Pharmacology Exam 1.docx

Pharmacology 1 Final Exam 40-50 questions Exam 1 Material History Served as a barrier from infection. Body healed itself. Chinses use potions. Pharmacology is the study of sciences that deal with drugs. a drug is any chemical compound given to the body and nurtures you. used for diagnostic purpos...

Pharmacology 1 Final Exam 40-50 questions Exam 1 Material History Served as a barrier from infection. Body healed itself. Chinses use potions. Pharmacology is the study of sciences that deal with drugs. a drug is any chemical compound given to the body and nurtures you. used for diagnostic purposes like: Types of medicines Over the counters Sold without prescription Controlled drugs Require a prescription from a doctor Has a life of 24 hours Illicit drugs Marijuana, cocaine, heroin, meth Drug discovery Most drugs derive from natural sources with a “therapeutic tradition” i.e. cocaine is derived from leaf of plant traditional uses like herbs and roots certain beneficial effects from certain ingredients Biological engineering Therapy of cancer Antibacterial formulated Some have developed defensive mechanisms from drugs used Modify molecule, have the same evidence Regulation of Drugs Timeline 1912- Pure food and drug act banned fraudulent therapeutic claims FDA was not around to regulate drugs on the market 1938- Food, Drug, and Cosmetic Act (FDA) was created Prevented marketing of untested drugs FDA required a (NDA) New Drug Application before marketing was allowed 1962- when pharmacology was first seen Required proof of effectiveness of drugs to allow them to be put on the market IRB (Institutional Review Board) was also created to help test drugs Clinical Phases of Drug Investigation Phase 1 Establish dose level where signs of toxicity first appear in 20-80 subjects age 18-45 First side effects are noticed during this phase. Phase 2 Dose response in sick subjects Phase 3 Effective dose is known, and efficacy is proven. Followed by a new drug application. This stage is complied with first identification of side effects. Company can apply for new name and gets approved. DRUG IS PUT ON MARKET Phase 4 Post market studies to make sure there are no new side affects Drug Controversies Price Most drugs a generic brand that does the exact same affects and is twice as cheap as original drug Be aware of the different types of brands Accessibility Some drugs are harder to find than others Basic Ocular Anatomy for Pharm (Lecture 2) Lids Protect Help with lubrication Distribute tear film over anterior part of eye Thin skin Muscles are very delicate Muller muscle involved in lid retraction Meibomian gland secrete the mucous portion of tear film Tarsal plate Back part of upper and lower lid in contact with eye globe Not allow penetration of topical drugs to area behind the eye Conjunctiva Transparent tissue covering the sclera Healthy eye conjunctiva is clear, no inflammation When conjunctiva is compromised, it is called hyperemia Hyperemic conjunctiva will absorb more medication Bulbar conjunctiva Covers the sclera Palpebral conjunctiva Covers the back of eyelids Allergic reactions can cause papilla Tear Film Only 25% of medication will make it into the anterior segment of the eye Tear production and drainage Tears Accessory glands in eyelid and conjunctiva Lacrimal glands Lubrication of the eye Also washes any bacteria or foreign body out of eye Punctum Systemic absorption of some medications Drain through the punctum Drug absorption through the nasal mucosa can be profound as this is a direct route to the circulatory system and skips the liver metabolism. Can slow this process down by punctual occlusion after administering the drops Eyedrops meant for local effect, like betablockers, can have impressive systemic side effects. Canaliculus More medications means more toxicity Lacrimal sac Drains to the nose Layers of tear film Mucous (inner) Secreted by the cornea Aqueous Secreted by the lacrimal gland Oil layer Secreted by the meibomian gland Sclera Strongest structure of eye Protects the shape of the eye and maintains shape White outer layer Fibrous layer composed of collagen Composed almost 90% of eye structure Episcleritis Inflammation of the episcleral Rose Bengal stain only stains the conjunctiva Cornea Clear front surface Provides refractive power Tear film is FIRST element associated with clear film Avascular- no vessels Layers Epithelium Basement membrane Bowman’s capsule Stroma- hardest layer of cornea Descemet’s membrane Endothelium Anterior Chamber Between cornea and iris Pupil dilation