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Pharm week 3
General Principles of Pharmacology
| Question | Answer |
|---|---|
| Pharmacotherapeutics | The area of pharmacology concerned with the use of specific drugs to prevent, treat, or diagnose a disease |
| All drugs used in pharmacotherapy exhibit what types of effects? | undesirable, or adverse effects, as well as desirable, or therapeutic effects. |
| Successful pharmacotherapy requires balancing | a drug’s desirable effects with the drug’s undesirable effects (i.e., benefit-to-risk ratio) |
| Drug of choice | which drug is most likely to provide the best “benefit-to-risk” ratio in a particular individual with a particular disease or disorder? |
| Dosage regimen | The manner in which a drug is takenHow much? -- What dose is taken?How often? -- What dosage frequency?How long? – What duration of therapy? |
| Choice of an appropriate drug requires: | comprehensive info regarding the pt’s clinical stateaccurate dx,sound understanding of the pharmacotherapeutic management of the disease or disorderthorough knowledge of the “benefit-to-risk” ratio of a specific drug for a particular individual |
| Dose | Magnitude of response (therapeutic or toxic) is typically a function of the amount of drug given |
| Dosage frequency | Magnitude of drug effect declines with time following a single dose of the drugTime between doses should allow for maintenance of adequate therapeutic concentrations at site of action |
| Duration of therapy | PRN, short-term, long-term, chronicConsider cost incurred with continued drug administrationside effects/adverse effectstoxicityeconomics |
| Dosing Regimine consisits of: | Dose, Dosage frequency, and duration of therapy |
| Achieving therapeutic objective | Drug must move from site of admin to site of actionSimultaneously, drug distributes to other tissues, including those that eliminate it from the body, Maintain an adequate [] of drug at the site of action for the appropriate duration of therapy |
| Therapeutic failureDrug therapy may be ineffective because: | concentration of the drug at the site(s) of action is too low, orthere is an unacceptable degree of toxicity because concentration of the drug at the site(s) of action is too high |
| Therapeutic Success part 1: | The optimal dosage regimen maintains the concentration of the drug in plasma within a “therapeutic window” |
| Therapeutic Success part 2: | The “therapeutic window” is the region between these two limits of concentration associated with therapeutic failure |
| The “therapeutic window” is the region between these two limits of concentration associated with therapeutic failure | It is not typically possible to measure concentrations of drug at the site(s) of actionTherefore, drug concentrations in plasma are measured |
| Drug administrationWhat is the therapeutic objective of administering a drug to an individual who is believed to have a disease or disorder? | to diagnoseto preventto cure to alleviate or mitigate symptoms |
| Drug administration is divided into two phases: | Pharmacokinetic phasePharmacodynamic phase |
| Pharmacokinetic phase of Drug Admin | Relates dose, frequency, & route of administration to drug level-time relationships in the body |
| Pharmacodynamic phase of Drug Admin | Relates concentration of drug at site(s) of action to the magnitude of the effect(s) produced |
| Optimal drug administration requires: | Requires knowledge of mechanisms of drug:AbsorptionDistributionEliminationAND, knowledge of the KINETICS of these processes… pharmacokinetics |
| Pharmacokinetics | The study of how a drug moves through the body and what the body does to the drug in that process:Drug AdministrationDrug AbsorptionDrug DistributionDrug Elimination |
| Routes of drug administration | Enteral and Parenteral |
| What is Enteral? | GI tractOral (p.o.)Sublingual (SL) & Buccal (BUCC)Rectal (p.r.) |
| What is Parenteral? | Any route other than the GI tractInhalationInjectionTopical |
| Oral drug administration Most absorption of drugs taken by mouth occurs in | Small Intestine |
| Oral drug administration Advantages: | Easiest & most convenient methodRelatively safeAffords large surface area to enhance entry of drug into body (small intestine microvilli) |
| Drug must have relatively high lipophilicity for absorptionis a disadvantage of what? | Oral drug administartion Disadvantages: |
| May irritate stomach or damage gastric mucosais a disadvantage of what? | Oral Drug admin disadvantage |
| Stomach acids & digestive proteases may degrade/destroy drug before GI absorption occursis a disadvantage of what? | Oral Drug admin disadvantage |
