Pharmacology 1 Final Exam.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 Exam 2 Material Drug Metabolism and Elimination Major routes of elimination are: Hepatic metabolism Biliary elimination Urinary elimination Metabolism leads to production of products with increased polarity- allows drugs to be eliminated. Clearance estimates amount of drug cleared from body per unit of time Zero-order kinetics Release of drug is constant over time Because enzyme is saturated by a high free drug concentration Conditions are satisfied when concentration of a drug released over time is independent of concentration. Drugs obey zero-order when: Rate-limiting barrier- when a carrier system is saturated by excess of drug i.e. Vitrasert implanted in vitreous cavity First-order kinetics Metabolic transformation of drugs is catalyzed by enzymes and they obey Michaelis- Menten kinetics RATE OF DRUG METABOLISM IS DIRECTLY PROPORTIONAL TO CONCENTRATION OF FREE DRUG Most common in ocular drug The rate of movement is directly proportional to concentration difference across the barrier i.e. passive diffusion of molecules across a non-saturated barrier Prodrug Metabolite of a drug is more active at the receptor site than the parent form To be therapeutically useful Prodrug must be metabolized predictably to the effective drug form before it reaches the receptor site Greatest advantage is potential to add groups that mask features of the drug molecule that prevent penetration The first successful ophthalmic prodrug is dipivaloyl epinephrine Prodrugs are useful for research because Lipophilic prodrugs can be induced to penetrate the blood-vitreous barrier readily and metabolized to a form that is trapped in vitreous Reaction of Drug Metabolism Kidney cannot efficiently eliminate lipophilic drugs that cross cell membrane They are reabsorbed in the distal convoluted tubules Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via: Phase 1 Phase 2 Phase 1: Convert lipophilic drugs into more polar molecules By introducing a polar functional group i.e. -OH, -NH2 Usually involve reduction, oxidation, or hydrolysis It can increase, decrease, or no effect on pharmacological activity Phase 1 utilizing the P450 system: Important for metabolism of many endogenous compounds Steroids Lipids Important for biotransformation of exogenous substances Xenobiotics CYP: Contains 12 isoforms Oxidation occurs when the drug binds to P450 and oxygen is added Primarily located in liver and GI tract CYP3A4 Most common in human body Isozymes have overlapping capacity with drugs Enzyme induction Net increased metabolism of the drug leading to therapeutic failure Xenobiotics- induce activity of these enzymes Certain drugs are capable of increasing synthesis of CYP isozymes This results in increased biotransformation of drug and leads to significant decrease in plasma concentration of drugs metabolized Increased drug metabolism causes: Decreased plasma drug concentration Decreases drug activity if metabolite is inactive Increased drug activity if metabolite is active Decreased therapeutic drug effect Enzyme inhibition: 2 drugs compete for active site, inhibiting metabolism of each other. Omeprazole is potent inhibitor for 3 CYP isozymes responsible for warfarin metabolism If both drugs are taken together, plasma concentration of warfarin increase Leads to greater anticoagulant effect Increased risk of bleeding Important CYP inhibitors are erythromycin, ketoconazole, and ritonavir Because they inhibit several CYP isozymes Phase 1 reactions NOT involving P-450 Include amine oxidation i.e. oxidation of catecholamines and histamine Alcohol dehydrogenation Ethanol Esterase Metabolism of aspirin in liver Hydrolysis Procainamide- ventricular arrythmia Phase 2: Conjugation reactions If metabolite from phase 1 is sufficiently polar, will be excreted by kidney If metabolite is too lipophilic; A subsequent conjugation reaction with endogenous substrate makes more polar, water-soluble compound Lipophilic metabolites Glucuronic acid reaction Most common conjugation reaction The highly polar drug conjugates are then excreted by kidney or bile Clinical implications: Liver dysfunction Has less CYP450 enzymes Reduces the clearance of drug through hepatic enzymes Plasma protein binding Significant reduction if Phase 1 metabolism Increases bioavailability leading to overdose and toxicity Prodrugs Inactive compounds activated by metabolism Excretion Drugs are eliminated from body either unchanged or as metabolites Excretory organs eliminate polar compounds