Pupil constriction Aqueous humor Drains through the Schlemm’s canal Posterior chamber Between iris and lens Ciliary bodies are muscles Produce aqueous humor that is used to nutrient to stabilize lens and cornea Vitreous chamber Area between lens and back of retina Contains vitreous humor that helps keep the eye inflated Most made of water Holds retina onto the choroid layer of eye Uvea Composed of Iris Ciliary body Choroid plexus Lens Behind the iris High protein concentration Relaxed in accommodation (NEAR VISION) Layers of the lens Capsule Associated with posterior subcapsular cataracts Cortex Nucleus Retina Layers Function Macula Central vision Houses photoreceptors Optic nerve Neurons Send signals from eye to the brain Arteries Bring oxygen from away from the eye Ophthalmic Drug Formulation (Lecture 3) Pharmacokinetics The study of time course of absorption, distribution, metabolism, and elimination of an administered drug. Movement of drugs within the body Drub absorption Depends of: Molecular properties of the drug Viscosity of its vehicle Functional status of the tissue forming the barrier Availability of drugs left over after metabolism Distribution Volume of drug that is available to absorb Metabolism Metabolic enzymes have been studied to design prodrugs Molecules that are activated after tissue penetration Where the drug is being used in the body Elimination Excretion through systems of body Can be delivered Locally Solutions, ointments, emulsions, intravitreally Systemically Orally, intravenously, intramuscular Ocular meds are different from regular because they are metabolized by the treat film first. Tear Film Three layers Lipid layer HELPS WITH EVAPORATION OF TEAR FILM Damaged layer can result is DES Helps repel water Secreted by meibomian gland Minor infections, by staphylococci, can decrease tear film stability Aqueous layer Water portion of tear PH 7.4 Produced from the lacrimal gland mostly Mucous Layer Hydrophilic portion Made from the goblet cells of conjunctiva Houses electrolytes, mucin, and water, and glycoproteins pH is roughly 7.45 Contains proteins like lysozymes, lactoferrins, gamma globulins, and other immune factors Volume of tear film is 8-10 microliters Flow rate is 0.5-22 microliters (mcl) When a drop size is increased, the systemic load is increased linearly Cornea To increase corneal absorption Manually block nasolacrimal ducts Administer a series of drops between 10 minutes each Made of 5 layers Epithelium Made of tight junctions Resist hydrophilic drugs (drug has to have lipid formula to penetrate) Lipophilic drugs penetrate the epithelium. Because barrier is composed of phospholipid membranes i.e. sodium fluorescein if a slight break in epithelium, fluorescein can penetrate agents that are very lipophilic have a longer half-life epithelial erosion or action of cationic preservatives can increase penetration of hydrophilic drugs BECAUSE IT CONTAINS 2/3 PLASMA MEMBRANE MASS, SIGNIFICANT STORAGE DEPOT FOR AGENTS THAT READILY PARTITION INTO LIPID MEDIA Too low partition coefficient Do not penetrate well into epithelial Too high partition coefficient Remain in epithelium and partition into anterior chamber slowly Bowman’s layer Surface layer adjourns to epithelial layer via hemidesmosomes Same drug penetration as the stroma Stroma (8-14 mm thick) Contains keratocytes Collagen fibers Increase path of diffusion 90% corneal thickness HYDROPHILIC DRUGS pass through easily Serves as a major ocular depot for topically applied hydrophilic drug Keratocytes- provide reservoir for lipophilic drugs Descemet’s layer Endothelial basal lamina Can pass molecular species as readily as does stroma Not known as separate drug reservoir Endothelium Simplest layer Monolayer Helps maintain osmosis Can pump its own weight in fluid out in approximately 5 minutes Provides interchanging of nutrients between anterior chamber and cornea Pinocytosis- allows transport of high-molecular weight proteins What type of drugs can penetrate the epithelium and endothelium? Lipophilic drugs What drugs can penetrate only the stroma? Hydrophilic drugs The difference between epithelium and stroma is the molecules pass through diffuse absorption channels. Sclera The conjunctiva and sclera are responsible for 1/5th drug absorption to the iris and ciliary body. Opaque vascular structure Conjunctiva is highly vascularized. Possess key transport processes that may allow for penetration into intraocular tissues Connective tissue that overlies to sclera Allows passage of drugs better than the sclera Limited absorption