| Limited or erratic absorption of some drugs is a disadvantage of what? | Oral drug admin disadvantage |
| First-pass effectis a disadavantage of what? | Oral drug admin disadvantage |
| First-PASS EFFECT | DRUG ABSORBED FROM ALIMENTARY CANAL ->PORTAL VEIN TRANSPORTS DRUG TO LIVER ->DRUG IS METABOLIZED BY HEPATIC ENZYMES |
| “first-pass effect” | - A large portion of the drug may be metabolized to an inactive substance before reaching the site of action- Some drugs are so extensively metabolized that they must be administered by non-oral route |
| Most drugs given orally are metabolized in the liver via the | “first-pass effect” |
| Sublingual | Place drug under tongue |
| Buccal | Place drug between cheek & gums |
| Sublingual and buccal administration- absorption- how does it reach systemic circulation | - Drug is absorbed through oral mucosa into venous system draining from mouth- Drug may reach systemic circulation without being subjected to “first-pass effect” in liver |
| RECTAL DRUG ADMINISTRATIONMay be useful if: | Patient is vomiting & cannot keep oral drugs downPatient is unconsciousMost commonly used for treating local conditions such as hemorrhoids (e.g., suppositories) |
| RECTAL DRUG ADMINISTRATION-Disadvantages: | Many drugs are absorbed poorly or incompletely via this routeIrritation of rectal mucosa may occur |
| Drugs that may be given via inhalation: | those in a gaseous or volatile state, orthose capable of being suspended as tiny droplets in an aerosol form |
| Inhalation Advantages: | Large surface area (alveoli) for diffusion of drug into pulmonary circulationRapid entry of drug into bloodstream |
| Inhalation Limitations: | Some drugs may irritate alveoli or other areas of respiratory tractSome individuals have difficulty administering drugs by inhalation & drug particles are trapped by cilia & mucus |
| injection | Systemic or local administrationNo “first-pass effect”Potential for introduction of infectionSome types are more difficult for patient to self-administer |
| Types of injection: | Intravenous Intra-arterialSubcutaneousIntramuscularIntrathecal |
| transdermal | Application of drug directly to surface of skinProvides slow, controlled release of drug into bodyMaintains plasma levels of drug at relatively constant concentration for prolonged periods of time |
| Transdermal Must possess two basic properties: | Ability to penetrate skinNot degraded to any significant extent by drug-metabolizing enzymes located in the dermis |
| Types of transdermal administration | Patches, Iontophoresis, Phonophoresis |
| Types of transdermal administration- Patches | nicotineopioid analgesicshormone preparations |
| Types of transdermal administration- Iontophoresis | Electric current used to facilitate movement of ionized form of drug through the dermis |
| Types of transdermal administration- Phonophoresis | Ultrasound waves used to enhance transmission of drug through dermis |
| DRUG absorption | After dose is administered, initially, rate at which drug enters the body exceeds rate drug is removed from the body |
| drug absorption (triangle thing...) | Drug Absorption > Drug Elimination ->Concentrations of drug in blood and tissue rise -> Therapeutic & possibly toxic effects occur |
| SOME Factors affecting intestinal absorption | Presence of foodIntestinal infectionRate of gastric emptyingAmount of visceral blood flow |
| what is Bioavailability | Extent to which drug reaches systemic circulation |
| Bioavailabilty Depends upon: | route of administrationability of drug to cross membrane barriers |
| Bioavailabilty is Expressed as the percentage | of drug administered that reaches the blood stream, |
| Bioavailabilty example of Orally administered drug | For every 100 g of drug administered, 50 g reaches systemic circulation = 50% bioavailability |
| Bioavailabilty example of Same drug administered intravenously | For every 100 g of drug administered, 100 g reaches systemic circulation = 100% bioavailability |
| Drug distribution- After a drug reaches systemic circulation, it is: | distributed further into peripheral tissues, where it may reach the site(s) of action (also known as “target sites”)- Leaves capillaries & enters other cells- Must cross cell membranes & tissue barriers to be distributed into the body |
| MEMBRANE STRUCTURE & FUNCTION-Biologic membranes separate the body into | “compartments” by acting as barriers to some substances, while allowing others to pass |