more efficiently Kidney 25- 30% of administered drugs Intestines Unabsorbed drugs Metabolites from bile Breast milk Small quantity but can affect the infant Lung Anesthetic gases Kidney (3 steps) Glomerular filtration ONLY UNBOUND DRUG IS FILTERED Drugs enter kidney through renal arteries- divide to form glomerular capillary plexus Free drugs (not bound to albumin) flow through capillary slits into Bowman space Lipid solubility and pH do not influence passage of drugs into glomerular filtrate Proximal tubular secretion (active) Drugs not transferred into glomerular filtrate leave through efferent arterioles These divide to form capillary plexus surrounding nephric lumen in proximal tubule Secretion primarily occurs by two energy-requiring transport systems Anions Deprotonated forms of weak acids Cations Protonated forms of weak bases Each system can transport many compounds This means that competition between drugs can occur within transport systems Neonates have incomplete developed tubular secretory mechanism Distal tubular reabsorption As drug moves toward distal tubule, concentration increases and exceeds perivascular space If drug is uncharged, diffuse out of nephric lumen, into systemic circ. Changing pH of urine to increase fraction of ionized drug in lumen may be done to minimize amount back diffusion and increase clearance Weak acids- eliminated by alkalinization of urine Weak bases- elimination increased by acidification of urine When urine is alkalinized, it keeps drug ionized and decreases reabsorption Notes to take home: Most drugs are lipid soluble and can diffuse out of tubular lumen When drug concentration in filtrate becomes greater that in perivascular space To minimize reabsorption Drugs are modified in liver into more POLAR substances via phase 1 and phase 2 The polar conjugates are unable to back diffuse out of kidney lumen Clearance from other routes Drugs not absorbed after oral administration are eliminated in feces Ophthalmic Drug Administration Topical Administration 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, therefore no benefit for diseases of posterior segment Main goal: Extend contact time Increase trans-corneal absorption Decrease systemic absorption Through conjunctiva---tight junctions do not allow absorption Episcleral vessel Nasal mucosa Packaging Typical volume now range from 25-56 mcl Cap color for ophthalmic drugs: Yellow- 0.50% beta blockers Used for dark iris Blue- 0.25% beta blockers Used for light iris Red- mydriatics and cycloplegics Used for dx purposes and pain management Mydriatic- pupil dilation Cycloplegic- ciliary body paralysis Green- miotics Used for glaucoma Pilocarpine- pupil constriction Orange- carbonic anhydrase inhibitors (CAI’s) Used for glaucoma Grey- NSAIDS Used for nonsteroidal anti-inflammatory Pink- steroids Used in inflammation and lowers pain management Brown- anti-infective Antibiotic (fight infection) Teal- prostaglandins Increase uveoscleral outflow Ideal characteristics of drug delivery system Corneal penetration Maximize absorption Lipophilic, hydrophilic, polar, nonpolar Simple instillation Reduced frequency administration More frequent a pt uses drop, less compliant they will be Compliance Low toxicity side effects Ideal concentration Solutions Most common use of topical ocular medications Particle sizes are less than 10^-7 cm Preferred over ointments because: Easily instilled. Less interference with vision Fewer potential complications 80% of drug lost to blinking Characterized by initial pulse (high concentration) followed by sudden reduction Increase in drug concentration to remain on cornea Disadvantages Short contact time Fast dissolution Inconsistent delivery of drug Suspensions Second most common High partition coefficient with water Particle size is greater than 10^-5 MUST BE SHAKEN Contains water insoluble substances Solid active drug particles are suspended in a transport system Large particles >10 micrometers Advantage Longer contact time which means better absorption Precipitate well-meaning they mix well Example: Steroids Most common is prednisolone (anti-inflammatory) Emulsions Oil-water mixture i.e. lubricant drops DO NOT PRECIPITATE Two phases’ liquids are not mutually soluble Dispersed phase Continuous phase Surfactant Stabilization Advantages Does not precipitate- no need to shake Enhances bioavailability Stays longer inside anterior segment Better absorption Protects ingredients from oxidation Most common mixtures Glycerin Polysorbates 80 Castor oil Examples Refresh, endura, restasis