of drugs Unless they are compromised Sulfonamides Prostaglandins Iris Regulates amount of light Can serve as depot for some lipophilic drugs Adrenergic and cholinergic innervation Adrenergic drug- stimulate certain nerves in the body Mimic the action of chemical messenger epinephrine and norepinephrine Or stimulate the release of those two chemicals Cholinergic- act upon binding of neurotransmitter acetylcholine Primary neurotransmitter in the parasympathetic nervous system Miosis can be accomplished by: Endogenous or exogenous acetylcholine Acetylcholine- allows relaxation of sphincter muscle Mydriasis can be accomplished by: Adrenergic stimulation Epinephrine- acts on dilator muscle Pigment granules- lipophilic drugs Reversible and releasing of drug overtime Persons with darkly pigmented eyes, dilation lasted lasted longer than light colored eyes Aqueous Humor Uveoscleral route accounts for 20% of aqueous humor outflow Formed from the ciliary body Contains nutrients for lens and cornea usage Exits through the trabecular meshwork or uveoscleral outflow Ciliary Body Produces the aqueous humor Accommodation (focus at near to help read) Systemic drugs to anterior chamber Major ocular source of drug-metabolizing enzymes Drug detox Barrier for some meds ADHD patients have trouble reading at near because amphetamine dilates pupils. Lens Double layer Grow with age and flexibility reduced @ older age Resistance to hydrophilic drugs with high molecular weight (capsule) Lipophilic slowly rate (cortex) Barrier to rapid penetrating drugs Lens removal (cat sx) Crystalline proteins After cat sx, capsule is not fully intact and is more suspectable to drugs. Vitreous Viscoelastic connective tissue 80% of ocular mass Some molecules can be diffused Can be a reservoir for drugs Retina and Optic Nerve Tight junctional complex (zonula occludent) Prevents passage of drugs both coming in and out Capillaries determine molecular selectivity Barrier effective toward hydrophilic drugs Lipophilic drugs can cross barrier Because of membrane fluidity Systemic Pharmacokinetics: Absorption (Lecture 4) Pharmacokinetics Absorption Distribution Metabolism Excretion Absorption From site of administration to the bloosdstream Predictors of movement and availability at sites of actions depends on: Molecular size Structure Degree of ionization Solubility Binding Passage of Drugs Across Membranes The plasma membrane is selectively permeable. Phospholipid bilayer Permeability Going to resist some meds Glycoprotein- protein with carbohydrate attached Glycolipid- lipid with carbohydrate attached Mode of Permeation and Transport Passive transport: most common transport Paracellular Movement of the drug thru intracellular gaps These cells will have tight junctions Only allow small drugs to pass through Diffusion Concentration gradient Region of high concentration to low concentration DOES NOT INVOLVE CARRIER, NOT SATURABLE, LOW STRUCTURAL SPECIFICIT Most drugs are absorbed by this mechanism Solubility of the lipid bilayer If lipid bilayer is neutral, drug will be more successful Lipid bilayer is also exposed to pH and pKa pH Weak acids Release a proton (+) causing a charged anion (-) to form Weak bases Protonated form loses a proton to produce an uncharged base Uncharged drug passes through membrane easily weak electrolytes pKa- determining factor Measure of the strength of the interaction of a compound with a proton Lower pKa = more acidic drug Higher pKa = more basic drug pH 50 % of drug is ionized “ion trapping” i.e. distribution of weak acid between the plasma components Excretion urine pH= 4-8 Acidic drugs (HA) Release H+ (uncharged) causing A- (charged) anion Associated with weak acids Basic drugs (BH+) Released H+ (charged) with B (uncharged) Associated with weak bases Passive transport Facilitated diffusion Specialized transmembrane carrier protein Carrier mediated transport Does NOT require energy Highly selective proteins All passive transports depend on Physical factors like: Blood flow in absorption sight Shock reduces blood flow to cutaneous tissues, minimizing absoprtion i.e. where a lot of vessels, have better absorption Surface area Bigger the size, higher probability drugs pass via facilitated diffusion The more microvilli, more absorption Contact time: A drug taken with a meal is generally absorbed slower Longer exposure time means better chances to be absorbed Paracellular- between cells Intracellular- across cells Active transport Involves specific carrier proteins Better penetration uses ATP and sodium calcium channels Energy-dependent