Pharmacokinetics & Pharmacodynamics PDF

PHAR TRANS 1.1 09/08/24 PHARMACOKINETICS & PHARMACODYNAMICS REGINA TALAVERA, MD OUTLINE Most protein drugs (“biol...

PHAR TRANS 1.1 09/08/24 PHARMACOKINETICS & PHARMACODYNAMICS REGINA TALAVERA, MD OUTLINE Most protein drugs (“biologicals”) are commercially produced in cell, bacteria, or yeast cultures using recombinant DNA technology I. Basic Principles of Pharmacy II. Nature of Drugs a. AA Size & Molecular Weight B. DRUG RECEPTOR BONDS b. Drug Receptor Bonds Drugs bind to receptors with a variety of chemical bonds c. Definition of Terms These include very strong covalent bonds (which usually result in III. Pharmacokinetic Principles irreversible action) a. Permeation b. Fick’s Law of Diffusion Somewhat weaker electrostatic bonds (e.g. between a cation and c. Water & Solubility of Drugs an anion) and much weaker interactions (e.g. hydrogen, van der d. Absorption of Drugs Waals, and hydrophobic bonds) e. Blood Flow f. Concentration C. DEFINITION OF TERMS g. Distribution of Drugs h. Apparent Volume of Distribution & Physical Drugs i. Metabolism of Drugs ○ Substances that act on biologic systems at the chemical j. Elimination of Drugs (molecular) level and alter their functions IV. Pharmacodynamics Drug Receptors a. Principles of Drug Action ○ The molecular components of the body with which drugs b. Mechanisms of Drug Action interact to bring about effects c. Drug Receptor Interaction d. Types of Receptors e. Drug Potency & Efficacy III. PHARMACOKINETIC PRINCIPLES f. Therapeutic Index To produce useful therapeutic effects, most drugs must be g. Combined Effect of Drugs ○ Absorbed V. References ○ Distributed ○ Eliminated LEGEND Pharmacokinetic principles make rational dosing possible by quantifying these processes Must Know Good to Know Lecturer Book A. PERMEATION The movement of drug molecules into and within the biologic environment I. BASIC PRINCIPLES OF PHARMACY It involves several processes Pharmacodynamics ○ Aqueous diffusion ○ Denotes the action of the drug on the body, such as ○ Lipid diffusion mechanism of action and therapeutic and toxic effects ○ Transcript by special carriers Pharmacokinetics ○ Endocytosis ○ The actions of the body on the drug, including absorption, distribution, metabolism and elimination. Elimination may be AQUEOUS DIFFUSION achieved by metabolism or by excretion The movement of molecules through the watery extracellular and ○ Biodisposition is a term sometime used to describe the intracellular spaces processes of metabolism and excretion The membranes of most capillaries have small water-filled pores that permit the aqueous diffusion of molecules up to the size of II. NATURE OF DRUGS small proteins between the blood and the extravascular space Drugs in common include This is a passive process governed by Fick’s Law ○ Inorganic ions The capillaries in the brain, testes and some other organs lack ○ Nonpeptide organic molecules aqueous pores and these tissues are less exposed to some drugs ○ Small peptides and proteins ○ Nucleic acid, lipids and carbohydrates LIPID DIFFUSION ○ Plants or animals ○ Partially or completely synthetic The passive movement of molecules through membranes and other lipid barriers Like aqueous diffusion, this process is governed by Fick’s A. AA SIZE & MOLECULAR WEIGHT Drugs vary in size from molecular weight (MW( 7 (lithium) to over MW 50,000 (thrombolytic enzymes, antibodies, other proteins) TRANSPORT BY SPECIAL CARRIERS Most drugs have MWs between 100 and 1000 Drugs that do not readily diffuse through membranes may be Drugs smaller than MW 100 are rarely sufficiently selective in their transported across barriers by mechanisms that carry similar actions, whereas drugs much larger than MW 1000 are often poorly endogenous substances absorbed and poorly distributed in the body A very large number of such transporter molecules have been identified [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 1 of 8  Unlike aqueous and lipid diffusion, carrier transport is not governed IONIZATION OF WEAK ACIDS & BASES by Fick’s law an is capacity limited Weak bases are ionized-and therefore more polar and more water Important examples are transported for ions (e.g. Na+/K+ATPase) soluble when they are protonated For neurotransmitters (e.g., transporters for serotonin, Weak acids are not ionized-and so are less water soluble-when norepinephrine) they are protonated For metabolites (e.g., glucose, amino acids) and for foreign molecules (xenobiotics) such as anticancer drugs D. ABSORPTION OF DRUGS ENDOCYTOSIS ROUTES OF ADMINISTRATION Endocytosis occurs through binding of the transported molecule to Drugs usually enter the body at sites remote from the target tissue specialized components (receptors) on cell membranes, with or organ and thus require transport by the circulation to the subsequent internalization by infolding of that area of the intended site of action membrane To enter the bloodstream, a drug must be absorbed from its site of The contents of the resulting intracellular vesicle are released into administration (unless the drug has been injected directly into the the cytoplasm of the cell vascular compartment) Endocytosis permits very large or very lipid-insoluble chemicals to The rate and efficiency of absorption differ depending on a drug’s enter cells route of administration For example, large molecules such as proteins may cross cell Bioavailability: amount of drug absorbed into the systemic membranes by endocytosis circulation Because the substance too be transported must combine with a membrane receptor, endocytic transport can be quite selective ORAL (SWALLOWED) Exocytosis is the reverse process, that is, the expulsion of material Offers maximal convenience that is membrane-encapsulated inside the cell from the cell Absorption is often slower Most neurotransmitters are released by the exocytosis Subject to First-Pass Event: significant amount of the agent is metabolized in the gut wall, portal circulation, and liver before it B. FICK’S LAW OF DIFFUSION reaches the systemic circulation Fick’s law predicts the rate of movement of molecules across a barrier BUCCAL (UNDER THE TONGUE) The concentration gradient (C1-C2) and permeability coefficient for Dissolved under the tongue the drug and the area and thickness of the barrier membrane are Direct absorption into the systemic venous circulation used to compute the rate are as follows Faster absorption because it bypasses the hepatic portal circuit and first-pass metabolism 𝑃𝑒𝑟𝑚𝑒𝑎𝑏𝑖𝑙𝑖𝑡𝑦 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡 INTRAVENOUS Rate =C1 - C2 x 𝑥 𝐴𝑟𝑒𝑎 𝑇ℎ𝑖𝑐𝑘𝑛𝑒𝑠𝑠 Instantaneous and complete absorption Figure 1. Fick’s Law of Diffusion By definition, bioavailability is 100% Very fast absorption Drug absorption is faster from organs with large surface areas, Potentially more dangerous such as the small intestines, than from organs with smaller absorbing areas (the stomach) INTRAMUSCULAR