| Cell membranes form a lipid bilayer made up of | PhospholipidsProteinsLipid-soluble compounds pass directly through, while nonlipid-soluble substances may pass through membrane pores or channelsThese pores are dynamic & can open & close to regulate flow of certain ions in & out of cell |
| Movement across membranes- Drugs may pass through biologic membranes by: | Passive diffusionActive transportFacilitated diffusionSome special process (e.g., endocytosis) |
| Factors affecting drug distribution | Tissue permeabilityBlood flowBinding to plasma proteinsBinding to sub-cellular components |
| Factors affecting drug distribution- Tissue permeability: | Highly lipid-soluble drugs pass through membranes readily & may reach all body compartmentsNon-lipid-soluble drugs do not pass through membranes readily & may remain in the compartment or tissue to which they were originally administered"BBB" |
| Factors affecting drug distribution- Blood flow | Any disease or disorder that reduces blood flow to specific tissues & organs will result in less drug delivered to those tissuesThe greater the blood flow to tissues or organs, the more drug is likely to reach the tissue or organ |
| Factors affecting drug distribution-Binding to plasma proteins | Some drugs form reversible bonds to circulating proteins (e.g., albumin) |
| Factors affecting drug distribution-Binding to sub-cellular components | Some drugs bind to lysosomes, which traps the drug in the cell (drugs with higher pH) |
| Blood brain barrier | Brain capillary endothelium have special characteristics that limit the passage of drugs out of the blood stream into the central nervous system |
| One of the most significant problems in treating CNS diseases and disorders is | developing drugs that can cross this “blood-brain barrier” |
| Volume of distribution | Vd is used to estimate a drug’s distribution by comparing the calculated Vd with the total amount of body water70 kg man total body fluid content ≅ 42 L |
| Ratio of the amount of drug administered to the concentration of drug in plasma | Vd = amount of drug administered concentration of drug in plasma |
| If the calculated Vd of a drug is approximately equal to the total amount of body water, the drug is | distributed uniformly throughout all of the body’s fluids |
| drug storage-Storage sites | Adipose (fatty tissue)BoneMuscleOrgans |
| drug storage- Adverse consequences | Local damage to tissues in storage sitesLiver-> Acetaminophen (Tylenol®)Kidneys-> LithiumDeposition of drug into a storage site prevents drug from reaching target site or site of actionRedistribution of drug from storage sites may occur |
| Drug elimination | Eventually, rate of removal of drug from body exceeds rate of entry of drug into bodyDrug Elimination > Drug Absorption->Concentration of drug in tissues declines->Drug effect(s) subside |
| Drug elimination-Biotransformation: | Drug metabolism via enzymatic breakdownResults in an altered version of the original drugLiver is the primary site for biotransformationOther sites are:LungsKidneysGI epitheliumSkin |
| Drug elimination-Excretion | Kidneys are the primary sites for drug excretionOther sites are:LungsGI tractSweatSalivaBreast milk |
| Biotransformation-refers to: | the chemical changes in the drug that occur after administration |
| Biotransformation-Is accomplished by: | via the action of enzymes, primarily in the liver |
| Primary function of biotransformation is to | inactivate or terminate drugs’ effects, after they are no longer needed by the body |
| In biotransformation the original drug compound is altered into | other substances called metabolites- Drug metabolites are usually LESS pharmacologically active than the “parent drug” |
| If the drug metabolite is MORE pharmacologically active than the “parent drug” | the drug may be administered as the less active or inactive “prodrug” form that is activated in the body via biotransformation |
| Drug metabolism usually occurs via one or more of the following chemical reactions: | Phase I Oxidation:primary method of drug metabolism via the cytochrome P450 monooxygenase enzyme systemReductionHydrolysisPhase II Conjugation |
| Drug biotransformation cellular mechanisms, which compound is made during these processes? | A more polar compound (metabolite) is created via any of these processes, which may then be excreted from the body |
| what is Enzyme induction | Activity of hepatic drug metabolizing enzymes is increased by some mechanism |
| The enzyme induction mechanism does: | The mechanism induces the enzymes to increase the breakdown or destruction of certain drugsThe drugs are metabolized more rapidly than usual, resulting in a decrease in their therapeutic effect |
