (eyes, face, fingers), then larger muscles (neck, trunk, limbs), and lastly, diaphragm o These muscles recover in the reverse manner  Curare Derivatives o MOA: Block NM receptors  immediate paralysis o Isoquinoline derivatives (~ curium)  Tubocurarine – prototype, long-acting  Atracurium – s/e: causes histamine release which results in vasodilation, decreased BP, flushing, reflex tachycardia; laudanosine  toxic metabolite  Cisatracurium – alternative for atracurium o Steroidal (~ curonium)  Pancuronium  Rocuronium  Vecuronium o Uses:  Used to facilitate mechanical ventilation and tracheal intubation o Toxicity:  Respiratory paralysis  Anaphylactoid reaction (tubocurarine) AUTACOIDS  Endogenous compounds  Localized hormones  Site of release: near the site of action AUTACOIDS ENDOCRINE HORMONES – Produced by virtually all cells – Produced by specific cells – Localized hormones – Systemic hormones  FOUR TYPES OF AUTACOIDS o Bradykinin o Eicosanoid o Serotonin o Histamine HISTAMINE  Synthesis: Produced by decarboxylation of histidine through L-histidine decarboxylase  Location: Highly concentrated in vesicles in mast cells and basophils (effectors during allergy), enterochromaffin cells in the gut, and some neurons  Mechanism of release: o Calcium-dependent degranulation – induced by IgE fixation to mast cells  anaphylaxis o Calcium-independent degranulation – induced by drugs (e.g. morphine, guanethedine, tubocurarine, amine, antibiotics)  anaphylactoid reaction  Histamine Receptors – Gq – coupled – Typical responses: o Pain and itching in the skin (pruritus) H1 o Bronchoconstriction  shortness of breath o Vasodilation (due to histamine-evoked release of nitric oxide by activating NOS) ↓BP o Local edema (due to contraction of capillary endothelial cells therefore opening gaps in the permeability barrier) o Wakefulness in CNS – Gs – coupled – Mediates gastric acid (HCl) secretion by parietal cells in the stomach H2 – Also has a cardiac stimulant effect – Reduce histamine release from mast cells  negative feedback – Gi – coupled – Involved mainly in the presynaptic modulation of histaminergic neurotransmission in the CNS H3 – Decreases transmitter release from histaminergic and other neurons, probably mediated by a decrease in calcium influx through N-type calcium channels in nerve endings – Gi – coupled H4 – Located on leukocytes (especially eosinophils) and mast cells – Involved in chemotactic responses  inflammation  Histamine Agonists o Exogenous histamine  No longer clinically used  Formerly used in pulmonary challenge test  Formerly used in determination of adequacy of HCl secretion o Betahistine  H1 agonist, H3 antagonist  Use: management of Meniere’s disease  characterized by presence of fluid in the inner ear; vertigo o Impromidine  Investigational histamine agonist drug  Histamine Antagonists o Functional/Physiologic Antagonist (different targets = opposite effects)  Epinephrine – act on effectors cells in the direction opposite to that of histamine  helps to suppress further chemical release of histamine o Pharmacologic Antagonist (same targets = opposite effects)  H1 Antihistamines  Mechanism, Effects, Uses: o 1st Gen H1 antihistamines: Lipophilic  can cross BBB  sedating effects o Possess central anticholinergic effects o Anti-motion sickness effects o Potent local anesthetics o Tx of allergic rhinitis o Tx of urticaria and atopic dermatitis o Appetite suppressants  1st Generation o Ethanolamines  Most sedating, most efficacious  Examples:  Diphenhydramine (Benadryl®) o DOC for acute dystonic crisis (caused by antipsychotics) o Anti-motion sickness o Also used for mgt of chemotherapy-induced vomiting  Dimenhydrinate – salt form of diphenhydramine  Doxylamine o Sleeping aid (Unisom®) o + pyridoxine = prevention of morning sickness in pregnancy  Clemastine  Carbinoxamine o Alkylamines  Components of cold medications  Examples:  Chlorpheniramine  Brompheniramine o Piperazines  Antiemetic, antivertigo  Examples:  Meclizine (Bonamine®)  Cyclizine  Hydroxyzine (Iterax®) – Prodrug of cetirizine o Ethylenediamines  Examples:  Pyrilamine  Tripelennamine o Phenothiazine  Examples:  Promethazine – Used to induce pre-op sedation (anesthetic adjunct) o Piperidine  Examples:  Cyproheptadine o Has antiserotonergic property; blocks 5-HT1 and 5-HT2 receptors o Used in the mgt of serotonin syndrome  2nd Generation o Longer duration of action than 1st gen o Less Sedating: Piperazines o True, Nonsedating: Piperidines  Recommended for people that require mental alertness (e.g. pilots, drivers, etc)  Examples:  Loratadine  Fexofenadine o Active metabolite of terfenadine ( cardiotoxic) o Alkylamines  Example:  Acrivastine  H2 Antihistamines  Clinical Use: o Gastric and duodenal ulcers o Mgt of acid peptic diseases o Adjuncts in the mgt of allergic reactions  Examples: o Cimetidine  Prototype; least potent  Toxic effects:  Enzyme inhibitor  Antiandrogen effects (gynecomastia, loss of libido, infertility) o Famotidine – Most potent o Ranitidine o Nizatidine SEROTONIN  Location: vesicles in the enterochromaffin cells of the gut (small intestine: >90%), platelets, and neurons of the CNS and enteric nervous system  Synthesis: produced from tryptophan through hydroxylase and decarboxylase forming 5-hydroxytryptamine  Serotonin Receptors: – Presynaptic receptors (CNS) 5-HT1A – Autoregulation – Inhibits further release of serotonin – Found in vascular smooth muscles (except blood vessels in the heart and skeletal muscles) 5-HT1B/1D – Vasoconstriction – Mediate synaptic excitation in the CNS and smooth muscle contraction (gut, bronchi, uterus, some vessels) or relaxation (other vessels) 5-HT2 – Probably mediates some of the vasodilation, diarrhea, bronchoconstriction that occurs as signs of carcinoid tumor 5-HT2C – Mediate a reduction in appetite that has been used in the tx of obesity – Found in the CNS especially in the chemoreceptive area and vomiting center, and in peripheral sensory and 5-HT3 enteric nerves – Found in the GI tract 5-HT4 – Play and important role in intestinal motility  Serotonin Agonists o 5-HT1A Partial Agonist  Buspirone – anxiolytic; therapeutic effects observed after 2 weeks o 5-HT1B/1D Agonist  Sumatriptan (prototype), Naratriptan  1st line tx for acute migraine and cluster headache attacks o 5-HT2C Agonist  Lorcaserin – approved for the tx of obesity; activates receptors in the CNS and appears to moderately reduce appetite  Fenfluramine, Dexfenfluramine  Withdrawn in the USA because their use was associated with pulmonary hypertension and damage to cardiac valves o 5-HT4 Partial Agonist  Cisapride, Tegaserod  Acts as agonist in the colon  Was approved and briefly marketed for use in chronic constipation and IBS  Now restricted because of cardiovascular toxicity o 5-HT4 Full Agonist  Prucalopride  Serotonin Antagonists o 5-HT2 Antagonist  Ketanserin – antihypertensive agenet  Phenoxybenzamine – mgt of carcinoid tumor  Cyproheptadine o 5-HT3 Antagonist  Ondansetron, Granisetron, Dolasetron, Alosetron, Palonosetron – Antiemetic o Ergot Alkaloids  From Claviceps purpurea  Nucleus: ergoline  Have varying agonist and antagonist effects in the ff receptors:   - receptors  Dopamine receptors  5-HT receptors o 5-HT2 receptor agonists  Ergotamine – vasoselective; for tx of acute migraine headache through cerebral vasoconstriction  Ergonovine – uteroselective; for tx of postpartum bleeding and tx of acute migraine o 5-HT2 receptor antagonist  Methysergide – prophylaxis of acute migraine headache  Toxic effects:  Prolonged vasospasm – most serious a/e; can lead to gangrene  GI disturbance – most common  Retroperitoneal fibrosis EICOSANOIDS  Endogenous fatty acid autacoids  Products of eicosanoic acid metabolism  Families: o Leukotrienes – straight-chain derivatives o Prostacyclin, prostaglandins, thromboxane – cyclic derivatives  Arachidonic acid – most common precursor; 20C FA  Biosynthesis:  Effects: o Thromboxane A2 (TXA2) – activates TPa,B