Drug absorption is faster from organs with thin membrane barriers Often faster and more complete (higher bioavailability) than oral (e.g. the lung( than those with thick barriers (e.g. the skin) administration Large volumes may be given if the drug is too irritating C. WATER & LIPID SOLUBILITY OF DRUGS First-pass metabolism is avoided Solubility Ionization of weak acids RECTAL (SUPPOSITORY) Offers partial avoidance of the first-pass effect SOLUBILITY Larger amounts of drug with unpleasant tastes are better The aqueous solubility of a drug is often a function of the administered rectally than by buccal or sublingual routes electrostatic charge (degree of ionization, polarity) of the molecule, because water molecules behave as dipoles and are to charged INHALATION drug molecules, forming an aqueous shell around them Route offers delivery closest to respiratory tissues (e.g., for Conversely, the lipid solubility of a molecule is inversely asthma) proportional to its charge Usually very rapid absorption (e.g., for anesthetic gasses) Many drugs are weak bases or weak acids. For such molecules, the pH of the medium determines the fraction of molecules charge TOPICAL (ionized) versus uncharged (nonionized) Henderson-hasselbalch equation Includes application to the skin or to the mucous membrane of the Molecules in the ionized state can be predicted by means of the eye, ear, nose, throat, airway, or vagina for local effect Henderson-hasselbalch equation Can be a cream, lotion, or drops “Protonated” means associated with a proton (hydrogen ion) TRANSDERMAL 𝑃𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 𝑓𝑜𝑟𝑚 Involves application to the skin for systemic effect 𝑙𝑜𝑔 ( ) = 𝑝𝑘𝑎 − 𝑝𝐻 Absorption usually occurs very slowly due to thickness of skin 𝑈𝑛𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 𝑓𝑜𝑟𝑚 First-pass effect is avoided Figure 2. Henderson Hasselbalch Equation [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 2 of 8  E. BLOOD FLOW H. APPARENT VOLUME OF DISTRIBUTION & Blood flow influences absorption from intramuscular and PHYSICAL subcutaneous sites and, in shock, from the gastrointestinal tract as The apparent volume of distribution (Vd) is an important well pharmacokinetic parameter that reflects the determinants of the High blood flow maintains a high drug depot-to-blood concentration distribution of a drug in the body gradient and thus facilitates absorption Vd relates the amount of drug in the body to the concentration in the plasma F. CONCENTRATION In contrast, the physical volumes of various body compartments The concentration of drug at the site of administration is important are less important in pharmacokinetics in determining the concentration gradient relative to the blood as However, obesity alters the ratios of total body water to body weight noted previously and fat to total body weight, and this may be important when using As indicated by Fick’s law, the concentration gradient is a major highly lipid-soluble drugs determinant of the rate of absorption. Drug concentration in the A simple approximate rule for the aqueous compartments of the vehicle is particularly important in the absorption of drugs applied normal body is as follows: 40% of total body weight is intracellular topically water and 20% is extracellular water; thus, water constitutes approximately 60% of body weight G. DISTRIBUTION OF DRUGS DETERMINANTS OF DISTRIBUTION I. METABOLISM OF DRUGS Drug disposition is a term sometimes used to refer to metabolism SIZE OF THE ORGAN and elimination of drugs The size of the organ determines the concentration gradient Some authorities use disposition to denote distribution as well as between blood and the organ metabolism and elimination For example, skeletal muscle can take up a large amount of drug Metabolism of a drug sometimes terminates its action, but other because the concentration in the muscle tissue remains low (and effects of drug metabolism are also important the blood tissue gradient high) even after relatively large amounts Some drugs when given orally are metabolized before they enter of drug have been transferred this occurs because skeletal muscle the systemic circulation. This first-pass metabolism is one cause of is a very large organ low bioavailability In contrast, because the brain is smaller, distribution of a smaller Drug metabolism occurs primarily in the liver amount of drug into it will raise the tissue concentration and reduce to zero the blood-tissue concentration gradient, preventing further DRUG METABOLISM AS A MECHANISM OF uptake of drug unless it is actively transported ACTIVATION OR TERMINATION OF DRUG ACTION BLOOD FLOW The action of many drugs (e.g., sympathomimetics, phenothiazines) is terminated before they are excreted because Blood flow to the tissue is an important determinant of the rate of they are metabolized to biologically inactive derivatives uptake of drug, although blood flow may not affect the amount of Conversion to an inactive metabolite is a form of elimination drug in the tissue at equilibrium In contrast, prodrugs (e.g., levodopa, minoxidil) are inactive as As a result, well-perfused tissues (e.g., brain, heart, kidneys, and administered and must be metabolized in the body to become splanchnic organs) usually achieve high tissue concentrations active sooner than poorly perfused tissues (e.g., fat, bone) Many drugs are active as administered and have active metabolites as well (e.g., morphine, some benzodiazepines) SOLUBILITY The solubility of a drug in tissue influences the concentration of the DRUG ELIMINATION WITHOUT METABOLISM drug in the extracellular fluid surrounding the blood vessels Some drugs (e.g., lithium, many others) are not modified by the If the drug is very soluble in the cells, the concentration in the body; they continue to act until they are excreted perivascular extracellular space will be lower and diffusion from the vessel into the extravascular tissue space will be facilitated For example, some organs (such as the brain) have a high lipid J. ELIMINATION OF DRUGS content and thus dissolve a high concentration of lipid-soluble Along with the dosage, the rate of elimination following the last agents rapidly dose (disappearance of the active molecules from the site of action, the bloodstream, and the body) determines the duration of action for many drugs BINDING Therefore, knowledge of the time course of concentration in plasma Binding of a drug to macromolecules in the blood or a tissue is important in predicting the intensity and duration of effect for compartment tends to increase the drug’s concentration in that most drugs compartment For example, warfarin is strongly bound to plasma albumin, which NOTE: Drug elimination is not the same as drug excretion restricts warfarin’s diffusion out of the vascular compartment A drug may be eliminated by metabolism long before the Conversely, chloroquine is strongly bound to