125 - E1 Trans.pdf

PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Caffeine - 118 Coffees OUTLINE...

PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Caffeine - 118 Coffees OUTLINE ○ Alcohol - 13 Shots I. DRUG The antidote for methanol poisoning is II. PHARMACOLOGY methanol. A. TERMS Ricin vs Insulin III. DRUG-RECEPTOR INTERACTION ○ Ricin is a substance that can be found A. SELECTIVITY in castor oil. It is a poison found B. AFFINITY naturally. C. BINDING ○ Insulin is a hormone used to regulate IV. DRUG TARGETS the blood sugar in the body. However, V. RECEPTORS it can be used as a poison through A. SIGNAL TRANSDUCTION Insulin Shock Therapy. It is a form of B. G PROTEIN torture where the patient is induced C. ION CHANNELS with high amounts of insulin that D. VOLTAGE-GATED/SENSITIVE ION would shock their body leading to a CHANNELS coma. E. TYROSINE KINASE Just because it is natural doesn’t mean it is F. CYTOKINE/JAK-STAT RECEPTORS safe or it is not a poison. Natural ≠ Safe. G. HORMONAL RECEPTORS Often, people assume that the major side H. SUMMARY OF RECEPTORS effect of taking drugs is liver injury. This is not I. COUPLING AND SPARE RECEPTORS true, most drugs do not cause liver damage. VI. BINDING Dietary and herbal supplements are the A. AGONIST SPECTRUM leading cause of liver damage. B. ALLOSTERIC MODULATOR It is all in the dosage. It is finding the right C. COMPETITIVE VS NONCOMPETITIVE balance between the drug being a poison ANTAGONIST and the drug being beneficial. i. COMPETITIVE ANTAGONIST ii. NONCOMPETITIVE ANTAGONIST NOTE: Some poison is repurposed as a drug. D. SUMMARY An example would be Semaglutide VII. EXERCISE (Ozempic). VIII. RECEPTOR REGULATION A. DESENSITIZATION IX. DOSE-RESPONSE RELATIONSHIP II. PHARMACOLOGY A. GRADED DOSE-RESPONSE CURVE Study of substances that interact with living B. QUANTAL (EITHER-OR) systems through chemical processes, DOSE-RESPONSE CURVE especially by binding to regulatory molecules C. RESPONSE: VARIATION and activating/inhibiting normal processes. D. ENHANCEMENT OF DRUG EFFECT Pharmacodynamics - What the drug does to E. BENEFITS VS RISKS the body (Effects and Mechanism of Action) X. SUMMARY Pharmacokinetics - What the body does to the drug (ADME - Absorption, Distribution, I. DRUGS Metabolism, Excretion) “All things are poison, and nothing is without poison, the dosage alone makes it so a thing A. TERMS is not a poison” Biologics - Large substances derived from Drugs are any substances, aside from food natural sources. and water, that alter the way our bodies Endogenous - Made within the body (e.g. work. hormones) LD50 - The dose of a substance that kills 50% Exogenous - From external sources (e.g. of the population. xenobiotics) ○ Water - 6 Liters Toxins - Biological/”organic” poisons PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 1 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 NOTE: Contrary to popular belief, herbal juices that promote the detoxification of toxins in the body do not work. We have our liver and kidneys to excrete toxins. III. DRUG-RECEPTOR INTERACTION Drug + Macromolecule = Effect These macromolecules act as receptors in receiving the drug. Macromolecules include Carbohydrates, Proteins, Lipids, and Nucleic Acid. Most receptors are proteins found in the cell membrane that enable the entry of substances inside the cell. A. SELECTIVITY Drugs exhibit selectivity. It can select which receptors it would bind to. Selective means that it bonds to one or a select number of receptors. Each level/basin of the fountain is the Non-selective means that it binds to many receptor and the water is the drug. The top receptors. basin, or the receptor with a higher affinity to Selectivity is relative to your reference. the drug, gets filled with water first. However, Example: Drug A binds to alpha-1 and alpha-2 this does not mean that the second basin receptors. Drug B binds to the alpha-1 would not have water in it. There are some receptor only. Drug C binds to all alpha splashes as the first basin is being filled with receptors. We can say that Drug A is water. non-selective if we compare it with Drug B As the drug enters and binds to the receptor, since Drug A can bind to both alpha-1 and it would bind first with H1, and small amounts alpha-2 receptors while Drug B can only bind of the drug would bind with M1 since it has a to alpha-1 receptors. Drug A becomes lesser affinity to it. The amount of drug selective if our reference is Drug C because in binding to a receptor depends on its dosage. comparison to Drug C, Drug A only binds to two types of alpha receptors. C. BINDING Once the drug binds to a receptor, it then B. AFFINITY releases its effects. The binding of drugs to a Ability of the drug to bind to the receptor. receptor does not equate to a positive effect. Drugs can have greater or less affinity to Its effect on the target is a spectrum. This receptors to which they would bind. effect is called the intrinsic activity of the The greater the affinity, the greater the drug once it binds with the receptor. chance that the drug would first attach to ○ Agonist - Once the drug attaches to this receptor. the receptor it gives off full effect and Think of it like a fountain: activates the receptor. Most endogenous ligands are agonists. ○ Partial Agonist - Once the drug attaches to the receptor it gives off partial effect and partially activates the receptor no matter the dosage. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 2 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Antagonist - Once the drug attaches to the receptor it does not give off any effects or does not activate the receptor and retains the basal activity of the target. The presence of an antagonist in a receptor prevents the binding of other drugs that may give off the full agonist effect. ○ Inverse Agonist - It is the opposite of agonist. It deactivates the receptor, hindering other substances from binding to it, reducing agonist activity. IV. DRUG TARGET The four major kinds of receptors are: Usually proteins: ○ G-protein-linked neurotransmitter ○ Transporters ○ Ion-Chanel-linked neurotransmitter ○ Enzymes ○ Hormone ○ Structural Proteins ○ Neurotrophin ○ Regulatory Proteins Understanding the signal transduction It can be other macromolecules: cascade helps in understanding how a drug Carbohydrates, Lipids, and Nucleic Acid. gives its effect. For example, beta-b blocker Receptors blocks the ion channels in the heart. When ○ Cellular macromolecules involved in these channels are blocked, sodium, cell signaling potassium, and calcium ions can not enter ○ Molecules that the drug targets to the cardiac cells, thus lowering the heart rate. produce an effect Binding ○ Covalent - Strong and not easily B. G PROTEIN reversible There are 4 elements in a G-protein-linked ○ Electrostatic - Weaker than covalent receptors. (Ionic, Dipole, H-bonds, etc.) ○ First Element - First messenger or ○ Hydrophobic - Weakest neurotransmitter ○ Second Element - Receptor that has seven transmembrane regions NOTE: The receptors in Pharmacology are ○ Third Element - G Protein itself different from the receptors of AnaPhy. capable of binding both to certain In AnaPhy, receptors detect changes conformations of the receptor (2nd that happen in the body and send a element) and the enzyme system (4th message to the brain. Receptors in element) AnaPhy is important in feedback ○ Fourth Element - Enzyme for the systems and in maintaining second messenger. homeostasis. NOTE: Enzymes end with -ase. Examples: V. RECEPTORS Protein Kinase, Amylase, Helicase, etc. A. SIGNAL TRANSDUCTION Illustrated here is how signals, once the drug attaches to the receptor, are transmitted into a cascade until it reaches the point where the desired effect is obtained. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 3 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ The enzyme, adenylyl cyclase, attached to the newly conformed G-protein, synthesizing a second messenger, cAMP (cyclic adenosine Steps in forming second messenger monophosphate) from ATP ○ First step is the binding of (adenosine triphosphate). neurotransmitter to the receptor. This leads to conformational changes to the receptor enabling it to attach to the G-protein. ○ Second step is the G-protein now ○ Types of G-Protein: attaches and binds to the newly Gs - Stimulatory, increases conformed neurotransmitter. Once adenylyl cyclase, producing attached, the G-protein now acts as a more cAMP neurotransmitter itself and changes its Gi - Inhibitory, decreases conformation for the enzyme to bind adenylyl cyclase, lower cAMP with it. levels Gq - Activates another class of enzymes called phospholipases C, PLC produces two secondary messengers: Diacylglycerol (DAG) and Inositol Triphosphate (IP3) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 4 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Activation of Protein Kinase ○ The cAMP produced then activates dormant protein kinases. Two copies of cAMP attach to the regulatory unit of the protein kinase, this regulatory unit then dissociates the enzyme, thus activating and phosphorylate the protein kinase. When dormant, these protein kinases come in pairs. ○ For protein kinase, sometimes it will activate, sometimes it will not. This is just one scenario. Protein Kinase VS Phosphatase ○ The secondary messenger Calcium, which comes from an ion-gated channel, activated the third messenger Calcineurin. Fourth Messenger ○ These activated protein kinases (third messenger) then ultimately target the 4th messenger, the phosphoproteins and genes that trigger gene expression. ○ They target 4th messenger through phosphorylation or giving a phosphate group to phosphoproteins (ligand-gated ion channels, voltage-gated ion channels, enzymes, etc.). ○ Calcineurin competes with protein kinases by taking the phosphate that protein kinases send to phosphoproteins. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 5 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Multiple protein units come together and they form a core where ions can enter. ○ The balance between phosphorylation and dephosphorylation of 4th messenger kinases and phosphatases plays a vital role in the regulation of many molecules critical to the chemical neurotransmission process. Summary Ion channels are opened and closed by actions of neurotransmitters ligands (drugs) at receptors. Ion channels acts both as a channel for extracellular molecules and receptors for drugs. Mechanism: ○ The neurotransmitter (ligands or drug ligands) attaches to the receptor and causes conformational change to the receptor/channel enabling the entry of ions. In the case of ion-gated channels, the ions are the secondary messenger. ○ For Calcium, it activates the third messenger Calcineurin that interferes with the phosphorylation of other phosphoproteins. (Look back at G-Protein) C. ION CHANNELS Called as ligand-gated ion channel or Ionotrophic Receptor. Ions cannot penetrate the cell membrane due to its charge. They enter the cell through channels. Most important ion channels regulate calcium, sodium, chloride, and potassium. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 6 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 D. VOLTAGE-GATED/SENSITIVE ION CHANNELS The opening and closing of these channels is regulated by the difference of charges of ions. Voltage-gated ion channels are regulated by electrochemical gradient. E. TYROSINE KINASE Summary: PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 7 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 would be your hormones. In the immune system, it is a messenger called cytokines. Cytokines would bind in these receptors. The difference between this receptor and tyrosine kinase is that this have JAK (Janus kinase). The enzyme is separate from the receptor. Since JAK is a kinase it would phosphorylate something. It would phosphorylate STAT that would lead to signal cascade. There are 4 types of this receptors: ○ JAK1 ○ JAK2 ○ JAK3 ○ Tyk2 G. HORMONAL RECEPTORS Requires two molecules to attach to the receptors. Once the two molecules attaches, it would cause the aggregation (coming together) of the two receptors. Once the two receptors joined, the “Y” region gets activated and phosphorylate. The enzyme is the y region. Once the enzyme is phosporylate, it would be activated and catalyze another reaction leading to a signal cascade. ○ “Y” region can be serine-threonine cyclase or guanylyl cyclase. In the case of tyrosine kinase, the receptor is the enzyme. F. CYTOKINE/JAK-STAT RECEPTORS Nuclear and intracellular receptor. The cell membrane is composed of a phospholipid layer with a hydrophilic head (polar) and hydrophobic tail (non-polar). Non-polar molecules, such as steroid, easily enters the cell. These drugs binds, dimerizes, and directly enters the nucleus. That is why drugs that binds to nuclear receptors are potent since it enters the cell easily. Hormones that are lipophilic are very potent. Binds to specific DNA sequences In the nervous system, the messengers that would counter your body are H. SUMMARY OF RECEPTORS neurotransmitters. In the endocrine system, it PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 8 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 G-Protein - When a molecule attaches to the receptor, the receptor changes conformation so that the G-protein can attach. Once the G-protein attaches it changes its conformation, making itself attacheable to the enzyme adenylyl cyclase. Adenylyl cyclase produces cAMP from ATP, cAMP then acts as the second messenger. Ion-Channels - When a molecule attaches to it, the channels open, letting ions enter the cell. These ions act as the second messenger. Spare Receptors Voltage-Gated - The difference between the ○ NOT REQUIRED for a maximum charges of the ions enables the opening and response closing of this channel. ○ Activating these receptors may result Tyrosine Kinase - Two molecules is needed to in increased side effects as maximum attach to two of these receptors. After, the effect has already been achieved. two receptors aggregate and activates the enzyme. The enzyme in this case is the receptor also, to be specific it is the receptor’s “Y” region, which can be serine-threonine cyclase or guanylyl cyclase. Cytokine/JAK-STAT - Similar mechanism with Tyrosine Kinase, however, then enzyme is separated from the receptor and the enzyme is JAK. Once JAK is activated, it would phosphorylate STAT that would lead to signal cascade. VI. BINDING Hormonal - Molecules that are lipophilic can easily enter the cell membrane due to their A. AGONIST SPECTRUM polarity. Agonist I. COUPLING AND SPARE RECEPTORS ○ Binds and activates certain receptor/s, resulting in a response. Coupling ○ Endogenous ligand ○ Occupancy (drug-receptor) + response ○ Full affinity, Max intrinsic activity ○ 𝐸 = 𝐸𝑚𝑎𝑥 × 𝐶 ○ Ex. Serotonin 𝐶 + 𝐸𝐶50 Drug effect (E) Partial Agonist Drug concentration © ○ Between full agonist and antagonist Half maximal effective ○ Full affinity, Low intrinsic activity concentration (EC50) refers to the C at which induces a Antagonist response halfway between the ○ Binds and blocks certain receptor/s baseline and maximum from binding with endogenous ligand/agonist, preventing a response. ○ Two Types Competitive - Reversible NonCompetitive - Irreversible Inverse Agonist PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 9 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Binds and deactivates the receptor, With enough [agonist], and can push away hindering other substances from the antagonist from the binding site, and binding to it. activate the receptor. ○ Prevents constitutive receptor activity in the absence of an agonist. Chemical Antagonist ○ Direct Binding ○ Inactivation of drug Prevent constitutive activity ○ Ex. Neutralization, chelation Physiologic Antagonist ○ Binds to a different receptor, inactivating the constitutive activity of the receptor (collateral damage) ii. NONCOMPETITIVE ANTAGONIST ○ Ex. Norepinephrine + Acetylcholine Does not compete with the agonist for the Intrinsic Activity same binding site ○ Degree of Response Binds to an allosteric binding site In terms of electric fan, 1-3 Prevents any biological response of an agonist Constitutive Activity ○ In terms of electric fan, presence of electricity B. ALLOSTERIC MODULATOR Binds to allosteric binding site ○ Alternative binding site Can boost (Positive Allosteric Modulator) or block (Negative Allosteric Modulator) what ligand does Positive Allosteric Modulator only works when full agonist/endogenous ligand is bound to D. SUMMARY the orthosteric site (usual) ○ Ex. Benzodiazepines with GABA (endogenous ligand) AFFINITY INTRINSIC CONSTITUTIVE REMARKS ACTIVITY ACTIVITY Full Agonist / MAX PRESENT Endogenous C. COMPETITIVE VS NONCOMPETITIVE Ligand ANTAGONIST Partial / LOW PRESENT Between full agonist and Two Classifications of Antagonist Agonist antagonist ○ Competitive ○ NonCompetitive Inverse / NONE ABSENT - Agonist i. COMPETITIVE ANTAGONIST Antagonist / NONE PRESENT Reversible Competitive Binds to the Competes with the agonist for binding to orthosteric site the receptor (orthosteric site). Antagonist / NONE PRESENT Irreversible NonCompetitive