Some may have preservatives that enhance shelf life Can get contaminated so want to use dosage and throw away Ointments Semisolid and solid hydrocarbons (paraffin) Oily antibiotics GREATEST CONTACT TIME Base (oily) Petrolatum Liquid lanolin These interfered with corneal wound healing Mostly used for certain corneal abrasions because the cornea can be easily infected Clinical pearl Administer solutions before ointments Disadvantage- causes blurred VA and difficult application Examples Erythromycin- antibiotic mostly used in pediatric population Tobramycin- antibiotic with different types of mechanism Tobradex- tobramycin and dexamethasone Antibiotic and anti-inflammatory Instilled into the inferior conjunctival sac or upper eyelash margin Disadvantages Contact dermatitis of lids Due to atropine or neomycin because of prolonged contact time Clinical guidelines Can be used immediately following intraocular surgery Because risk of entrapment is minimal Used with caution in jagged corneal laceration Used for superficial corneal abrasions of the epithelium Preferred in patients undergoing macular hole surgeries Less frequent dosing of antibiotics and steroids Gels Semisolid Phases One phase- particles are evenly distributed in the gel Two phase- small active particles are suspended in a gel solvent Example is hand sanitizer DOES NOT HAVE CONTACT TIME LONGER THAN OINTMENT Examples Pilocarpine Carbopol gel- agent with high water-binding affinity that transforms gel to liquid once contacted Timoptic XE GenTeal Contains Carbopol 980 Glaucoma treatment Gelrite and xanthan gum are used to deliver timolol Contact time Longer shorter Ointment----- gel ----- emulsions –---- suspensions –----- solution Spray Used for mydriatics and cycloplegics Mydriatics- dilation Cycloplegic- ciliary body paralysis Diagnosing purposes Used most in pediatric patients Advantage Drug can be applied to closed eyelid Other examples Natures tears and Tears again Lid Scrub Cotton tip applicator, gauze, eyelid cleanser Used to treat blepharitis Filter Paper Strips Used to disclose corneal injuries and findings Three staining agents Sodium fluorescein Used in Goldman and corneal defects VERY BIG PARTICLES Lissamine green DES diagnostic filter paper Rose Bengal Used for dx of keratoconjunctivitis (severe DES) Lissamine green and rose Bengal stain dead cells NaFl paper stripes eliminate contamination with Pseudomonas aeruginosa Clinical uses Corneal injury Herpes simplex DES or DED RGP fitting Solid Devices Attempts to overcome initial period of overdosage followed by period of underdosage Most common is Ocusert Pilocarpine Contact Lenses Therapeutic or bandage contact Absorbs water soluble drugs Lenses with high water content absorb more water-soluble drug for later release Maximum drug delivery is obtained by presoaking lens Silicone hydrogel material (High DK value) High oxygen transmission Puervision Air Optix Clinical use Corneal erosion SPK Epithelial defects Corneal dystrophies Corneal Shield Collagen shields are thin membrane of porcine or bovine scleral collagen Conform to cornea when placed on eye Packaged in dehydrated state Used to deliver antibacterial, antifungal, antiviral, anti-inflammatory, and immunosuppressive drugs Scleral Lenses Larger diameter RGP lenses used for ocular surface diseases Cotton Pledges Allow prolonged ocular contact time with solutions that are normally topically instilled Small cotton piece from applicator Pledge in placed in inferior conjunctival sac after drops of solution are placed on it Clinical use Mydriasis- pupil dilation with phenylephrine Synechia- sectorial dilation Happens when attachment of iris to cornea or lens of eye from blunt trauma Artificial Tear Insert Rod shaped pellet “Lacrisert” Made of hydroxyl cellulose w/o preservatives Administered in inferior conjunctival sac on lower eyelid Releases polymers for 24 hours Clinical use DES because administer 1x day Disadvantage Pt with tremors or visual loss with have hard time administering Niosomes Also known as topical liposomes Used as a alternative to liposomes and polymerases for chemical drug delivery Bilayer vessels Possess Hydrophobic shell Non-aqueous, non-ionic surfactant Hydrophilic cavity Aqueous compartment Categories Nanoparticles- polymeric colloidal particles Nanosuspension- submicron colloidal system Microemulsion- thermodynamics stable, small Iontophoresis (LAST RESORT ADMINISTRATION) Low density electrical current Pushes medication through epithelium I.e. Eyegate 2 Sonophoresis Ultrasound at frequencies