extravascular tissue modified molecules are excreted from the body proteins, which results in a marked reduction in the plasma concentration of chloroquine For most drugs and their metabolites, excretion is primarily by way of the kidney Volatile anesthetic gasses, a major exception, are excreted primarily by the lungs For drugs with active metabolites (e.g., diazepam), elimination of the parent molecule by metabolism is not synonymous with termination of action For drugs that are not metabolized, excretion is the mode of elimination [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 3 of 8 FIRST-ORDER ELIMINATION IRRITATION The term first-order elimination indicates that the rate of elimination A nonselective, often noxious effect and is particularly applied to is proportional to the concentration (ie, the higher the less specialized cells (epithelium, connective tissue) concentration, the greater the amount of drug eliminated per unit Example: time) ○ Strong irritation results in inflammation, corrosion, necrosis The result is that the drug’s concentration in plasma decreases and morphological damage exponentially with time Drugs with first-order elimination have a characteristic half-life of REPLACEMENT elimination that is constant regardless of the amount of drug in the Use of natural metabolites, hormones or their congeners in body deficiency states The concentration of such a drug in the blood will decrease by 50% ○ Levodopa in parkinsonism for every half-life ○ Insulin in diabetes mellitus Most drugs in clinical use demonstrate first-order kinetics ○ Iron in anemia ZERO-ORDER ELIMINATION CYTOTOXIC ACTION The term zero-order elimination implies that the rate of elimination Selective cytotoxic action on invading parasites or cancer cells, is constant regardless of concentration attenuating them without significantly affecting the host cells This occurs with drugs that saturate their elimination mechanisms Utilized for cure/palliation of infections and neoplasms at concentrations of clinical interest. ○ E.g. penicillin, chloroquine, zidovudine, cyclophosphamide As a result, the concentrations of these drugs in plasma decrease in a linear fashion over time. Such drugs do not have a constant half-life. This is typical of B. MECHANISM OF DRUG ACTION ethanol (over most of its plasma concentration range) and of Only a handful of drugs act by virtue of their simple physical or phenytoin and aspirin at high therapeutic or toxic concentrations. chemical property; examples are: ○ Bulk laxatives (ispaghula) - physical mass ○ Paraaminobenzoic acid - absorption of UV rays ○ Activated charcoal- adsorptive property ○ Mannitol, MgSO4 - osmotic activity ○ 131 I and other radioisotopes - radioactivity ○ Antacids - neutralization of gastric HCl ○ K+ permanganate - oxidizing property ○ Chelating agents (EDTA, dimercaprol) -chelation of heavy metals Majority of drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. Such mechanism confers selectively of action to the drug Functional proteins that are targets of drug action can be grouped into 4 major categories ○ Enzymes Figure 3. Comparison of First-Order & Zero Order Elimination ○ Ion channels For drugs with first-order kinetics (left), rate of elimination (units per hour) is proportional to concentration; this is the more common process. In the case of ○ Transporters zero-order elimination (right), the rate is constant and independent of ○ Receptors concentration ENZYMES IV. PHARMACODYNAMICS Almost all biological reactions are carried out under catalytic Pharmacodynamics is the study of drug effects influence of enzymes It describes what the drug does Drugs can either increase or decrease the rate of enzymatically How the drug does it mediated reactions A. PRINCIPLES OF DRUG ACTION STIMULATION Selective enhancement of the level of activity of specialized cells Example: ○ Adrenaline (epinephrine) stimulates the heart ○ Pilocarpine stimulates salivary glands DEPRESSION Selective diminution of activity of specialized cells ○ Barbiturates depress CNS Figure 4. Enzymes ○ Quinidine depresses heart ○ Omeprazole depresses gastric acid secretion Enzyme inhibition: ○ Selective inhibition of a particular enzyme is a common mode of drug action ○ Such inhibition is either competitive or noncompetitive [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 4 of 8  Table 1. List of Enzymes, their Endogenous Substrate, & Competitive Inhibitor Enzyme Endogenous Competitive Inhibitor Substrate Cholinesterase Acetylcholine Physostigmine, Neostigmine Monoamine-oxidase A Catecholamines Moclobemide (MAO-A) Dopa decarboxylase Levodopa Carbidope, Benserazide Xanthine oxidase Hypoxanthine Allopurinol Figure 7. Receptor Angiotensin converting Angiotensins-1 Captopril enzyme (ACE) 5α-Reductase Testosterone Finasteride C. DRUG-RECEPTOR INTERACTION Aromatase Testosterone, Letrozole, Anastrozole AGONIST Androstenedione An agent which activates a receptor to produce an effect similar to Bacterial folate Para-amino benzoic Sulfadiazine that of the physiological signal molecule synthase acid (PABA) Have both affinity and maximal intrinsic activity E.g.: adrenaline, histamine, morphine ION CHANNELS Ligand gated channels: nicotinic receptors INVERSE AGONIST G-protein receptor channels: cardiac beta-1 adrenergic An agent which activates a receptor to produce an effect in the receptor activated Ca2+ channel opposite direction to that of the agonist Drugs can also act on voltage operated and stretch sensitive Have affinity but intrinsic activity with a minus sign channels by directly binding to the channel and affecting ion E.g.: DMCM on benzodiazepine receptor, chlorpheniramine on H1 movement through it, e.g. local anesthetics which obstruct voltage histamine receptor sensitive Na+ channels Certain drugs modulate opening and closing of the channels Antagonist ○ Nifedipine blocks L-type of voltage sensitive Ca2+ channel An agent which prevents the action of an agonist on a receptor or ○ Ethosuximide inhibits T-type of Ca2+ channels in thalamic the subsequent response, but does not have any effect of its own neurons Have affinity but no intrinsic activity E.g.: propranolol, atropine, chlorpheniramine, naloxone PARTIAL AGONIST An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist Have affinity and submaximal intrinsic activity E.g.: dichloroisoproterenol on beta-adrenergic receptor, pentazocine on µ opioid receptor Figure 5. Ion Channel D. TYPES OF RECEPTORS ION CHANNEL RECEPTOR TRANSPORTERS Cell surface receptors = ligand gated ion channels Several substrates are translocated across membranes by binding Enclose ion selective channels (Na+, K+, Ca2+ or Cl) within their to specific transporters (carriers) which either facilitate diffusion in molecules the direction of the concentration gradient or pump the Agonist binding opens the channel and causes metabolite/ion against the concentration gradient using metabolic depolarization/hyperpolarization