| Mechanisms that trigger enzyme induction are: | Ingestion or use of certain drugs or other chemicals such as:Some anticonvulsant drugsAlcoholCigarette smokeEnvironmental toxins |
| What is Enzyme inhibition | A drug or other substance may inhibit the hepatic enzyme(s) that normally metabolize other drugs |
| Enzyme inhibition causes | causes a decrease in the metabolism or breakdown of those drugs, resulting in an increase in drug concentrations and potential toxicity |
| Hepatic enzyme induction & inhibition are responsible for | MANY drug interactions, as well as for many therapeutic failures and drug toxicities |
| Drug excretion: what is it? and where is the primary site? | Movement of drug out of the bodyKidneys are the primary site |
| What occurs after drugs are metabolized by the liver? | After drugs are metabolized by the liver to more polar, water-soluble metabolites, these metabolites travel to the kidneys & ultimately leave the body through the urine |
| During drug excretion, can anything be reabsorbed? | Non-polar compounds are relatively lipophilic & can be reabsorbed back into the body rather than being excreted |
| What happens to some drugs during active transport | Some drugs are secreted into the nephron by active transport |
| Other drug excretion routes | Lungs excrete volatile drugs usually administered by inhalationGI tract plays only minor roleOther minor routes for drug excretion:SweatSalivaBreast milkInfant may be exposed to substantial concentrations of some drugs |
| Rate of drug elimination from the body is one of the major factors determining the dosage frequency necessary for any drug | Drug administration > Drug eliminationDrug elimination > Drug administrationDrug administration = Drug elimination |
| Drug administration > Drug elimination | Possible drug accumulation & toxicity |
| Drug elimination > Drug administration | Possible inadequate drug concentrations & therapeutic failure |
| Drug administration = Drug elimination | Maintenance of relatively stable drug concentrations |
| Two major parameters used to determine rate of drug elimination are: | ClearanceHalf-Life |
| Drug clearance | Amount of plasma drug is removed from per unit time (i.e. mL/min) |
| Drug clearanceDependent upon the organ or tissue’s | ability to remove drug from plasmaperfusion of the organ or tissue |
| Systemic clearance is | elimination of drug from the entire body, & is calculated as the sum of all individual clearances from each organ |
| Drug half-life | Amount of time required for 50% of the drug remaining in the body to be eliminatedHalf-life (t1/2) is a function of:clearance (CL), and volume of distribution (Vd) |
| Half-life may be affected by anything that alters CL or Vd, for example: | Sequestering of drug into storage sites (e.g., skeletal muscle)Disease states (e.g., chronic kidney failure) |
| Dosing schedulesDetermined primarily on the basis of drug: | plasma concentrationshalf-life |
| Newer drug delivery techniques | Controlled-release preparationsOralInjectableImplanted drug delivery systemsTargeting drug delivery to specific cells & tissues |
| Controlled-release preparations | Allow slower & more prolonged absorption from GI tract & other administration areasDecrease number of daily doses neededPrevent large fluctuations in plasma levelsMaintain plasma levels over time (e.g., over night)Decrease side effects related to |
| Controlled-release preparationsExamples: ORAL FORMS and Injectable | ORAL FORMS INJECTABLE FORMSControlled-release (CR) DepoSustained-release (SR) DecanoateExtended-release (ER) MicrospheresDelayed-release (DR)Prolonged-action (LA, XL) |
| Implanted drug delivery | Drug “reservoir” surgically implanted in some area of the body from which drug is released in a controlled mannerParticularly useful for administration hormones, analgesics, & muscle relaxants |
| Targeted drug delivery | Targeting drugs to specific tissues through cellular and chemical mechanismsMonoclonal antibodiesVirus transportersEncapsulation (e.g., liposomes)Protein attachmentEnzyme activationDrug modification (e.g., “prodrug”) |
| Pharmacodynamics | The analysis of what the drug does to the body, including the mechanism by which the drug exerts its effectsInvolves drug receptors |
| Drug receptors | Components on the outside or inside of a cell where a drug molecule may attach or “bind” and trigger a chain of biochemical events |
| Drug receptors- a drug's effects: | therapeutic and adverse – are most often a function of the type of receptors to which they bindReceptors may be any cellular macromolecule, often proteins or protein complexes |