Binds to an PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 10 of 14  PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 allosteric ○ Answer: Yes but not very selective binding site ○ Selectivity is relative for each drug. As for Norepinephrine binding to alpha-1 Chemical / NONE ABSENT Direct Antagonist binding and alpha-2 receptors, there are actually sub-receptors under these Physiologic / NONE ABSENT Indirect two: alpha-1A, alpha-1B, alpha-1C, binding Antagonist alpha-2A, alpha-2B, and alpha-2C, making it actually bind to 6 different Positive / MAX PRESENT Indirect Allosteric (lvl 4) binding receptors. Compared to Guanfacine for Modulator ONLY when example, it only binds to alpha-2A, (PAM) endogenous ligand is hence Norepinephrine actually looks bound to less selective as compared to the orthosteric Guanfacine. site Phentolamine is a competitive antagonist at alpha-1 and alpha-2 receptors Ranking based on Activity ○ Does it have affinity for alpha ○ PAM > Full Agonist > Partial Agonist > receptors? Yes, because affinity Inverse Agonist > Antagonist > pertains to BINDING to alpha Chemical Antagonist > Physiologic receptors, not intrinsic activity Antagonist (effects) ○ Is it selective? Relatively no Orthosteric Binding Site ○ If the body started producing more ○ The location to which the endogenous norepinephrine, would Phentolamine or natural agonist binds. be displaced from alpha receptors? Yes because it is competitive, it Allosteric Binding Site won’t be displaced if Phentolamine ○ Effector binding sites is not competitive. ○ An effector is any molecule that binds 2.) Aripiprazole is a partial agonist at D2 receptors to the enzyme that is not the substrate and binds to more of them at low doses. It is also an of the active site and modifies the antagonist at alpha-2 receptors, but is a weak one. enzyme's activity. Which receptor does Aripiprazole have more affinity for? D2 receptors VII. EXERCISE Which will produce stronger D2 receptor 1.) Norepinephrine is an endogenous ligand for effects, dopamine or Aripiprazole? noradrenergic receptors and activates its full effects. ○ Dopamine is one of our body’s It binds to alpha-1 and alpha-2 receptors. endogenous ligands for the D2 Is norepinephrine an agonist, antagonist, receptors and a full agonist at D2 partial agonist, or inverse agonist at these receptors. receptors? ○ Hence, Dopamine ○ Answer: Agonist 3.) Protamine sulfate is used as an antidote for ○ As to why it is important to take note heparin toxicity. It works via a neutralization reaction. of its full effects: Is it a physiologic antagonist or a chemical There are endogenous ligands antagonist? and molecules in our body that Chemical Antagonist - because it binds are partial agonists or directly or works via a reaction antagonists. Hence it is not (neutralization). But when a physiologic about if it is naturally occurring antagonist acts, its mechanism works against in your body, you consider the each other electric fan analogy with For example in the electric fan, a chemical regards to the agonist antagonist could be setting the room in fire spectrum. until it reaches the electric fan itself. It could Is norepinephrine a selective ligand? get the job done but has a lot of collateral PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 11 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 damage; that is how chemical antagonists work in nature. (A physical antagonist could be ripping out the socket). VIII. RECEPTOR REGULATION In anaphysio, in cytology, endocytosis happens because it is how the body regulates receptors. There is also the concept of homeostasis, the body cannot have too much of an agonist and too much of an antagonist; it will adjust for that ○ Too much agonists (DOWNREGULATION) - lessen the receptors which lessens the effect ○ Too much antagonists (UPREGULATION) - add the receptors for more agonists to bind IX. DOSE-RESPONSE RELATIONSHIP A. GRADED DOSE-RESPONSE CURVE A. DESENSITIZATION The key difference of downregulation to tachyphylaxis is the response time/speed: ○ Downregulation - 2 weeks at minimum ○ Tachyphylaxis - matter of hours before the receptors shut off (this happens with beta receptors) One way to express the activity of a drug given its dose X axis - dose, y axis - response PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 12 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Potency - how much of the drug you need to Cons of graded get the desired response ○ Graded curves vary per patient ○ 500 mg drug vs 1 mg drug (both 100% ○ Not useful for either-or events efficacy - 1 mg drug is more potent Median effective dose (another ED50) ○ In the given graph, which of the drugs ○ Dose at w/c 50% experience would be considered most potent? therapeutic effect Which would first reach 50% of the Median Toxic Dose (TD50) and Median Lethal maximum efficacy at the lowest dose? Dose (LD50) Answer: A ○ Dose that causes toxicity to the ○ EC50 or ED50 to obtain 50% effect population or dose that kills about half ED95 - The dose to get 95% Therapeutic Index/Window (TD50/ED50): At the response therapeutic index window, you have a good The drawback of graphs in graded balance between the benefits and the harms dose-response curves is that this only refers ○ E.g. Lithium - lower the dose a bit to one response but oftentimes drugs will means no effect and higher the dose a target multiple receptors, resulting to bit means toxic levels reached. multiple effects ○ Some drugs are equally efficacious, it ○ Very simplified diagram just so happens that one drug’s ○ We don’t just look at one response/one window is narrower receptor ○ We prefer the drug with a wider Maximal efficacy therapeutic index ○ Maximum achievable response ○ Minimum Effective Dose vs Minimum ○ E.g. Antihypertensives Toxic Dose Shape E.g. SSRIs vs TCAs ○ For example, the problem of Drug D Potencies comparable compared to Drug A is that its therapeutic index is narrower: more C. RESPONSE: VARIATION difficult to adjust the dose to avoid Since you can’t really predict the phenomena harm in its response. behind response with various drugs (not a ○ Hence, if steep change ends in harm, dose thing anymore): it is dangerous ○ Idiosyncratic - You are not sure what ○ E.g. bupropion and seizures might cause the response (immune, genetic, etc.). B. QUANTAL (EITHER-OR) DOSE-RESPONSE Combination of many factors CURVE but you cannot pinpoint the exact cause Also used to describe diseases (e.g. idiosyncratic parkinson’s disease) ○ Tolerance - loss of response over time; from receptor adaptations Downregulation Receptors lessen over time ○ Tachyphylaxis - rapid diminishing of response; from depletion of endogenous substances TO BE CLEAR, ENDOGENOUS SUBSTANCE IS THE ONE BEING LESSENED Mechanisms of varied response ○ Pharmacokinetics Good for either-or events: do they die or not? PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 13 of 14 PHARMACODYNAMICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Endogenous ligand concentration (e.g. ○ Useless if they survive heart attacks Propranolol) but bleed out to die If your body is in overdrive Same receptor, different mechanisms producing norepinephrine and ○ E.g. Aripiprazole D2 receptors you have a competitive An antipsychotic mainly used antagonist, there are some to treat depression and other disease states that the drug manic disorders would work better or you may This also reduces your have too much of the inhibitions, which makes you endogenous ligand that the more impulsive drug won’t work well. There are ○ The receptor is beneficial but has variations. different effects ○ Receptor number/function Or different receptors entirely has different Depends on your patient effects ○ Homeostasis ○ How do we dose such that: Benefits are maxed D. ENHANCEMENT OF DRUG EFFECT Side effects are minimized The effects of multiple medicines can vary among patients taking it: X. SUMMARY Drug vs Poison - Dose 1. Addition - “1+1 = 2” ○ Everything is a poison, natural is not Just add Drug A and Drug B to have better! additive effects. Drug-receptor Interactions and Drug Targets 2. Synergism - “1+1 = 3” ○ Intrinsic Activity - Refers to the Drug A and Drug B have a baseline Agonist spectrum effect, but when you measure their ○ Affinity - Refers to receptor selectivity effect, it turns out higher than Types of receptors expected. ○ G-Protein 3. Potentiation - “1+0 = 2” ○ Ion channels Drug A has an effect and Drug B does ○ Nuclear receptors not. But when you combine them, the ○ Tyrosine Kinase/JAK receptors effect of Drug A is higher. Drug B ○ These receptors are seen on the helps indirectly in turning up Drug A’s membrane of the cell effect (like an enhancer) Agonist vs Antagonist Spectrum Competitive vs Noncompetitive Antagonists E. BENEFITS VS RISKS Receptor Regulation -Upregulation and With drugs, it is always about balancing the Downregulation benefits and the risks - Therapeutic Response Dose-Response Relationships vs Toxic Response Same receptor-effector mechanism ○ E.g. Aspirin which is used to prevent heart attacks ○ We know it works, but apparently the same receptor (cyclooxygenase) and the same effects of that receptor’s inhibition is also what increases the risk of internal bleeding ○ Hence, you do not just throw aspirin to everyone: you have to check their vulnerability to the drug to avoid risks PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman Page 14 of 14 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Example: A drug that does excellent in OUTLINE pre-clinical trials, in vitro tests, etc. but I. PHARMACOKINETICS has 0.01% absorption can’t be made II. LIBERATION into a tablet. III. ABSORPTION A. AREA UNDER THE CURVE II. LIBERATION B. BIOAVAILABILITY Before the drug gets absorbed, drugs have to C. BIOEQUIVALENCE be liberated from its respective dosage form. IV. DISTRIBUTION Dry mouth? A. ONE COMPARTMENT DISTRIBUTION ○ Dry mouth can affect drug liberation. B. TWO COMPARTMENT DISTRIBUTION ○ This is because saliva helps to dissolve C. PLASMA CONCENTRATION drugs and facilitate their absorption D. VOLUME OF DISTRIBUTION into the bloodstream. E. PROTEIN BINDING ○ When the mouth is dry, the drugs may V. METABOLISM not dissolve as easily or be absorbed A. FIRST ORDER KINETICS as quickly. This can lead to a decrease B. ZERO ORDER KINETICS in the bioavailability of the drug, which C. FIRST PASS METABOLISM means that less of the drug reaches D. METABOLISM BY THE LIVER the bloodstream. E. PHASE II REACTIONS No stomach acid? VI. PHASE 0 AND III ○ Lack of or no stomach acid can affect A. PHASE 0 drug liberation. B. PHASE III ○ This is because stomach acid helps to VII. EXCRETION dissolve drugs and facilitate their A. CLEARANCE absorption into the bloodstream. B. GLOMERULAR FILTRATION RATE ○ When there is no stomach acid, the VIII. EXERCISES drugs may not dissolve as easily or be IX. CLINICAL PHARMACOKINETICS absorbed as quickly. This can lead to a A. TIME COURSE OF EFFECTS decrease in the bioavailability of the B. DOSING drug, which means that less of the X. PHARMACOKINETICS: SUMMARY drug reaches the bloodstream. XI. DRUG DISCOVERY AND DEVELOPMENT A. PRECLINICAL STUDIES III. ABSORPTION B. INVESTIGATIONAL NEW DRUG Requirements of the drug to be absorbed: APPLICATION ○ Unionized C. CLINICAL TRIALS ○ Aqueous D. DRUG DEVELOPMENT TL;DR Un-ionized – recall Henderson-Hasselbalch ○ An ionized (charged) ion would have a harder time to enter the phospholipid I. PHARMACOKINETICS bilayer, which indicates the What the body does to the drug importance that a molecule should be ○ Liberation (If applicable) unionized. ○ Absorption ○ Different from Adsorption. ○ Distribution ○ Metabolism ○ Excretion It is important to understand what the body In acidic environments, drugs like Aspirin, does to the drug, because if the drug does which are weak acids, will be unionized. not enter the body, it is rendered useless. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 1 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Given that there is a lot of HCl in the The literal area where you can it into many stomach, Aspirin would be better trapezoids, where the area of a trapezoid is: absorbed there. (base1+base2)(height)/2 In basic environments, drugs like ○ What does the area say? Pyrimethamine, a weak base, will be Height is time unionized. Base1 at the y-axis is ○ Given that there is a lot of bicarbonate concentration in the intestines, Pyrimethamine Area is concentration by time would be better absorbed there. which corresponds to exposure Depending on the drug, we make drugs with of body to drug other dosage forms for delayed release, which Importance: AUC proportional to dose get liberated and absorbed in the intestines. (linear kinetics) Aqueous (Refer to Anaphy) ○ x2 dose → x2 AUC ○ Not necessarily x2 effect! There are other factors that could determine the effect of the drug on our body. Some drugs’ effects/toxicity apparent with cumulative doses → better measured by AUC B. BIOAVAILABILITY Rate and extent of absorption of the drug. ○ Drugs could be metabolized in the Drugs need to go through cellular membrane liver, absorbed in the heart, systemic transport via passive or active diffusion. circulation or bloodstream In certain areas such as capillaries where they If a drug is injected into the veins, it would have a small opening in the middle of cells have 100% bioavailability because it directly where cells as large as the red blood cells can goes into the bloodstream. pass through. ○ When drugs are administered orally, it passes through the stomach then passes through the liver, where AUC A. AREA UNDER THE CURVE (AUC) will be reduced. Compared to a drug administered through IV will go straight into the bloodstream; thus, the BA of the drug is 100%. F=BA%/100 Absolute BA = AUCEV/AUCIV x DoseIV/DoseEV ○ In absolute, we have the parameters for a drug that is administered in extravascular (hindi diretso sa blood vessel) and we compare it to the intravenous kinetic parameters, which is always 100%. ○ In the parameters involved, we utilize the same drug and same brand. Relative BA = AUCtest/AUCstd. x Dosestd/Dosetest ○ Similar to absolute BA, but the drug is Total exposure of body to drug relative to the brand. ○ We wanna know not just how much drug is being absorbed in one point in time, we want to know the ENTIRE C. BIOEQUIVALENCE time period how much drug the body When 2 products have equivalent is exposed to. Bioavailability. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 2 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 In the generics act, it is stated that two drugs go to the different organs including the ones that are bioequivalent could be interchanged. where we want it to go? Or is it just confined There are certain scenarios which that to specific compartments? statement would NOT hold true. Wide distribution is not always good, depending on what we want to achieve. ○ If the drug is widely distributed (it can go to all organs), it can give off side effects to all of these organs. ○ We want a drug for the heart, but it travels to many organs like the thyroid, liver, lungs, etc. It may cause unnecessary side effects on those organs. A. ONE COMPARTMENT DISTRIBUTION The 95% confidence intervals of the AUC and Cmax fall within 80-125% of the innovator. ○ The dichotomy is NOT between generic vs branded, it is the innovator vs everything else. ○ There are times where the criteria is more strict, such as narrow therapeutic drugs which require within 90-110%. A drug administered (whether orally, IV, EV) goes straight into the blood. While that’s happening, it will be eliminated by the liver or kidneys. This model is more on drugs which are only confined to the blood. If we can define how the drug behaves in terms of distribution, then we can predict what is going to happen when the drug is administered. Some drugs can not be interchanged with their generic alternatives. Example: B. TWO COMPARTMENT DISTRIBUTION ○ ADHD drugs (Ritalin and Concerta) ○ Drugs that have a narrow therapeutic index ○ Peptides Innovator refers to the reference product of a drug. NOTE: Cmax refers to the maximum concentration of the drug (the peak). While the drug goes into the blood, it could IV. DISTRIBUTION appear that we have eliminated the drug, but We have to check on the distribution of the drug, whether it is widely distributed, does it PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 3 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 some of the drug still gets trapped within protein-bound drugs are stuck in the tissues, especially the more fatty drugs. bloodstream. Additionally, they are stuck in a sense that they won’t be able to reach the C. PLASMA CONCENTRATION liver for metabolism. Also known as Cp Albumin – acidic drugs Drug concentration in plasma ○ Bulk of the proteins that do the binding in the blood. D. VOLUME OF DISTRIBUTION α-acid glycoprotein/orosomucoid – basic Also known as Vd drugs Part of calculating for it is plasma Lipoprotein concentration (Cp), once we get the Cp, we Importance: can use that to calculate Vd ○ Bound drugs not metabolized ○ Once we get the value, we can get the ○ Bound drugs don’t leave plasma (low idea on how wide