energy Changes cytosolic ionic composition, depending on the ion that Many drugs produce their action by directly interacting with the flows through solute carrier (SLC) class of transporter proteins to inhibit the ○ E.g. Nicotinic cholinergic, GABA, glycine (inhibitory AA), ongoing physiological transport of the metabolite/ion excitatory AA-glutamate (kainate NMDA, and AMPA) and 5HT3 receptors Figure 6. Transporter RECEPTORS Macromolecule or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule/drug and Figure 8. Ion-channel Receptor initiate the response to it, but itself has no other function [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 5 of 8 TRANSMEMBRANE ENZYME-LINKED RECEPTORS Ligand receptor have modulatory influence on its capacity to alter gene function Utilized primarily by peptide hormones ○ E.g. All steroidal hormones (glucocorticoids, Made up of a large extracellular ligand binding domain mineralocorticoids, androgens, estrogens, progesterones), Connected through a single transmembrane helical peptide chain thyroxine, vit D and vitamin A to an intracellular subunit having enzymatic properties. → E.g. Insulin, epidermal growth factor (EGF), nerve growth factor (NGF) and many other growth factor receptors Figure 9. Other Types of Transmembrane Enzyme-linked Receptors See APPENDIX A for Table 6. for Other Types of Enzyme-linked Receptors TRANSMEMBRANE JAK-STAT BINDING RECEPTORS Figure 11. Transcription Factors, Nuclear Receptors Agonist induced dimerization alters the intracellular domain conformation Increase its affinity for a cytosolic tyrosine protein kinase JAK E. DRUG POTENCY & EFFICACY (Janus kinase) Drug potency - amount of drug needed to produce a certain On binding, JAK gets activated and phosphorylates tyrosine response residues of the receptor Drug efficacy - maximal response that can be elicited by the drug Binds another free moving protein STAT Pairs of phosphorylated STAT dimerize and translocate to the nucleus to regulate gene transcription resulting in biological response Many cytokines, growth hormones, prolactin, and interferons act through this type of receptor Figure 12. Drug Potency vs Efficacy Figure 10. Transmembrane Jak-Stat Binding Receptors Drug B is less potent but equally efficacious as Drug A RECEPTOR REGULATING GENE EXPRESSION Drug C is less potent and less efficacious than Drug A Drug D is more potent than Drugs A, B, C but less efficacious than (TRANSCRIPTION FACTORS, NUCLEAR drugs A & B but equally efficacious as Drug C RECEPTORS) Are Intracellular soluble proteins which respond to lipid soluble chemical messengers that penetrate to the cell Ligand receptor dimer moves to nucleus and binds other co- activator/co-repressor proteins [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 6 of 8  F. THERAPEUTIC INDEX ANTAGONISM 𝑀𝐸𝐷𝐼𝐴𝑁 𝐿𝐸𝑇𝐻𝐴𝐿 𝐷𝑂𝑆𝐸 Antagonistic - when one drug decreases or abolishes the action Therapeutic index = 𝑀𝐸𝐷𝐼𝐴𝑁 𝐸𝐹𝐹𝐸𝐶𝑇𝐼𝐶𝐸 𝐷𝑂𝑆𝐸 of another or Effect of drugs A+B > Effect of drug A + effect of drug B 𝐿𝐷⬚50 𝐸𝐷⬚50 Figure 13. Therapeutic Index PHYSICAL ANTAGONISM Based on the physical property of the drugs Therapeutic Index - window that can use a drug at a certain ○ E.g. charcoal absorbs alkaloids and can prevent their dosage which gives a good effect on individuals absorption - used in alkaloidal poisonings Median effective dose (ED50) - dose produces the specified effect in 50% individuals CHEMICAL ANTAGONISM Median lethal dose (LD50) - dose which kills 50% of the recipients The two drugs react chemically and form an inactive product ○ E.g. Potassium Permanganate (KMnO4) oxidizes alkaloids - G. COMBINED EFFECT OF DRUGS used for lavage in poisoning SYNERGISM ○ Chelating agents (BAL, Calcium disodium edetate) to eliminate complex metals (As, Pb) Synergistic - action of one drug is facilitated or increased by the other Drugs that help each other to increase the effect. PHYSIOLOGICAL/FUNCTIONAL ANTAGONISM Two drugs act on different receptors or by difference mechanism Table 2. Synergistic Drug Combination Have opposite overt effects on same physiological function Augmentin Amoxicillin + Clauvanic acid Have pharmacological effects in the opposite direction Twynsta Telmisartan + Amlodipi ○ E.g. Histamine and adrenaline on bronchial muscles. Histamine - Bronchoconstriction, Adrenaline - Bronchodilation ADDITIVE SYNERGISM ○ Glucagon and insulin on blood sugar level The effect of the two drugs is in the same direction and simply adds up RECEPTOR ANTAGONISM Effect of drugs A+B = effect of drug A + effect of drug B Also called “Competitive antagonism” (Equilibrium type) Side effects of the components of an additive pair may be The antagonist is chemically similar to the agonist, and competes different - do not add up with it to the same site to the exclusion of the agonist molecules ○ Combination is better tolerated than higher doses of one The antagonist has affinity but no intrinsic activity component No response is produced and the log DRC of the agonist is shifted to the right Table 3. Additive Synergism Aspirin + Paracetamol As analgesics/antipyretics Nitrous oxide As general anesthetics Amlodipine + atenolol As Antihypertensive Glibenclamide + metformin As Hypoglycemic SUPRA ADDITIVE SYNERGISM The effect of combination is greater than individual effects of the components Effect of drugs A+B > Effect of drug A + effect of drug B Figure 14. Receptor Antagonism This is always the case when one component given alone produces no effect, but enhances the effect of the other NONCOMPETITIVE ANTAGONISM (potentiation) The antagonist is chemically unrelated to the agonist Binds to a different allosteric site altering the receptor in a way that Table 4. Supra Additive Synergism it is unable to combine with agonist or transduce the response Drug Pair Basis of Potentiation Acetylcholine + physostigmine Inhibition of break down Levodopa + carbidopa/ Inhibition of peripheral benserazide metabolism Adrenaline + cocaine/ Inhibition of neuronal uptake desipramine Sulfamethoxazole + Sequential blockade trimethoprim Enalapril + hydrochlorothiazide Tackling two contributory factors (antihypertensive) Tyramine + MAO inhibitors Increasing releasable CA store Figure 15. Noncompetitive Antagonism [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 7 of 8  Table 5. Competitive vs. Non-Competitive Competitive (Equilibrium Competitive (Equilibrium V. REFERENCES 1. Talavera, R. (2024).Pharmacokinetics and Pharmacodynamics. Department of Type) Type) Medicine. Chinese General Hospital Colleges Agonist binds with the same Agonist binds with the same 2. Batch 2026 Trans receptor as the agonist receptor as the agonist Antagonist resembles Antagonist resembles chemically with the agonist chemically with the agonist Parallel rightward shift of agonist Parallel rightward shift of agonist DRC DRC The same maximal response The same maximal response can be attained by increasing can be attained