receptors; causes platelet aggregation, vasoconstriction o Prostacyclin (PGI2) – activates IP receptors; reduces platelet aggregation, causes vasodilation  Analogs:  Epoprostenol – vasodilator in pulmonary hypertension, antiplatelet agent in extracorporeal dialysis  Treprostinil – for pulmonary hypertension o Prostaglandins  PGE1  Relaxes smooth muscle in ductus arteriosus  Protective effects on gastric mucosa  Analogs: o Misoprostol – protective agent in peptic ulcer disease; banned due to being abortifacient o Alprostadil - used in the transposition of great vessels to maintain patent ductus until surgery; used for erectile dysfunction  PGE2  Major inflammatory prostaglandin; endogenous vasodilator  Released in large amounts from the endometrium during menstruation and can cause dysmenorrhea  Involved in the physiologic softening of the cervix at term; may play a role in labor  Analog: o Dinoprostone – abortifacient (therapeutic abortion), cervical ripening  PGF2  Increase aqueous humor outflow  reduces IOP  Analog: o Latanoprost – for glaucoma o Leukotrienes  LTB4 – chemotactic factor in inflammation  LTC4, LTD4  Components of important mediator of bronchoconstriction and shock, slow-reacting substance of anaphylaxis (SRS-A)  Bronchoconstrictors important in anaphylaxis, asthma; causes edema  Leukotriene antagonists  Zileuton o MOA: Lipooxygenase inhibitor; blocks synthesis of leukotrienes o For asthma prophylaxis  Montelukast, Zafirlukast o MOA: Leukotriene receptor inhibitors; block CysLT1 receptor; reduces bronchoconstriction in asthma o For asthma prophylaxis DRUGS FOR RHEUMATOLOGIC DISORDERS RHEUMATOLOGIC DISORDERS  Inflammation o A nonspecific immune response against an adverse stimulus o Can be due to microbial invasion and physical injury o Purpose: for protection and a part of healing process o Cardinal Signs of Inflammation  Rubor - redness  Dolor - pain  Calor - heat  Tumor - swelling  Functio laesa – loss of function  Autoimmune Diseases o Arise from overreactive immune responses (T cells, B cells) o Adversely target substances and tissues normally present in the body  Rheumatoid arthritis (RA)  Osteoarthritis (OA) – most common; non-inflammatory disease  Systemic Lupus Erythematosus (SLE)  Ankylosing Spondylitis (AS) – autoimmune  Gaps/Problems encountered in rheumatoid disorders: o Majority are autoimmune o There is accompanied pain and inflammation ANALGESIC AGENTS  Induce analgesia (loss of pain perception)  Two Classes: o Non-Narcotics  Para-aminophenol Derivative  Acetaminophen/Paracetamol o MOA: Weak prostaglandin synthesis inhibitor in the periphery; reversibly inhibits COX, mostly in CNS; inactivated peripherally o Clinical Use:  Antipyretic, analgesic, but not anti-inflammatory even at higher doses  Used as substitute of aspirin to avoid Reye syndrome in children with viral infection  1st line for osteoarthritis o Metabolized by hepatic microsomal enzymes to sulfate and glucuronide o A/E: overdose produces hepatic necrosis  acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue byproducts in liver (antidote: N-acetylcysteine)  Risk factors associated with paracetamol-induced hepatotoxicity:  Dose taken is > 5 mg/kg/day or > 4 g/day  Patient has pre-existing liver disease  Concomitant use of CYP1A2 inducers o Advantages:  Safe in pregnant and lactating women and among children  Non-Steroidal Anti-inflammatory Drugs (NSAIDs)  Majority are weak organic acids (have low pKa values) except Nabumetone (which is a prodrug; upon metabolism, it becomes acetic acid derivative) Actions of COX/PGHS:  Cyclooxygenase (COX) Isoforms:  COX-1 (Constitutive/Housekeeping/Homeostatic Enzyme)  For maintenance functions (for survival)  Cytoprotection, renal vasodilation (↑ GFR  diuresis)  COX-2 (Inducible Enzyme)  For pain and inflammation (PGE2)  Peroxidase (POX)  NONSELECTIVE COX INHIBITORS o Aspirin (prototype)  MOA: Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by covalent acetylation  ↓ synthesis of TXA2 and prostaglandins; ↑ bleeding time; no effect on PT, PTT; effect lasts until new platelets are produced  Clinical Uses:  Low dose (< 325 mg/day): antiplatelet (80 mg  optimal dose)  Intermediate dose o 300–1200 mg/day: antipyretic (inhibits response to IL-1) o 140 mmHg or a sustained diastolic blood pressure of > 90 mmHg  Results from increased peripheral vascular arterial smooth muscle tone  Classification of Blood Pressure  Hypertensive Crises HYPERTENSIVE EMERGENCY HYPERTENSIVE URGENCY Significant elevation of BP Yes Yes SBP >180; DBP >120 Yes No Target Organ Damage Yes No IV medications required Yes No Associated conditions Heart attack, aortic bleeding, Nose bleed, severe optic swelling, hypertensive hypertension, scleroderma encephalopathy, excess circulatory fluid (edema)  Hypotension – SBP 90 % Volume of distribution 6.3 L/kg 0.6 L/kg Elimination Renal Hepatic o Toxicity:  Serum levels exceed 2 ng/mL  Electrolyte abnormalities  Chronic kidney disease  Antidote for digoxin toxicity: Digoxin antibodies (Digibind, DigiFab)  Beta-adrenergic Agonists o Dopamine (low dose)  B1 > B2 o Dobutamine  Useful for patients with acute decompensated HF secondary to myocardial infarction manifesting with hypotension  Bipyridines o Amrinone, Milrinone o MOA: increase cyclic adenosine monophosphate (cAMP) by inhibiting its breakdown by phosphodiesterase isozyme 3 (PDE-3) and cause an increase in cardiac intracellular calcium  Brain Natriuretic Peptide (BNP) Analogue o Nesiritide (Natrecor®)  MOA: Activates BNP receptors, increases cGMP  Effects: Vasodilation; diuresis  Uses: Acute decompensated failure; has not been shown to reduce mortality  Toxicity: Renal damage, hypotension, may increase mortality AGENTS USED IN CARDIAC ARRHYTHMIAS ACTION POTENTIAL OF CARDIAC MUSCLES  5 PHASES: o Phase 0: Rapid depolarization (Na+ influx) o Phase 1: Early repolarization (K+ efflux) o Phase 2: Plateau phase (Ca2+ influx, K+ efflux) o Phase 3: Final repolarization (persistent K+ efflux, now exceeding Ca2+ influx) o Phase 4: Hyperpolarization/slow depolarization (resting phase)  Classes of Anti-arrhythmic Drugs (Vaughan-William Classification) o CLASS I: Na+ Channel Blockers  Class IA  Disopyramide o A/E: Torsades de pointes (DOC: MgSO4)  Quinidine o A/E: cinchonism (headache, dizziness, tinnitus), Torsades de pointes o  Procainamide o A/E: Torsades de pointes o  Class IB  Best for the management of conduction abnormalities following myocardial infarction or digitalis toxicities  Tocainide  Mexiletine  Lidocaine  Phenytoin  Class IC  Moricizine  Encainide  Flecainide  Profapenone  o CLASS II: Beta Blockers  Has been proven to reduce mortality CARDIOSELECTIVE BETA BLOCKERS  Propranolol  Metoprolol  Atenolol o CLASS III: K+ Channel Blockers  Bisoprolol  Amiodarone  Acebutolol  DOC for atrial fibrillation and ventricular tachycardia  Betaxolol  Multi-ion channel blocker  Esmolol  Contains iodine (32%) and is related structurally to  Cineprolol thyroxine; exerts Wolff-Chaikoff effect  Nebivolol  A/E: hypo/hyperthyroidism, pulmonary fibrosis,  Dronedarone  Multi-ion channel blocker  Vernakalant  Multi-ion channel blocker  Ibutilide  Bretyllium  Dofetilide o CLASS IV: Ca2+ Channel Blockers  Inhibit phase 2 of myocardial action potential  Verapamil  Diltiazem  Miscellaneous Agents o Digoxin o Adenosine  DOC for paroxysmal supraventricular tachycardia (IV) o Magnesium Sulfate DRUGS USED IN GOUT PURINE METABOLISM HYPERURICEMIA  Conditions associated with hyperuricemia o Gout  Monosodium urate (MSU) crystal deposition syndrome  Serum uric acid (UA) 6-7 mg/dL  Differs in men and women  Pathogenesis:  Synoviocyte phagocytosis of urate crystals  Secretion of inflammatory mediators (PG, IL-1, LTB4)  Amplification by PMNs and MNPs o Leukocytes o Macrophages  Manifestations:  Asymptomatic hyperuricemia  Acute gouty flare o Metabolic inflammatory disease; monoarticular (metatarsophalangeal joint in the big toe of one foot) o Constitutional symptoms: fever, hypotension  Intercritical