higher than 20 Khz (enhances K. penetration) Ocular Injections and Oral Medications Subconjunctival Injection Outer sclera covered by conjunctiva Less invasive technique Advantage Used by antibiotic with poor intraocular penetration High local concentrations of drug is obtained with small quatities of meds High tissue concentration of drugs with poor intraocular penetration through epithelial layer of cornea Involve passing of needle between anterior conjunctiva and Tenon’s capsule Amount of drug absorbed by sclera is minimal Used in treatment of severe corneal diseases i.e. bacterial ulcers Subconjunctival anesthesia is now used as alternative to peribulbar or retrobulbar anesthesia for trabeculotomy or cataract sx Clinical uses Corneal and intraocular infections Corticosteroids Triamcinolone acetonide Sub- Tenon’s Injection Delivers lower quantity of drugs to eye Associated with greater risk of perforating the globe Clinical usage Anterior- injections can be used to treat severe uveitis or iridocyclitis Posterior- injections used to treat cystoid macular edema and diabetic macular edema Advantage Longer drug action Disadvantage Difficult molecular penetration Globe penetration in not well-trained hands Retrobulbar Injection- into muscle cone Deposition of drug INTO muscular cone Fast drug movement with high concentration Clinical use Anesthesia to globe during cat sx Macular region Inflammation- last resort if pt is almost blind Complications Retrobulbar hemes Puncture of eyeglobe Retinal detachment Vitreous hemes Least common for infections but most common for anesthesia usage Injected between inferior and lateral rectus muscles Peribulbar Injection- around muscle cone Lower risk of injury Because does not reach muscle cone Less effective for anesthesia Complications Diplopia Orbital heme Artery occlusion Brainstem anesthesia Helps reduce potential for inadvertent globe penetration Intracameral Drug delivery directly into anterior chamber Viscoelastic substance during cataract surgery Used to maintain shape of cornea Glaucoma filtering surgeries Protect against corneal endothelial cell loss and flat anterior chamber Smaller quantities of drugs used Clinical use Bacterial infections Iridocyclitis Inflammation of iris and ciliary body Intravitreal Injected directly into the vitreous Used for macular, retinal, ONH diseases or injuries Antibacterial and antifungal injections used to treat endophthalmitis Antivirals for retinitis Clinical use Liquid silicone injected for retinal detachments Cytomegalovirus retinitis- inflammation of macula in immunocompromised pt Ganciclovir (Vitraset) Steroids Retisert Wet AMD- Macugen (anti VEGF) Systemic Drug Administration Systemic administration Delivered to vascularized ocular tissues Anterior segment Conjunctiva and episcleral vessels Posterior segment Retinal and choroidal circulation Deliver lower drug dose Multiple barriers Oral Most common Can treat anterior and posterior disease through blood stream Clinical uses Infection of ocular adnexa Ocular pain Less effective for ocular surface disease Dosage forms Tablets, capsules, liquids, and suspension Enteric coating help sustain release and metabolism by stomach Advantages Cost effective Variety of forms Reduced contamination Disadvantages Pt with dysphagia (not able to swallow) Absorption by GI tract Systemic toxicity Anaphylactic response Most common allergy to aspirin, penicillin, sulfa, tetraclycline Drug infections Toxicity is more that topical administration Parenteral Directly into the systemic circulation Used for drugs that are poorly absorbed from GI tract Highest bioavailability Not subject to first- pass metabolism Provides most control over actual dosage Intravenous High serum concentration Most common is Angio therapy used to see about retinal occlusion Severe ocular infections and enophthalmos Used for orbital cellulitis and perceptual cellulitis of eye lids Disadvantages Precipitate blood constituents Induce hemolysis Cause adverse reactions if delivered too rapidly Two types Continuous infusion Pt is hospitalized Slow and prolonged administration Single intravenous pulse Tourniquet upper arm Released after drug administration Intramuscular Drugs can be in aqueous solutions- absorbed rapidly Specialized depot preparations- absorbed slowly Provides a sustained dose over extended period of time Injected into ventral or dorsal aspect of gluteus muscle Contraindicated in children under 3 Deltoid muscle Used more for kids because gluteus is under developed and can injury sciatic