by increasing dose of agonist (surmountable dose of agonist (surmountable antagonism) antagonism) Intensity of response depends Intensity of response depends on the concentration of both on the concentration of both agonist and antagonist agonist and antagonist Eg.ACh- Atropine, Morphine- Eg.ACh- Atropine, Morphine- Naloxone Naloxone APPENDIX APPENDIX A. Types of Transmembrane Signaling Receptors Table 6. Types of Transmembrane Signaling Receptors Receptor Type Description Intracellular, often steroid receptor-like Steroid, vitamin D, nitric oxide, and a few other highly membrane-permeant agents cross the membrane and activate intracellular. The effector molecule may be part of the receptor or separate Membrane-spanning receptor-effector enzymes Insulin, epidermal growth factor, and similar agents bind to the extracellular domain of molecules that incorporate tyrosine kinase activity in their intracellular domains. Most of these receptors dimerize upon activation Membrane receptors that bind intracellular Many cytokines activate receptor molecules that bind intracellular tyrosine kinase enzymes (Janus tyrosine kinase enzymes (JAK-STAT receptors) kinases, JAKs) that activate transcription regulators (signal transducers and activators of transcription, STATs) that migrate to the nucleus to bring about the final effect Ligand-activated or modulated membrane ion Certain Na+/K+ channels are activated by drugs: acetylcholine activates nicotinic Na+/K+ channels, channels serotonin activates 5-HT3Na+/K+ channels. Benzodiazepines, barbiturates, and several other sedative hypnotics allosterically GABA-activated modulate Cl- channels G-protein-coupled receptors (GPCRs) GPCRs consist of 7 transmembrane (7-TM) domains and when activated by extracellular ligands, bind trimeric G proteins at the inner membrane surface and cause the release of activated Gα and Gβγ units. These activated units, in turn, modulate cytoplasmic effectors. The effectors commonly synthesize or release second messengers such as cAMP, IP3, and DAG. GPCRs are the most common type of receptors in the body AMP, cyclic adenosine monophosphate; IP3, inositol triphosphate; DAG, diacylglycerol APPENDIX B. Definition of Major Concepts Table 7. Definition of Major Concepts Major Concept Description Nature of drugs Drugs are chemicals that modify body functions. They may be ions, carbohydrates, lipids, or proteins. They vary in size from lithium (MW 7) to proteins (MW ≥ 50,000) Drug permeation Most drugs are administered at a site distant from their target tissue. To reach the target, they must permeate through both lipid and aqueous pathways. Movement of drugs occur by means of aqueous diffusion, lipid diffusion, transport by special carriers, or by exocytosis and endocytosis Rate of diffusion Aqueous diffusion and lipid diffusion are predicted by Fick’s law and are directly proportional to gradient, area, and permeability coefficient and inversely proportional to the length or thickness of the diffusion path Drug trapping Because the permeability coefficient of a weak base or weak acid varies from the pH according to the Henderson- Hasselbach equation drugs, may be trapped in a cellular compartment in which the pH is such as to reduce their solubility in the barrier surrounding the compartment Routes of administration Drugs are usually administered by one of the following routes of administration: oral, buccal, sublingual, topical, transdermal, intravenous, subcutaneous, intramuscular, rectal, or by inhalation Drug distribution After absorption, drugs are distributed to different parts of the body depending on concentration gradient, blood flow, solubility, and binding in the tissue Drug elimination Drugs are eliminated by reducing their concentration or amount in the body. This occurs when the drug is inactivated by metabolism or excreted from the body Elimination kinetics The rate of elimination of drugs may be zero order (i.e., constant regardless of concentration) or first order (i.e., proportional to the concentration) [GROUP 6] Aquino. B, Mateo, Pocong, Villa-Abrille 8 of 8  PHAR TRANS 1.2 16/08/24 PRESCRIPTION WRITING EMELITA A. GAN, MD OUTLINE C. GENERIC NAME OR GENERIC TERMINOLOGY Identification of drugs and medicines by their scientifically and I. Definition of Terms c. Transdermal internationally recognized active ingredients or by their official a. Prescription d. Topical (Skin) generic name b. Drugs e. Suppository c. Generic Name f. Ophthalmic d. Generic Drug Preparation D. GENERIC DRUG e. Brand Name g. Otic Preparation Generic Drug Intended to be interchangeable with an innovator f. Drug Product h. Surgical products that is manufactured without a license from the innovator g. Chemical Name Dressings company and marketed after the expiry date of the patent h. Active Ingredient i. Apothecary and II. International Metric Nonproprietary Name Conversion E. BRAND NAME (INN) j. List of Commonly The proprietary name given by the manufacturer to distinguish its a. Purposes of INN Used product from those of competitors b. Advantages of Abbreviations Using Generic VI. Fixed Dose F. DRUG PRODUCT Nomenclature or Combinations (FDC) The finished product form that contains the active ingredients, INN Products c. Drugs Belonging to a. Characteristics of generally but not necessarily in association with inactive the Same Class a Rational FDC ingredients Share a Common VII. Rational Use of Stem Drugs G. CHEMICAL NAME III. Essential Medicines a. The Rule of Right The description of the chemical structure of the drug or medicine a. Essential Drug b. Process of and serve as the complete identification of a compound Concept Rational b. Importance of the Therapeutics Essential Medicines c. Elements of H. ACTIVE INGREDIENT or National Drug Rational Drug The chemical component responsible for the claimed therapeutic Formulary Use effect of the pharmaceutical product. c. Classification of VIII. Factors Influencing Example: Chemical Name: N-(4-Hydroxyphenyl) ethanamide | Drugs according to Prescribing Generic Name: Paracetamol Prescription a. Factors that Dispensing Adversely Requirement Influence IV. Elements of the Prescribing Prescription IX. Fundamental Errors (Outpatient in Prescribing Prescription) X. Patient Compliance V. Pharmaceutical Forms XI. Problem-Based a. Oral Pharmacology b. Injectable XII. The Prescription as an Experiment XIII. References LEGEND Must Know Good to Know Lecturer Book Figure 1. Brand Names of Drugs Source 1 I. DEFINITION OF TERMS See APPENDIX A. for a bigger photo of Figure 1. A. PRESCRIPTION Written order and instruction of a validly registered physician, II. INTERNATIONAL NONPROPRIETARY NAME dentist or veterinarian for the use of a specific drug product for a (INN) specific patient. The doctor’s order on the in-patients chart (chart The official generic or non-proprietary name given to a order) for the use of specific drug(s) is also considered a pharmaceutical