| cell surface receptors | Cell surface is the primary site for receptors that recognize endogenous & exogenous compoundsResponsive to specific amino acid, peptide, or amine compounds |
| cell surface receptors Can affect cell function: | By alt cell mem permeability acting as an ion channelDirectly influencing enzyme function w/in the cellLinkage to regulatory proteins (G proteins) controlling other enzymatic processes within the cell via activation or inhibition (2nd messenger) |
| Intracellular receptors | May be located in the cell cytop or nucspecific for certain endogenous hr and hr-like compoundsHR form a complex with the receptor where it may affect F of specific genesCell F is alt due to changes in gene expression and msngr RNA transcription |
| Drug-receptor interactions | Process not well understoodBinding of drug to receptor may cause a temporary change in shape or conformation of receptorChange in structure of active receptor mediates change in cell function? |
| Drug-receptor interactionsKey-in-lock analogy | Drug is the keyReceptor is the lock |
| Drug-receptor interactionsAffinity: | Amount of attraction between drug & receptorDrug with high affinity binds readily to receptor, even when drug concentrations are relatively lowDrug with low affinity require higher drug concentrations in order for drug to bind to receptor |
| Drug selectivity & receptor subtypes | Selective drug affects only one type of cell or tissue & produces specific physiologic responseRelative term only used to compare one drug to another in terms of ability to affect one type of tissue or organ more than another |
| Drug selectivity & receptor subtypes"subtypes" | Related to the fact that receptor populations have “subtypes”– different drugs may bind preferentially to one subtype of receptor over another subtype |
| Dose-response | Response to a drug is believed to be proportional to the number of receptors occupied by that drug, although there are other factors involvedLower dose -> Lower drug concentration-> Fewer receptors occupied ->Less drug effect |
| Agonist | is a drug that binds to a receptor and initiates a change in the cell functionAffinity – drug wants to bind to the receptorEfficacy – drug will activate the receptor & lead to a change in cell function |
| Antagonist | is a drug that binds to the receptor and keeps the usual agonist compound from having an effect on the cell (referred to as blockers due to ability to block the effect of another chemicalHas affinity for receptor, but no efficacy |
| Competitive antagonists | Compete for the same receptor as the agonists & have an equal opportunity to occupy the receptorSubstance present in the highest concentration will “win”! |
| Non-competitive antagonists | Form strong, potentially permanent bonds to the receptor & cannot be displaced by the agonist |
| Partial agonists | Drugs that evoke some response on binding to the receptor, but NOT a maximal response as compared to a strong agonistMay be because the partial agonist does not completely activate the receptor on binding |
| Does Partial agonists have anything to do with the drug’s affinity for the receptor | NO, it has nothing to do with drug's affinity |
| Mixed agonist-antagonist drugs will stimulate certain receptor subtypes while | blocking the effects of endogenous substances on other receptor subtypes |
| Inverse agonists will bind to the same receptor as the agonist, but | have the opposite effect on cellular function compared to the agonist |
| Receptor regulation | DesensitizationDown-regulationSupersensitivity |
| Desensitization | Brief, transient decrease in the number of receptors secondary to over-stimulation of post-synaptic receptors byEndogenous neurotransmitters or hormonesExogenous agonist drugs |
| Down-regulation | Similar to desensitization, although a slower, more prolonged process |
| Supersensitivity | Functional increase in receptor sensitivity secondary to a prolonged decrease in post-synaptic receptor stimulation (e.g., denervation supersensitivity)Increase in receptor numbers secondary to post-synaptic receptor blockade by antagonist drugs |
| Non-receptor mechanisms | Some drugs DO NOT exert their effects by binding to receptors on or in cellsDirect chemical reactions (e.g., antacids)Bind directly to harmful compounds (i.e., chelating agents)Become incorporated into the manufacture of specific cell components & a |
Created by:
NicoleB
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