gout (latency period) - Interstitial nephritis  Chronic tophaceous gout - Tophi (deposition of crystals in the joints), renal calculi, podagral (joint deformation)  Urate neuropathy  Asymptomatic hyperuricemia o Risk factors: male, high purine diet, signs/sx of gout, elderly  Uric acid crystals o Microscopy: needle-shaped crystals; (+) birefringent, (-) elongation o Anthrocentesis  aspirated from affected joint spaces  Goals of Pharmacotherapy o Relieve attacks  Leukocytes (Colchicine)  Inflammation, WBCs (SA-NSAIDs, glucocorticoids and ACTH) o Prevent recurrence  Uric acid production (Xanthine oxidase inhibitors)  Uric acid retention (Uricosuric agents)  Uric acid abundance (Uricase analogs) DRUGS  Microtubule Assembly Inhibitor o Colchicine  Colchicum autumnale (autumn crocus) alkaloid  MOA: binding to cellular tubulin thus inhibiting its polymerization into microtubules; decreasing macrophage migration and phagocytosis  Use: first-line for acute and chronic gout (before); for intercritical gout (now)  Dose: 0.6 mg every 6-8 hrs  every 8-12 hrs  Duration of therapy: 6 – 9 months  A/E: diarrhea, throat pain/odynophagia, hematochezia, hematuria, oliguria, hypovolemia (shock), severe liver and kidney damage in overdose  NSAIDs o MOA: inhibits COX, urate crystal phagocytosis o Now preferred as the first-line therapy for symptomatic acute gouty attacks (with joint pain, swelling, redness) o Use short-acting NSAIDs: indomethacin, phenylbutazone, ibuprofen, diclofenac (except Aspirin, Salicylates, Tolmetin) o Given for ≤ 5 – 7 days  Adrenocorticotropic Hormone (ACTH)/Corticotropin o A pituitary hormone analog administered parenterally in the management of acute attacks of gout o Given to patients who are refractory or contraindicated to colchicine  Glucocorticoids o Prednisone, Methylprednisolone, Triamcinolone acetonide o MOA: Inhibits phospholipase A2, macrophage activity o Uses: severe polyarticular acute gout by intraarticular, SQ, IV o ADR: Cushing syndrome, hyperglycemia  Uricosuric Agents (Promotes urate excretion) o Probenecid, Sulfinpyrazone, Penicillamine o MOA: Prevents uric acid reabsorption as organic acids favored by glomerular anionic transport sites o Uses: Used in patients with chronic tophaceous gout, shortening intercritical gout, underexcretion o ADR: GI irritation, renal calculi (remedy: adequate hydration), urine alkalinization (to solubilize acid crystals)  Xanthine Oxidase Inhibitors o Allopurinol  Prototype; a prodrug of alloxanthine  MOA: Active metabolite irreversibly inhibits xanthine oxidase and lowers production of uric acid  Uses: DOC for intercritical and chronic tophaceous gout, asymptomatic hyperuricemia, adjunct to cancer chemotherapy; prophylaxis of tumor lysis syndrome  Dose: 100 – 300 mg/day  A/E: GI upset, hypersensitivity reactions, peripheral neuropathy, exfoliative dermatitis (SJS/TEN), bone marrow suppression, necrotizing vasculitis o Febuxostat  Nonpurine  MOA: reversible inhibitor of xanthine oxidase  Uses: first line for intercritical and chronic gout, asymptomatic hyperuricemia, intolerance to allopurinol  A/E: hepatotoxicity  Urate Oxidase Analogs (Uricase)  NOT INHIBITORS o Pegloticase, Rasburicase  MOA: Promote conversion of uric acid to soluble allantoin  Use: chronic refractory gout, management of tumor lysis syndrome  A/E: hemolytic anemia in G6PD deficiency, infusion reactions, acute gouty flare NONPHARMACOLOGIC THERAPY FOR GOUT FIRST-LINE THERAPY FOR:  Hydration – helps dissolve crystals Asymptomatic hyperuricemia – xanthine oxidase inhibitors Acute gouty flare - NSAIDs  Cold compress – in the affected area; TID for 10-15 minutes Intercritical gout – xanthine oxidase inhibitors Chronic tophaceous gout – xanthine oxidase inhibitors Urate nephropathy – hydration, urine alkalinizers Severe polyarticular gout – glucocorticoids, ACTH Refractory gout – urate oxidase analogs Allopurinol intolerance - febuxostat Tumor lysis syndrome – urate oxidase analogs (prevention), allopurinol (tx) DRUGS USED FOR COAGULATION DISORDERS PHYSIOLOGY OF CLOT FORMATION  Sequence of Clot Formation: 1. Vasospasm of the damaged blood vessels 2. Formation of a platelet-fibrin plug at the site of puncture  GPIa – binds to platelets  GPIb – binds to von Willebrand factor  GPIIb/IIIa – binds platelets to von Willebrand factor and fibrinogen  Proaggregants:  Thromboxane A2 (TXA2)  Serotonin (5-HT)  ADP  Phosphodiesterase (PDE)  Anti-aggregants: PGE, PGI2, cAMP 3. Coagulation cascade (creation of an unwanted thrombus)  Goal: to form cross-linked fibrin o Virchow’s Triad – the three factors that contribute to and stimulate clot formation  Endothelial injury  Stasis of blood flow  Arterial clots: platelet – rich “white thrombi”  Venous clots: fibrin – rich “red thrombi”  Hypercoagulability o Presence of foreign bodies (e.g. implants, stents, prosthesis, etc) can also trigger clot formation ANTICOAGULANTS  Indirect Thrombin Inhibitors o Heparin  A heterogenous mixture of sulfated mucopolysaccharides  Also known as unfractionated heparin/HMW heparin  500 – 3000 g/mol  MOA: Binds and forms stable complexes with antithrombin III and inhibit factors IX, X, XI, and XIII  Targets intrinsic pathway  Use: initial therapy in acute coronary syndrome, deep vein thrombosis, pulmonary embolism  Safe to use in pregnant patients  Given parenterally  Its systemic effects are adequately controlled by aPTT monitoring  A/E: heparin-induced thrombocytopenia  CI: bleeding disorders  Antidote for toxicity: protamine sulfate o Low Molecular Weight Heparins/Anti-Factor Xa  MOA: Inhibit Xa >>> IXa, Xia, XIIIa, VIa, IIa  Fondaparinux, Enoxaparin, Tinzaparin, Dalteparin, Danaparoid  Administered parenterally (SQ)  Rivaroxaban, Apixaban  Administered orally  Have better safety profiles  Use: initial anticoagulation, acute coronary syndrome, deep vein thrombosis, pulmonary embolism  Its systemic effects are adequately controlled by aPTT monitoring  A/E: active and potential bleeding  Antidote: discontinue use; protamine sulfate, plasmapharesis o Coumarins  Warfarin, Dicumarol  WARFARIN = Wisconsin Alumni Research Foundation  Racemic mixture: Levo-/S- >>>> Dextro-/R-  MOA: inhibits vitamin K epoxide reductase; interfere with the synthesis of clotting factors (IX, X, VII, II) and proteins C and S  Uses: chronic anticoagulation, hypercoagulable states (e.g. atrial fibrillation etc.), long term therapy in xenografts, rheumatic heart disease  A/E: Active and potential bleeding  PT-INR (prothrombin time – International Normalized Ratio) monitoring  Administered orally  Antidote of toxicity: Vitamin K, fresh frozen plasma, platelet transfusion, recombinant factor VIIa  Factors that would require the need to review the dose or stop the administration of warfarin  Elevated baseline PT-INR  Increased vitamin K intake  Low hemoglobin and hematocrit level  Direct Thrombin Inhibitors o MOA: Directly inhibits IIa by active site binding o Parenteral:  Lepirudin, Hirudin  Hirudo medicinalis  Indicated for heparin-induced thrombocytopenia (HIT)  ADR: anaphylaxis (lepirudin)  CI: renal insufficiency (CKD)  Argatroban  Use: HIT  Bivalirubin  Use: PTCA o Oral: Dabigatran etexilate mesylate, Ximelagatran  Use: atrial fibrillation, venous thromboembolism ANTIPLATELETS  Aspirin o MOA: irreversibly and selectively inhibits COX and TXA2 synthesis through acetylation o Uses:  1st line prevention of stroke/MI  Reduce incidence of recurrence of stroke/MI o Duration of action: ~7 to 10 days; thus requiring postponement of surgery for this duration o Doses:  75 mg – complete inactivation of platelet  50 mg – 325 mg – recommended dose o ADR: prolonged bleeding time  P2Y12 ADP Receptor Inhibitors o Clopidogrel, Ticlopidine, Prasugrel o MOA: Irreversible blockade of ADP receptors o Uses: coronary stent placement (PCI), acute coronary syndrome, transient ischemic stroke (Ticlopidine) o Adjunct to aspirin therapy for conditions such as acute coronary syndrome o Drug Interactions: strong CYP2C19 