substance or an active ingredient prescription Each INN is a unique name that is globally recognized & is public property B. DRUG Should be distinctive in sound and spelling Any substance that is used to modify a physiological, biochemical Should not be inconveniently long or anatomical function or abnormality for the benefit of the recipient Should not be liable to confusion with names in common use substance used in the treatment, diagnosis or prevention of disease [GROUP 3] Aquino, Caisip, Carandang, Lacaste, Membrebe 1 of 6  A. PURPOSES OF INN C. CLASSIFICATION OF DRUGS ACCORDING TO Clear identification PRESCRIPTION DISPENSING REQUIREMENTS Safe prescription and dispensing Non-prescription medicine (OTC) For communication & exchange of information among health Prescription medicines professionals ○ Ordinary prescription medicines – no special prescription requirements B. ADVANTAGES OF USING GENERIC ○ Medicines in PNDF with specific requirements NOMENCLATURE OR INN The basis for control & regulation is the danger of addiction, abuse, Rationalizes drug use physical & mental harm. The trafficking by illegal means, & the ○ Avoids drug duplication thereby prevent over dosage or drug dangers from actions by those who have used the substances toxicity ○ Dangerous Drugs - Requires S2 license and DOH ○ Minimizes drug-drug interactions prescription form ○ Minimizes medication errors ○ Controlled chemicals – drugs requiring S2 license using Internationally understood and accepted – ensures continued personalized prescription form administration of drugs in long term therapy Precursor & essential chemical that may be used to Valuable teaching tool for doctors, dentists, veterinarians, manufacture controlled substances; may be pharmacists, and nurses at various stages of training and practice dispensed under a physician’s prescriptio Reduces the total cost of drug treatment ○ List "B” Medicines – Pharmaceuticals products that require in-vivo bioequivalence studies C. DRUGS BELONGING TO THE SAME CLASS ○ Multisource Pharmaceuticals Products” – Pharmaceutically SHARE A COMMON STEM equivalent or pharmaceutically alternative products that may olol - betablockers (ex. Propranolol, metoprolol) be or may not be therapeutically equivalent coxib - selective COX-2 NSAIDs adol - centrally acting analgesics IV. ELEMENTS OF THE PRESCRIPTION cef - antibiotics, derivatives of cephalosporanic acid (OUTPATIENT PRESCRIPTION) cillin - antibiotics, derivatives of 6-aminopenicillanic acid dipine - calcium antagonists of the nifedipine group terol - bronchodilators, phenethylamine derivatives tidine - H2 receptors antagonists nidazole - antibiotics, nitro-imidazole group floxacin - antibiotics, fluorinated quinolone group pril - angiotensin converting enzyme (ACE) inhibitor sartan - Angiotensin Receptor Blocker III. ESSENTIAL MEDICINES Drugs that are proven effective, safe, of good quality and suitable to satisfy the needs of the country in the prevention, diagnosis, treatment of diseases and maintenance of health A. ESSENTIAL DRUGS CONCEPT National drug consumption should correspond to actual health needs Figure 2. Parts of a Prescription 1 Essential drugs in proper amounts and dosage forms should be available to the population See APPENDIX B. for a bigger photo of Figure 2. Implementing policies and effective delivery system to achieve the above should be formulated and enforced (1) Identity of the prescriber National Formulary ○ Name ○ A list of drugs prepared & periodically updated by the DOH on ○ Professional degree a basis of health conditions obtaining in the Philippines as well ○ Telephone number as on internationally accepted criteria ○ Prescriber’s signature Core List ○ PRC license number and PTR ○ List of drugs that meets the health care needs of the majority ○ S2 license for dangerous drugs and controlled chemicals of the population (2) Identity of the patient Complementary list ○ Name of the Patient ○ A list of alternative drugs used when there is no response to ○ Age the core drug or when there is hypersensitivity reaction to the ○ Address core drug or for whatever reason, core drug cannot be given (3) Date the prescription was written (4) Body of the prescription B. IMPORTANCE OF THE ESSENTIAL MEDICINES ○ Superscription – “take thou” LIST OR NATIONAL DRUG FORMULARY ○ Inscription – specifies the INN of the active ingredient(s), the For educational purposes, as a teaching tool to help rationalize strength, and dosage form drug prescribing ○ Subscription – direction to the pharmacists on the quantity For rationalization of drug production, distribution, procurement of the medication to be dispensed and consumption [GROUP 3] Aquino, Caisip, Carandang, Lacaste, Membrebe 2 of 6  ○ Transcription – directions for use to the patient regarding G. OTIC PREPARATIONS amount of the drug/dose per take, route of administration. Drops Intervals of administration or time and frequency of dosing, Solution duration of therapy, purpose of medication, other instructions Suspension ○ Refill information ○ Prescriber’s signature H. SURGICAL DRESSING ○ Factors to consider in determining the quantity to be NOTE: dispensed GIVE SPECIFIC INSTRUCTIONS Anticipated length of therapy When you give instruction in the prescription, you have to state Need for the continued contact with the physician Stability of the preparation the actual and correct verb Potential for abuse ○ Ex. if the px is a child it should be “GIVE” because the Potential for toxicity or overdose instruction is set for the mother, father, or guardian to deliver Mental state of the patient to the child Cost of the drug ○ “Take one tablet” if the patient can drink tablet already There is no minimal limit to the quantity of medication ○ If you are to give nasal drops to an infant your prescription prescribed. The maximal limit for drugs with abuse must be “Instill one drop on each nostril two times a day”. potential has been set by the Dangerous Drugs Board (DDB), PDEA and DOH I. APOTHECARY & METRIC CONVERSIONS 1 grain (gr) = 0.065 grams (g) V. PHARMACEUTICAL FORMS ○ often rounded to 60 milligrams (mg) 15 gr = 1 g A. ORAL 1 ounce (oz) by volume = 30 milliliters (mL) Tablet 1 teaspoonful (tsp) = 5 mL Caplet 1 tablespoonful (tbsp) = 15 mL 1 quart (qt) = 1000 mL Capsule 1 minim = 1 drop (gtt) ○ Specify if CR (controlled release), SR (sustained release), SA 20 drops = 1 mL (short acting), ER (extending release), etc. 2.2 pounds (lb) = 1 kilogram (kg) Spansule Drops J. LIST OF COMMONLY USED ABBREVIATIONS Suspension μg – microgram Syrup AD, AS, AU – right ear, left ear, each ear HS – bedtime q.d. – everyday B. INJECTIBLE Ampule b.i.d. – 2x a day Vial t.i.d. – 3x a day Bottles (IV infusion) q.i.d. – 4x a day q.o.d. – every other day a.c. – before meals C. TRANSDERMAL p.c. – after meals Applied in the skin but is intended to be used systemically (i.e. PRN – as necessary transdermal patch of nitroglycerin- attach to skin but the