Able to move against a concentration gradient Moves solute against Electrochemical gradient Saturability Selectivity Competitive inhibition Primary ABC transporter Exchanges ATP for ADP Moves only a selective molecule out of cell NA+, K+, ATPase Exchange ATP for ADP Sodium out, potassium in SLC co-transporters Anti- sodium in, x out Symporters- sodium in, x in Drug Absorption Corneal absorption Depends on integral tear film concentration Diffusion of drugs from cornea to aqueous humor is similar to tears and cornea Except the corneal depot, aqueous humor receives major proportions of drugs A lipophilic drug that is also water soluble penetrates the cornea more readily than does fluorescein, a more hydrophilic drug Absorption Refers to the process of drug transfer from its sites of administration to the blood stream Medications NEED to be absorbed Bioavailability The extent of a drug that reaches the active site From site bloodstream Systemic circulation to free drug Drugs typically enter the body via Enteral (oral PO) Lower concentration with longer affects Intravenous (IV) Higher drug concentration and quicker affect Intramuscular (IM) Intrapulmonary Subcutaneous Topical All drugs are absorbed into the blood stream as a free drug Bioavailability Amount of drug present at desired receptor site Indicates the fractional (F) extent to which a drug dose reaches its site of action Increase percentage of drug, increase bioavailability. F= Qty of drug reaching systemic circulation Qty of drugs administered. Determination of bioavailability Comparing plasma levels of drug to route of administration Area under the plasma concentration The concentration of the drugs in the plasma over time The area under the curve (AUC) can be measured. Reflects extent of absorption of the drug This is why bacteria can grow and become resistive of drugs if not finished full prescription Multiple doses last longer than a single dose because of drop off of the plasma concentration Factors that influence bioavailability First pass hepatic metabolism Absorbed drug enters portal circulation before systemic circulation This is called first-pass metabolism By intestine or kidney can limit efficacy of many oral medications Solubility of a drug Very hydrophilic drugs are poorly absorbed Because inability to cross lipid-rich membranes Extremely lipophilic drugs are poorly absorbed Because totally insoluble in aqueous body fluids Chemical instability Penicillin G- unstable in the pH of gastric contents Insulin- destroyed in GI tract Nature of drug formulation Absorption rates are altered by: Particle size Salt form Crystal polymorphism Enteric coatings Higher hydrophilic means poor drugs Routes of Administration Oral Absorption by gastrointestinal tract Most common method Fastest, convenient, and inexpensive In occasions have limited absorption Physical characteristics (tablets, capsule, solution) Irritation GI mucosa Destruction of ensymzes Presence of food or other drugs Gastric emptying rate Various factors Enteric coat (Advil, Tylenol)---------most common for pt’s with stomach ulcers Coating to protect GI mucosa Controlled release preparations Slow uniform absorption for 8 hr or longer Sublingual (tablet below tongue for quicker absorption) Absorption in oral mucosa I.e. nitroglycerin Smaller pills dissolve faster w/ saliva Parenteral Injection Delivery of a drug in their active form (not by GI system) Availability is more rapid, expensive, and predictable Reaction is faster Routes of parenteral injections Intravenous Intramuscular Subcutaneous Intra arterial Intrathecal Intravenous 2nd most common method Provides most complete drug availability with a minimal delay Complete absorption and fast distribution (100% bioavailability) Advantages High concentration rapidly reach plasma and tissues Absorbed very quickly Used for compounds poorly absorbed by GI system Disadvantages Careful dosage and constant monitoring for potential adverse effects Dosage calculation is very important Intramuscular: inside muscle Absorption of intramuscular injection depends on the rate of blood flow to injection site and fat versus muscular composition Common injection sites Gluteus maximus Better for solutions in oil and depot (slow release) vehicles Slow releases over time to permit less frequent administration Deltoid and Vastus Lateralis Better absorption for aqueous compounds The solvent of the drug is water Drugs are absorbed quickly because these areas are very close to blood supply Subcutaneous Most common drug is insulin injection of drug in the