inhibitors (e.g. omeprazole)  reduce antiplatelet effect o A/E: neutropenia, leukopenia, thrombotic thrombocytopenic purpura  Phosphodiesterease (PDE) Inhibitors o MOA: Inhibits cGMP phosphodiesterase activity; vasodilatory effect o Cilostazol  Indicated for intermittent claudication o Dipyridamole  Used for stress echocardiography (alternative to threadmill test)  GPIIb/IIIa Receptor Blockers o Abciximab, Eptifibatide, Tirofiban o MOA: Inhibits GPIIb/IIIa receptor responsible for platelet aggregation  Additional MOA of Abciximab: inhibits vitronectin receptor o Uses: acute coronary syndrome, PTCA prophylaxis o A/E: Glanzmann’s thrombasthenia THROMBOLYTICS/FIBRINOLYTICS  MOA: Catalyzes the conversion of plasminogen to plasmin ( dissolves clots)  Antidotes: -aminocaproic acid, tranexamic acid  Streptokinase o Extracellular protein purified from culture broths of group C -hemolytic streptoccoci o Uses: preferred in acute MI o ADR: hypersensitivity reactions  Alteplase o Formerly known as tissue plasminogen activator (TPA) o Uses: massive pulmonary embolism, central deep vein thrombosis, acute ischemic strokes o Posology: Typically given IV where a bolus loading dose of over hundreds of thousand units are given followed by an infusion maintenance dose over 12 – 72 hrs  Tenecteplase  Urokinase PROTHROMBOTICS  Vitamin K o Found in green, leafy vegetables; intestinal microflora o Indications:  Prophylaxis for hemorrhagic disease of the newborn  Vitamin K deficiency  Warfarin toxicity o K1 – phytonadione o K2 – menaquinone o K3 – menadione o A/E: dyspnea, chest and back pain, death  Tranexamic Acid o Derivative of  - aminocaproic acid o MOA: inhibits plasminogen conversion to plasmin o Uses: minimize post-surgical bleeding, hemophilia (hemathroses), antidotes to fibrinolytics  Aprotinin o MOA: inhibits free plasmin  Plasma Fractions o Cryoprecipitate (VIII), Cryosupernatant (IX) o Use: Uncomplicated hemorrhage, soft tissue hematomas, surgery and major trauma  Viable replacement source of clotting factors for Hemophilia A o Cryoprecipitate o Fresh frozen plasma  Viable replacement source of clotting factors for Hemophilia B o Recombinant factor IX products o Cryposupernate AGENTS USED IN DYSLIPIDEMIA LIPID METABOLISM  Apo A- 1 – found in HDL  Apo B-100 and Apo B-48 – found in LDL and chylomicrons  Complications of Uncontrolled: o Hyperlipemia  pancreatitis o Hyperlipidemia  atherosclerosis DRUGS FOR HYPERLIPIDEMIA  HMG – CoA Reductase Inhibitors o HMG-CoA – 3-hydroxy-3-methylglutaryl coenzyme A o MOA: Inhibits HMG-CoA reductase enzyme o Effects: ↓ total cholesterol, ↑ LDLr, ↓ LDL, ↓ TAG o Use: Drugs of choice for hyperlipidemia (hypercholesterolemia) and coronary artery disease o They stabilize atherosclerotic plaques by primarily reducing oxidative stress and vascular inflammation o Short-acting:  Simvastatin  Lovastatin  Fluvastatin o Long-acting  Atorvastatin  Rosuvastatin o A/E: rhabdomyolysis (breakdown of skeletal muscle cells), hepatotoxicity, transaminitis (↑ ALT, AST) o Drug Interactions: CYP3A4, CYP2C9  Fibrates o MOA: agonist of PPAR -  (peroxisome proliferator-activated receptor – alpha); upregulate the enzyme lipoprotein lipase for the catabolism of triglycerides o Effect: ↓ TG, ↓ HDL, ↓ VLDL o Fenofibrate  Fibrate of choice for hypertriglyceridemia (hyperlipemia), HDL deficiency o Gemfibrozil o Clofibrate  Withdrawn due to hepatocellular cancer o A/E:  Formation of gallstones (cholelithiasis)  Rhabdomyolysis, myositis, leukopenia  Bile Acid Sequestrant (Bile Acid Binding Resins) o Cholestyramine, Colesevelam, Colestipol o MOA: bind bile acids in the jejunum and ileum and prevent their absorption; increases cholesterol catabolism o Effects: Adjunctively lower isolated elevations of LDL, but also increase VLDL o Use: LDL excess, digitalis toxicity o A/E: bloatedness, constipation, malabsorption of lipids and vitamin ADEK, cholelithiasis, steatorrhea  Sterol Absorption Inhibitor o Ezetimibe  MOA: Blocks sterol transporter