use is for p.o. – per orem (by mouth) the heart , to prevent angina pectoris or chest pain) IM – intramuscular IV – intravenous D. TOPICAL (SKIN) SC – subcutaneous Applied on the skin where you intend it to act (i.e. cream on rashes) NOTE: Cream DO NOT ABBREVIATE WHEN WRITING A PRESCRIPTION Gel Ointment It is not recommended to use abbreviations to avoid errors. Paste Write the full word Patch Plaster VI. FIXED DOSE COMBINATIONS (FDC) PRODUCTS E. SUPPOSITORY Pharmaceutical preparations containing two or more Rectal pharmacologically active ingredients in a single formulation or Vaginal dosage form (BFAD) Usually used for TB treatment F. OPHTHALMIC PREPARATION Co-amoxiclav = Amoxicillin + Clavulanic acid. For increased Drops Liquid efficacy in treating certain bacteria. Some bacteria degrade Ointment amoxicillin. Clavulanic acid Protect amoxicillin from degradation Solution Suspension A. CHARACTERISTICS OF A RATIONAL FDC The active ingredients as well as the inactive ingredients, should be pharmaceutically and pharmacologically compatible in combination [GROUP 3] Aquino, Caisip, Carandang, Lacaste, Membrebe 3 of 6  The FDC taken as a whole should have clinical and therapeutic Co-morbid conditions advantage over the individual active ingredients taken separately ○ Example: Diabetic and hypertensive patient. What It should include such advantages as complementary or synergistic hypertensive drug do you give? pharmacological action or therapeutic effect or reduction in ADR ○ Choose Angiotensin Receptor Blocker/ACE inhibitor (e.g., magnesium hydroxide + aluminum hydroxide) because it is protective for proteinuria (a common ○ Magnesium Hydroxide and Aluminum Hydroxide are complication in diabetes) antacids. Aluminum hydroxide causes constipation. Magnesium hydroxide causes diarrhea. They cancel each DRUG FACTORS others adverse effects, so they are combined. It is the PK (Pharmacokinetics) synergistic pharmacological action PD (Pharmacodynamic) It must not contain any ingredient whose proper administration or Safety (benefit VS risk ratio) clinical use requires special adjustments different from or in conflict Drug Interactions with its other ingredients. (e.g.: different T 1⁄2 [theophylline + Cost (cost/benefit ratio) diazepam]) Optimal drug and dosage regimen It must not contain ingredients with abuse potential, with a narrow End points for efficacy and toxicity margin of safety and/or which requires special precautions in its use and/or with bioequivalence problems (e.g., Theophylline + Ephedrine-HCL + Guaifenesin and Diazepam) VIII. FACTORS INFLUENCING PRESCRIBING VII. RATIONAL USE OF DRUGS Use of medicinal preparations only in cases where they are needed and entails the utilization of only the scientifically proven efficacious drugs A. THE RULE OF RIGHT The use of the Right Drug for the Right Patient with the Right Diagnosis, given at the Right Dose, Right Route, Right Intervals, and Right Duration of therapy under prevailing constraints B. PROCESS OF RATIONAL THERAPEUTICS Reasonable certainty of the diagnosis ○ Clinical presentation of the patient (laboratories and examinations) ○ Absence of lab rely on educated guess. Based on a scientific basis Understand the pathophysiology of the disease Figure 3. Factors Influencing Prescribing 1 Understand both non-pharmacologic and pharmacologic approaches to the treatment of the disease A. FACTORS THAT ADVERSELY INFLUENCE ○ Hindi lahat ng disease bibigyan mo ng gamot Understand the clinical pharmacology of the drugs that could be PRESCRIBING Apparent need to use many drugs for multiple complaints i.e. a pill used for every ill Choose the optimal drug and dosage regimen for the particular Multiple physicians treating the same patient without full knowledge patient (INDIVIDUALIZE treatment) of one another’s therapeutic decision Pick endpoints of efficacy and toxicity for careful monitoring of Latest fad or “it make sense” clinical outcome Established prescribing habits based on one’s limited personal Develop a contract or alliance with the patient; ensure compliance experience regardless of scientific merits ○ Suitability of the drug with the patient Prescribing to satisfy patient’s expectations ○ Example pregnant should not take teratogenic drugs Inaccurate generalizations/conclusions of a study and/or Consider the cost (of the medication) testimonials of colleagues especially from a teacher or respected peer C. ELEMENTS OF RATIONAL DRUG USE Aggressive promotions by drug companies including liberal PATIENT FACTORS samples Age Internal pressure or conflicts Pregnancy and Lactation To make the patient feel that the doctor did something Pharmacogenetics Nutritional status IX. FUNDAMENTAL ERRORS IN PRESCRIBING Polypharmacy overprescribing due to excessive symptomatic DISEASE STATES treatment Incorrect prescribing due to erroneous diagnosis or inadequate Pathophysiology knowledge about the drug Severity (life-threatening VS non-life threatening) Inappropriate prescribing of harmful and/or ineffective products in Hepatic Impairment the presence of safer and/or affective essential drugs Renal Impairment ○ Do not give nephrotoxic or modify dose [GROUP 3] Aquino, Caisip, Carandang, Lacaste, Membrebe 4 of 6  Uneconomical prescribing i.e., using drugs of questionable value XIII. PROBLEM-BASED PHARMACOTHERAPY or using more expensive agents when less expensive and equally Identify the basic problem(s) - the basic problem is that which effective agents exist directly threatens the life and well-being; it must be distinguished Prescribing two or more drugs that produce unintended or from symptoms unnecessary drug interactions Define the therapeutic goal(s) Illegible, incoherent, incomplete, incorrect prescriptions Plan the effective therapy Generic and brand name mismatch ○ Non-drug Therapy ○ Drug Therapy - compare the efficacy, safety, suitability and X. PATIENT COMPLIANCE cost of all the drugs considered Faithful adherence to the treatment regimen (e.g., drug diet, ○ Criteria for the selection of drug exercise, or other interventions) designed by a physician for a ○ Efficacy - ability to accomplish what has been intended to do particular individual in a cause and effect manner ○ Safety - risk in taking the drug is less than the risk in not taking XI. ENHANCING PATIENT COMPLIANCE it. Effective communication between the physician and patient by ○ Suitability - has properties that are right for a specific purpose verbal and non-verbal means; use of individualized written for a particular patient. instructions ○ Cost-effectiveness - economical in terms by the benefits Simple drug regimen received for the money spent. ○ “Prioritized” regimen; avoid routine use of non-essential drugs ○ Choose the most appropriate for the patient Less frequency of dosing: single vs multiple doses ○ Write a prescription(s) with instructions/precautions/warnings Match regimen schedule to patient’s regular activities ○ Monitoring of