the distribution of Vd ) ++no receptor interaction the drug is. (Poor, Moderate, High) For ○ Depot: drug displacement example, if it is about 3L or less, dugo interactions lang yan. ○ Higher Vd will last longer in the body In theory, you have Drug A that is because it will not pass through the 90% protein-bound, and Drug B blood vessels which is 99% protein-bound. If we Volume needed to dissolve dose to get a give Drug A at first, then suddenly specific Cp followed by Drug B, the classic idea Volume you are dissolving the dose into to would be that Drug B would displace get a certain Cp Drug A. Vd=Dose/Cp This leads Drug A to other E. PROTEIN BINDING compartments of the body, in theory, increasing its effect. In practice, it is NOT what actually NOTE: happens as it is VERY RARE that the displacement would lead to a significant elevation in effect because all of the processes mentioned happen in microseconds. In a graphical sense, a slight blip* would happen, but it would go back immediately. IF there is an interaction, it is not due to displacement, and probably due to another phase or aspect in pharmacokinetics (e.g. metabolism) In our blood, there are proteins which help in distribution, wherein if the drug is bound to a protein (protein-bound), a large protein won’t be able to pass through the gaps. Generally, PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 4 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 V. METABOLISM B. ZERO ORDER KINETICS A. FIRST ORDER KINETICS Rate of drug elimination is SAME throughout Also known as linear pharmacokinetics. the whole period of time. Rate of drug elimination is dependent on the Half-life is not constant and becomes useless. concentration. The concept of half-life, as opposed to the first The half-life (t1/2) is constant. order kinetics, can not be applied here. ○ Half-life – time it takes to reach 50% of Since elimination is generally slower, there is the drug also higher toxicity risk. Half-life relates the time it takes to reach Problem: steady-state plasma concentration. ○ If a drug initially with first order, shifts ○ Usually, it takes 5 half-lives before to zero order; or vice versa. reaching the steady state. For example, a drug initially If the half-life is several hours, having zero order suddenly we would have to multiply it shifts into first order, the drop by 5 to get an approximate in drug levels can be too rapid time of the steady state. and could cause withdrawal ○ For example, Amlodipine has a half-life symptoms. of 50 hours and is multiplied by 5, which equals ~10 days. If hindi pa C. FIRST PASS METABOLISM bumababa ang BP ng patient ng naka Amlodipine within 3 days, it might mean that the drug is still adjusting to the steady state. The main goal of metabolism is to make the drugs more polar to be ready for excretion via urine. There are two phases that could do that: PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 5 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Phase I: Functionalization phase ○ The blood levels of the drug will be Mostly redox reactions, lower because they will get because they create more polar metabolized faster. subgroups. CYP Inhibitors Usually done in the liver, most ○ An enzyme that metabolizes a CYP of which in the Cytochrome inhibitor gets their activity decreased. P450 system. ○ The blood levels of the drug will be In Cytology most of it happens higher because they will get in the Smooth ER. metabolized slower. ○ Phase II: Conjugation Phase A drug can be a substrate, inducer, or Drugs are stabbed with polar inhibitor, and the 3 are NOT related to each subgroups until they are polar other. enough to be eliminated. ○ If a drug, for example, is metabolized by CYP2D6, we can not predict if it is D. METABOLISM BY THE LIVER an inducer or inhibitor. CYP INDUCERS CYP INHIBITORS Ma’am Ethel takes Phen SICKFACES.COM GRouP Phen and Refuses Greasy Carbs Shakes Ethanol (Chronic) Sodium Valproate Phenobarbital Isoniazid Phenytoin Cimetidine Rifampicin Ketoconazole The enzyme of the liver involved in Griseofulvin Fluoxetine metabolism, is the Cytochrome P450 Fluconazole (CYP450) Drugs can be metabolized by one or more Carbamazepine Amiodarone CYP enzymes. Alcohol (Acute) CYP enzymes will metabolize particular drugs, meaning that some drugs are only St. John’s Wort Chloramphenicol metabolized by a certain enzyme (e.g. Smoking CYP2D6, CYP3A4). There are 3 important concepts in Erythromycin metabolism: ○ CYP Substrates Sulfonamides ○ CYP Inducers Ciprofloxacin ○ CYP Inhibitors Omeprazole CYP Substrates Metronidazole ○ We call drugs as substrates if they are the ones being metabolized by the Grape Juice CYP enzymes. Protease Inhibitors CYP Inducers Paroxetine ○ An enzyme that metabolizes a CYP inducer gets their activity increased. Other Phase 1 Enzymes ○ Monoamine Oxidase ○ Xanthine Oxidase PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 6 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Alcohol and aldehyde dehydrogenases Water Water Epoxide - the enzyme responsible for alcohol conjugation hydrolase metabolism (microsomes) (cytosol) “Asian flush syndrome” - due to a slow metabolizer, the alcohol accumulates to acetaldehyde and not metabolized into acetate E. PHASE II REACTIONS addition of polar functional groups to the original molecule formed in phase 1 to increase polarity Type of Endogenous Transferase Conjugation Reactant (Location) Glucuronidation UDP UDP-glucuron Glucuronic osyl-transferas acid (UDPGA) e (microsomes) Acetylation Acetyl-CoA N-Acetyltransfe rase (cytosol) Most common in interactions and clinical practice: Glutathione Glutathione GSH-S-transfer ○ Glucuronidation conjugation (GSH) ase (cytosol, ○ Glutathione microsomes) Example: the