nerve Quadriceps muscle Clinical use Hyperacute bacterial conjunctivitis Neisseria gonorrhea Subcutaneous Absorption via simple diffusion Slower than IV injection Minimizes the risk of hemolysis or thrombosis associated with IV injection Common drugs: Insulin Heparin Metabolism of Ophthalmic Drugs The eye is well protected against absorption of drugs and xenobiotics. Anterior barriers- tears, cornea, conjunctiva Hydrophilic drugs penetrate the cornea by paracellular transport. Posterior barriers- retinal vessels, RPE, Bruch’s membrane and choroids Other barriers- vitreous, iris, lens, ciliary body Phase 1 Metabolic activity of Eye Metabolic activities in ocular structures adjacent to regions of highest uveal blood flow Cytochrome P450 activity identified. Cytochrome P-450-dependent metabolism of endogenous substrates such as arachidonic acid, prostaglandin, and steroids was found to occur in corneal epithelium. Phase 2 Metabolic activity in Eye Transport of endogenous substances by way of transferases (phase 2 enzymes) Catalytic activity induces the biotransformation of metabolites which are eventually removed from eye circulation. Iris and ciliary body have highest glutathione S-transferase activity. Cornea exhibited highest specific activities for N-acetyl, sulfo-, and UDP-glucuronosyl-transferase. The iris, retina, choroid, and uveal tracts result in most drug accumulation. Slow elimination has been associated with drugs binding to melanin (pigmented epithelium) Final Material Pharmacokinetics Clearance If bioavailability is complete, steady state concentration of a drug will be achieved when the rate of elimination equals the rate of drug administration Rate of elimination to the plasma concentration CL=rate of drug eliminated Plasma drug concentration Total clearance Volume of biological fluid from which drugs have completely removed Zero order kinetics will NOT have a constant clearance First order kinetics WILL have constant clearance Example: Drug X is infused @ 5mg/min, producing a plasma rate concentration of 8 mg/L. what is the clearance rate of this drug? CL=rate of eliminated drug Plasma drug concentration Example: An 80 kg patient with a negative medical history has orbital cellulitis. Cephalexin is administered as a treatment. The drug plasma excretion concentration of uncharged drug is 93%, and the plasma clearance is 12 mL/min/Kg. what is the plasma clearance for this patient? Half-life (t1/2) Sole determinant of the rate that a drug achieves steady state is half-life The time it takes plasma concentration to be reduced to 50% Constant for drugs that follow FIRST ORDER KINETICS Patients with increased drug half-life will have: Diminished renal or hepatic blood flow Heart failure, hemorrhage Decreased ability to extract drug from plasma Renal disease Decreased metabolism Cirrhosis These patients require a decrease in dosage or less frequent dosage The half-life of a drug may be decreased by Increase hepatic blood flow Decrease protein binding Increased metabolism Steady state The rate of elimination is balanced with the rate of administration Usually, at 4t1/2 time frame Example: Drug X is administered every 8 hours in a formulation of 25 mg. the half-life of drug X is known to be 6 hours. What would be the total amount of drug administered to achieve the steady state? Dose regimen Plan of administration over a period of time Therapeutic window Concentration range that provides efficacy without toxicity Important in long-term therapy Ocular Bioavailability Bioavailability The amount of drug present at desired receptor site Fraction of administered drug gain access to systemic circulation chemically unchanged In ocular therapy, Bioavailability is used to measure the side effects and toxicities and not an indication of the therapeutic efficacy Topical ocular delivery Low bioavailability Because tear film dilutes the drugs Low local and systemic effects Physiological protective mechanisms from the eye Pre-corneal clearance Less that 5% bioavailability Tear turnover and drainage Dilution by tear flow Reflex blinking- innervated by CN 2 Drug induced lacrimation Tear film, blinking mechanism Low corneal permeability Major route for absorption Tight intercellular junctions Layers of cornea and structure Molecules cross by: Simple diffusion- most common penetration Paracellular- hydrophilic, between cells (water liking) Transcellular- lipophilic, through cell outer layers Blood-ocular barrier Tight junctions will not allow meds to pass Stroma has more affinity to hydrophilic