patient outcome Short term therapy vs long term therapy Supervision by physician and family members hospital vs home XIV. THE PRESCRIPTION AS AN EXPERIMENT care Only when a physician approaches each prescription as the Close contact or continued dialogue or frequent visits beginning of a therapeutic experiment of uncertain outcome and not just a concluding act to an office visit, will the chances that the XII. COMMON ERRORS OF COMPLIANCE experiment will be as safe, effective and fruitful as possible be Omission optimized Wrong dosage Wrong timing and sequence XIII. REFERENCES Taking medicines for the wrong indication 1. Gan, E. A. (2024). Prescription Writing (PPT). Department of Pharmacology, Chinese General Hospital Colleges Adding medications not prescribed Premature termination of the therapy APPENDIX APPENDIX A. Brand Names of Drugs Source [GROUP 3] Aquino, Caisip, Carandang, Lacaste, Membrebe 5 of 6 APPENDIX B. Parts of a Prescription [GROUP 3] Aquino, Caisip, Carandang, Lacaste, Membrebe 6 of 6  PHAR TRANS 1.3 30/08/24 ANTI-SEIZURE DRUGS ROSIE LU KOH, M.D. OUTLINE Decreased inhibition of neurons due to lack of: ○ Ionic inward Cl-, outward K+ currents I. Definition of Terms II. Seizure ○ Inhibitory neurotransmitter GABA a. Cellular Mechanisms of Seizure Medications b. Classification of Seizure Types B. CLASSIFICATION OF SEIZURE TYPES III. Classification of Anti-seizure Medications Focal Onset (formerly partial onset) seizures a. Based on History or Evolution ○ Focal aware seizure (formerly simple partial seizure) b. Based on the Response to Laboratory Tests to Animal Models of Epilepsy ○ Focal impaired awareness seizure (formerly complex partial c. Based on Structure seizure) d. Based on Compounds Derived from ○ Focal-to-bilateral tonic-clonic seizure (formerly partial seizure e. Based on Mechanism of Action secondarily generalized or grand mal seizure) IV. Pharmacokinetics of Anti-Seizure Medications Generalized onset seizures a. Serum Concentrations Reference Ranges for ASM (Old ○ Generalized tonic-clonic seizure (formerly primary vs New) generalized tonic-clonic seizure or grand mal seizure) b. Interactions of Anti-Seizure Drugs with Hepatic Microsomal Enzymes ○ Generalized absence seizure (formerly petit mal seizure; c. Non-Enzyme Inducer or Inhibitor occurs, for example, in absence epilepsy) d. Metabolism of ASM ○ Myoclonic seizure (occurs, for example, in juvenile myoclonic V. Side effects of Anti-Seizure Medications epilepsy and Dravet's syndrome) a. Steven-Johnson Syndrome/Toxic Epidermal Necrolysis ○ Atonic seizure (drop attack/seizure or astatic seizure; occurs, b. Bone Marrow Suppression for example, in the Lennox-Gastaut syndrome) c. Liver Failure d. Cardiac Conduction Abnormality ○ Epileptic spasms (as in infantile spasms also known as West's e. Neuropsychiatric Effects syndrome) f. Kidney Stones g. Hyponatremia HISTORY OR EVOLUTION OF ANTI-SEIZURE h. Multi-Organ Hypersensitivity i. Other Effects MEDICATION VI. ASM & Women with Epilepsy 1857 - Bromides discovered by Sir Charles Locock, a British VII. Intravenous ASM Gynecologist, used to treat women with menstrual seizures VIII. Other Routes of ASM 1882 - Paraldehyde for status epilepticus IX. References 1912 - Alfred Hauptmann discovered Phenobarbital (Pb) X. Appendix 1938 - Tracy Putman and Houston Meritt discovered Phenytoin (PHT) LEGEND 1944 - Trimethadione for absence seizures 1954 - Primidone Must Know Good to Know Lecturer Book 1958 - Ethosuximide (ESM) 1965 - Carbamazepine (CBZ) 1975 - Clonazepam 1978 - Valproate (VPA) I. DEFINITION OF TERMS 1989 - Vigabatrin, Zonisamide (ZNS approved in the US 2000) Anti-seizure medications (ASMs) (used in Japan) ○ Drugs which control or decrease the frequency and/or severity 1993 - Felbamate (FBM), Gabapentin (GBP) of seizures/epilepsy 1994 - Lamotrigine (LTG) ○ Not meant to treat the underlying cause of the 1996 - Topiramate (TPM), Tiagabine (TGB), Fosphenytoin seizures/epilepsy 1999 - Levetiracetam (LEV) Seizure 2000 - Oxcarbazepine (OXC), ZNS (USA) ○ A transient alteration of behavior due to disordered, 2001 - Stiripentol for Dravet’s syndrome synchronous and rhythmic firing of a population of neurons 2005 - Pregabalin (PGB), Zonisamide (EU) Epilepsy 2007 - Rufinamide (RFN) (EU) ○ A condition where there is periodic and recurrent seizure 2008 - Lacosamide (LCM) attacks (at least 2 occurring > 24 hours apart) 2009 - Eslicarbazepine (EsliCBZ); Vigabatrin for infantile spasms and refractory focal seizures in adults II. SEIZURE 2011 - Retigabine (RTG) A. CELLULAR MECHANISMS OF SEIZURE 2012 - Perampanel 2018 - Cannabidiol (USA) for Lennox Gastaut and Drivet’s MEDICATIONS syndrome in patients >2 years old Excessive excitation of neurons due to: ○ Ionic inward Na+, Ca2+ currents ○ Excitatory neurotransmitter glutamate and aspartate [GROUP 9] Blanza, Chang, Chua, De Jesus 1 of 7  III. CLASSIFICATION OF ANTI-SEIZURE MAXIMAL ELECTROSHOCK SEIZURE (MES) TEST MEDICATIONS Makes use of electrical current A. BASED ON HISTORY OR EVOLUTION In the MES test, 60 Hz alternating current (mice 50 mA; rats 150 mA) is delivered for 0.2 second through corneal electrodes See APPENDIX A. for Table of Drugs Based on History or Evolution Before the placement of the corneal electrodes, a drop of saline is placed on each eye. At the time of administration of the test substance (ASM), a drop of 0.5% tetracaine in saline is applied to the eyes of all animals The animals are restrained by hand and released immediately after stimulation then observed for seizures Abolition of the hindlimb tonic extensor component is taken as the end point for the test and the test substance is considered to have the ability to prevent the spread of seizure discharge through neural tissue Tonic extensions are considered abolished if the hindlimbs are not fully extended at 180 degrees with the plane of the body If a drug is positive for the MES Test, it is effective for tonic/clonic generalized seizures SUBCUTANEOUS METRAZOLE SEIZURE THRESHOLD (scMET) TEST OR PENTYLENETETRAZOLE TEST Figure 1. Timeline of the Evolution of the ASMs Makes use of the Pentylenetetrazole A convulsive dose of MET (56 mg/kg for mice; 85 mg/kg for rats) is Inside the circle are the new generation ASMs injected subcutaneously. Outside are the old generation ASMs The animals are placed in isolation cages and observed for the next Sodium Valproate is the last old generation ASM 30 minutes for the presence or absence of an episode or clonic spasms persisting for at least 5 seconds. Absence of a clonic seizure suggests that the test substance has the ability to raise the seizure threshold If a drug is positive for the scMET Test, it is effective for Myoclonic Absence seizures Table 1. Classification of ASM based on MES and scMET Test1 Seizure Type MES scMET Tonic/Clonic Carbamazepine (CBZ) Generalized Oxcarbazepine (OXC) Seizure (GTC) Phenytoin (PHT) Benzodiazepine (BDZ) Valproic Acid (VPA) Phenobarbital (Pb)