maximum dose for paracetamol per day is 4 Glycine Glycine Acyl-CoA ○ Paracetamol requires glutathione to conjugation glycinetransfer be metabolized ase ○ Too much paracetamol decreases (mitochondria) gluta stores which increases the amount of reactive toxic intermediates Sulfation Phosphoaden Sulfotransferas that accumulates in the body (since osyl e (cytosol) there is not enough glutathione to phosphosulfat metabolize the paracetamol) and e (PAPS) damage the liver ○ The antidote for paracetamol toxicity is Methylation S-Adenosylme Transmethylas N-acetyl cysteine which is used to thionine es (cytosol) replenish glutathione stores in the (SAM) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 7 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 body and eliminate the reactive VII. EXCRETION intermediates A note on proteins Example: what happens to the amount of ○ T1/2 similar (~2 weeks) drug in the body if the drug is an inhibitor of ○ Target mediated disposition – target its enzyme UDP-glucuronosyl-transferase? eliminated → increased clearance → ○ Rate of glucuronidation decreases shorter t1/2 ○ Increases concentration of the drug Organs for excretion: in the blood ○ Renal - Kidney ○ Biliary (Hepatic) - Liver VI. PHASE 0 AND III ○ Sweat (skin), milk, lungs, etc. NOT metabolism, but transport ○ Getting the drug to the target A. CLEARANCE Measurement for excretion Efficiency of irreversible elimination of drug from body ○ Unit: VPlasma cleared of drug per unit time ○ ClT = Clh + Clr +…. ○ mL/min A. PHASE 0 Blood to metabolizing cell (facilitated diffusion) ○ Transporters: SLC (solute carrier) family ○ Organic anion transporting polypeptides (OATPs) ○ Organic anion transporters (OATs) ○ Organic cation transporters (OCTs) B. PHASE III Assumption: 5 half-lives to eliminate drug Excretion (active transport) from the body (may vary like with impaired ○ Transporters: ATP-binding cassette kidneys) (ABC) family ○ P-glycoprotein (most common in B. GLOMERULAR FILTRATION RATE (GFR) phase III) – gut, placenta, liver/kidney Blood flow through glomeruli per minute (bile excretion), BBB, cancer cells, To check/measure how the kidneys are still some overlap with CYP3A4 filtering ○ Breast cancer reactive protein (BCRP) ○ For renal impairment - drug dose ○ Other multidrug resistance proteins adjustment (MRPs) - inherent drug resistance due ○ Lower GFR; Less functioning kidneys to certain pumps that pump the drug Measurement: inulin (complex assay) or out where it needs to be EDTA/iodinated compounds (simpler, with drawbacks) Surrogate: creatinine clearance (CrCl) - practical substance used in measuring GFR (inserted in the body and checked how much is peed out) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 8 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Cockroft-Gault Equation: VIII. EXERCISES Oral bioavailability of Paracetamol is about 𝐶𝑟𝐶𝑙 (𝑚𝐿/𝑚𝑖𝑛) = [140−𝐴𝑔𝑒(𝑦𝑒𝑎𝑟𝑠)] 𝑥 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔) 𝑥𝐹 70%. What does this mean? 𝑆𝐶𝑟 (𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒) 𝑥 72 ○ 70% of paracetamol is absorbed after ○ F=1 for males, F=0.85 for females you take it orally. Can you predict Warfarin’s distribution given Caveats: the fact it is highly protein bound? ○ Creatinine changes throughout the ○ Distribution of Warfarin is found in the day; formula is an estimate of an bloodstream since it is attached to average of varying CrCl large proteins that can not pass ○ Only applies when SCr is stable for through gaps. This is perfect because white Americans Warfarin is an anti-coagulant, it emits ○ F=0.85 for women only an assumption its effect in the bloodstream ○ Original method: colorimetric wet lab ○ If Warfarin is given at the same time (new method: spectroscopy) with a drug less protein-bond, nothing ○ Which weight? will happen since it will rapidly Other formulas used: MDRD, CKD-Epi (more distrubute to the compartment. accurate, esp in those with normal/higher Smoking cigarettes induces CYP1A2 enzymes GFR) ○ What happens to the rate of metabolism via CYP1A2? The cockroft-gault equation is the The metabolism fastens since most common equation used for smoking is an inducer. NOTE: drug dosing adjustment for patients ○ What happens to the concentration of with renal impairment but is not the Olanzapine, a CYP1A2 substrate? most accurate formula. The concentration would be lower since the enzyme that metabolizes Olanzapine is induced. ○ What will occur as a consequence? Less benefit, since Olanzapine is metabolized fast. Carbamazepine does what to CYP enzymes? ○ Induces ○ Do the enzymes it affects predict which enzyme will metabolize it? No, since substrate and inducer is a different concept to each other. True or False ○ When metformin 500 mg brand/generic X is said to be bioequivalent to innovator metformin 500 mg (Glucophage), it means both brand/generic X and innovator Peak effect - Cmax metformin contain about 500 mg of MECdesired - minimum concentration for metformin, with some leeway for benefits variation. MECadverse - minimum concentration for side False, since the basis for effects bioequivalence is not the dose Therapeutic window - in between MECdesired but AUC and Cmax (specifically and MECadverse 95% confidence interval within 80%-125%). PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Chua, De Guzman, Go, Magalued, Mendoza Page 9 of 13 PHARMACOKINETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Doubling the AUC automatically ○ The greater the value of fuplasma, the doubles a drug’s effects greater the volume of drug distributed False (Vd). Describe Esquvidu’s elimination kinetics. Assume 1st order initially. Elmo Esquvidu ○ The rate of elimination of Esquvidu is dependent on the concentration of Tmax