intestinal brush border NPC1L1 (Niemann Pick C1 – like 1) and thus cholesterol/phytosterol absorption  Effects: ↓ total cholesterol, LDL, phytosterol  Use: LDL excess, phytosterolemia  A/E: low incidence of hepatotoxicity, myopathy o Anacetrapib, Dalcetrapib  Additional MOA: Inhibits cholesteryl ester transfer protein (CETP)  Niacin, Nicotinic Acid (Vitamin B3) o NOT NIACINAMIDE o MOA: Inhibits VLDL secretion; decreases catabolism of apolipoprotein AI o Effects: ↑ HDL, ↓ LDL, ↓ TAG o Most effective agent for increasing HDL levels in the blood o Use: HDL deficiency; LDL and TAG excess o A/E: intense cutaneous flushing (tx: NSAIDs, aspirin), gastric irritation, hyperuricemia  Adjuncts in dyslipidemia pharmacotherapy o Fish Oils – decreases LDL and TAGs o Probucol – strong antioxidant that lower LDL and some HDL o Evolocumab – inhibit PCSK9  lower LDL  Conditions that require treatment with a combination of lipid-lowering agents: o LDL and VLDL levels are both elevated initially o HDL deficiency coexisting with other hyperlipidemias o Refractory hyperlipidemias  Counseling Points o Initiation depends on serum lipid profile, 10-year ASCVD risk, and other comorbidities o Monitoring is crucial o Adherence may be difficult in polypharmacy and in elderly AGENTS USED IN ANEMIAS, HEMATOPOIETIC GROWTH FACTORS HEMATOPOIESIS  Deficiencies o Anemia  erythrocytes/RBCs  Iron deficiency anemia (IDA)  Megaloblastic anemia  Pernicious anemia  Hemolytic anemia  Aplastic anemia o Leukopenia  leukocytes/WBCs  Neutropenia o Thrombocytopenia  thrombocytes/platelets  Essentials o Nutrients  Iron  Vitamin B9 (folic acid)  Vitamin B12 (cobalamin) o Hemapoietic Growth Factors  Erythropoietin (EPO)  Granulocyte colony-stimulating factor (G-CSF)  Granulocyte – macrophage CSF (GM-CSF)  Megakaryocyte GF: thrombopoietin (TPO)  Iron Therapy o Oral: Ferrous gluconate, ferrous sulfate, ferrous fumarate o Parenteral Iron Therapy  Parenteral therapy should be reserved for:  Patients with documented iron deficiency who are unable to tolerate or absorb oral iron  Patients with extensive chronic anemia who cannot be maintained with oral iron alone o This includes patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin, various post gastrectomy conditions and previous small bowel resection, inflammatory bowel disease involving the proximal small bowel, and malabsorption syndromes  Agents include iron dextran, sodium ferric gluconate complex, and iron sucrose o MOA: Absorbed by ferroportin, complexed with apoferritin, stored as ferritin, transported by transferrin all for heme o Use: treatment and prevention of microcytic, hypochromic iron deficiency anemia, CKD o A/E: GI discomfort, blackened stools o Antidote: whole bowel irrigation, deferoxamine (IV, acute toxicity), deferasirox (PO, chronic iron excess) o Chronic Iron Toxicity  Chronic iron toxicity (iron overload)  Also known as hemochromatosis  Results when excess iron is deposited in the heart, liver, pancreas, and other organs  can lead to organ failure and death  It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, individuals with β-thalassemia).  Treatment: o Intermittent phlebotomy o Iron chelation therapy using parenteral deferoxamine or the oral iron chelators deferasirox or deferiprone  Vitamin B9 (Folic acid) o Also known as pteroylglutamic acid o Consists of heterocycle pteridine, PABA, and glutamic acid moieties o MOA: reduction by dihydrofolate reductase to dihydrofolate, trihydrofolate o Use: Prevention of congenital malformation o Reduced forms of folic acid are necessary for the synthesis of amino acids, purines, and nucleic acids o Deficiencies lead to megaloblastic anemia and fetal neural tube defects  Pregnant women should take folic acid 400 mcg/day  Px with history of miscarriage  4000 mcg/day o Deficiency of folic acid may be due to methotrexate, pyrimethamine, and trimethoprim (they inhibit dihydrofolate reductase which is important in the synthesis of folic acid)  Vitamin B12 o