fatty tissue layer of the subcutaneous tissue under dermis and epidermis provides prolonged effect slower absorption than intramuscular high bioavailability Parenteral injection Intra arterial Directly into the artery Intra thecal Injected into spinal subarachnoid space i.e. anesthesia, brain tumor, epidural Pulmonary (inhalation) Absorbed through pulmonary epithelium and mucous membrane of respiratory tract Rapid access to blood stream Corticosteroid can form cataracts Topical Most common route of administration for ophthalmic usage Topically applied anesthetics are primary anesthetic Primary source of drug loss is diffusion into circulatory system Takes place in blood vessels of conjunctiva, episcleral, intraocular vessels, and nasal mucosa Because of this loss, not penetrate the posterior ocular structures Drugs applied to mucous membrane Skin- transdermal Conjunctiva Nasopharynx Oropharynx Vagina Urethra Urinary bladder Rectal- commonly used to administer antiemetic agents Most common usage in kids Provides partial avoidance of first pass metabolism Systemic Pharmacokinetics: Distribution (Lecture 5) Distribution How drugs cross the membranes and interact with system Drugs distributed into interstitial and intercellular fluids Determined by: Cardiac output Blood flow High blood flow with high lipophilicity increase distribution Capillary permeability In liver and spleen- basement membranes is exposed due to large, discontinuous capillaries Tissue volume Phase 1: higher distribution at these areas Liver Kidney Cannot efficiently eliminate lipophilic drugs that cross cell membrane Drug is reabsorbed in the distal convoluted tubules Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in liver via Phase 1 and Phase 2 reactions. Brain Other well profuse organs Phase 2: slower because not a lot of vessels Muscles Viscera Skin Fat- slower because drug gets trapped in fat cells and excreted slowly Binding to Plasma Proteins-reversible Albumin (most common plasma protein) Drug reservoir As the concentration of free drug decreases due to elimination, the bound drug dissociates from the protein Acidic and hydrophobic drugs Binding is reversible- some drug will remain and be released later Alpha 1- acid glycoprotein Basic drugs Reversible Hormone specific Fraction of total drug in plasma is determined: Concentration of drug Affinity and number of binding site Very competitive between drug and receptor Binding to Plasma Membrane Unbound drug (Free) Competition between drugs Class 1 drugs Dose is less than binding capacity (capacity ratio is LOW) Class 2 drugs Dose exceeds number of bindings to albumin Example Tolbutamide 95% is bound only 5% is free If antibiotic is administered, displaces tolbutamide from albumin leading to rapid increase in concentration Volume of Distribution Volume and distribution V relates the amount of drug in the body to the concentration of a drug plasma Body water compartments Plasma compartment Large molecules are “trapped” Distributed about 6% of patient’s body weight Extracellular fluid Low molecular weight and hydrophilic Sum of plasma and extracellular Apparent Volume of Distribution- helps with calculating the loading dosage of drugs Volume into which a drug distributes Demonstrates how drugs will behave in blood Vd= amount of drug in the body (gm) plasma drug concentration (gm/L) Liver disease will have reduced protein loss, loss of albumin in urine Urinary test to measure albumin in urine Determination of Vd: First order- constant fraction of drug is eliminated per unit of time Vd=Dose/concentration of drug Lipophilicity Lipophilic drugs readily move across the biologic membranes Dissolve in the lipid membrane and penetrate entire cell surface Major factor influencing distribution Blood flow to area Hydrophilic drugs do not cross barrier that easily Distribution Tissue distribution Accumulates in higher concentrations Proteins Phospholipids Nuclear proteins Reversible Toxicity When there is too much meds CNS, BBB, and CSF Tight junctions Drug penetration depends on transcellular transport Transcellular transport Lipid soluble Drug has to be very liposoluble to pass through the CNS Bone (not reversible) Absorbed by bone crystal surface and eventual incorporation into the crystal lattice i.e. tetracycline- is not rx’d to kids and pregnant women because the bones are still growing Fat Reservoir of lipophilic drugs Low blood flow Placental transfer of drugs Selective barrier Fetal plasma is more acidic than the mother Influx transporters The placenta provides protection for the baby