drugs Physiochemical factors Molecular solubility Max amount of solute dissolved under standard conditions of temp., pressure, and pH Cornea would prefer too acidic drops than too basic drops Topical drugs are mainly absorbed through cornea, some through conjunctiva, and sclera Deferential solubility Intracellular Intercellular Molecular size and shape Determinant in ocular permeation Epithelium diameter 2nm (biggest) Large molecules Fluorescein- particle are large, so will attach to disturbed cornea Determinant rate of diffusion Bigger molecule, harder it is to diffuse through the cell Smaller the molecule, better corneal penetration through cells pH and Dissociation Behaves similar to systemic, pH should be similar to anterior segment Too acidic, too basic medication will alter charge of molecule of drug Part of drug that has therapeutic action is non-ionized form Aqueous solubility depends on: Solution pH, pKa, pKb Tear pH- 7.45 Maintained by bicarbonate system of the eye Continue regeneration of tear film Great influence to maintain equilibrium of drug to penetrate cornea Ophthalmic solutions The chemical equilibrium state in which the nonionized (more lipophilic) portion is in balance with the ionized (more hydrophilic) portion Weak acids and weak bases Non-ionized form pH has to be about 7.5 to not cause toxicity of the eye Medication pH is achieved with buffers by counteract shifts Help preserve drug in bottle and protects from oxidation In addition, buffer systems may momentarily alter the pH of tears after installation Factors that alter pH Inadequate shelfing Exposure to sun Formulation factors 1 gtt= 30 microliters Tear volume in eye= 11 microliters Type Bottle tip or dropper design- allows no more or less than 30 microliters Dispensing rate- slow enough to allow drug to go into eye without excess meds Angle of bottle Vertical tip will have more administration drug Optimal angle is 45 degrees, allows smaller amount of drug Conjunctiva holds around 36 microliters of liquid This means that 6 microliters are out 80% of drug is removed by blinking The adrenergic system will dilate the pupil (sympathetic system) Formulation factors Viscosity Drug retention cul de sac Increase contact time Ointments, gels will have longer contact time because more viscose Cohesiveness with the ocular surface tends to increase trans corneal penetration More viscose, lower displacement 15-30 cps optimal (centistokes) Greater viscosity slower velocity of flow displacement Osmolarity Measure of solute concentration Hypertonic solutions = decrease drug concentration Hypotonic solutions = adverse symptoms Isotonic formulations less irritating to eyes do not alter osmolarity 290 osmol (0.9% saline solution) 1 milliliter has 30 drops A patient has allergic conjunctivitis is both eyes, Bid-OU, how many milliliters is a 30 day supply? Systemic Pharmacodynamics Pharmacodynamics describes actions of a drug on the body Drug-receptor complex initiates alterations in biochemical and molecular activity in process called signal-transduction Receptors transduce their recognition of a bound agonist Agonist- naturally occurring small molecule of drug that binds to a site on a receptor protein and activates it Receptors and their sites Receptors exist is two states, active or inactive In reversible equilibrium, usually favoring inactive state The binding of agonist, activates to produce biologic effect Antagonists help stabilize the receptor in the inactive state A ligand- molecule that bind to the activation site on receptor Types Ligand-gated ion Ligand-binding site regulates shape of pore Closed until receptor is activated by agonist Voltage-gated channels may also house ligand-gated Example: cholinergic nicotinic receptor G protein-coupled This receptor contains ligand-binding areas Alpha subunit binds guanosine triphosphate (GTP) Beta and gamma subunits anchor g-protein in subunit Binding of agonist increase GTP binding to alpha-subunit Example: alpha and beta adrenoreceptor Enzyme-linked Protein forms dimer complexes When activated, these receptors undergo conformational changes resulting in increased cytosolic enzyme activity Example: insulin receptor Intracellular receptors Receptor is intercellular Ligand must diffuse into the cell to interact with receptor To move across target cell membrane, ligand must have sufficient lipid solubility Primary targets are transcription factors in nucleus Physiological Receptor Agonist Binds to receptor and produce a biologic response based on Concentration of the agonist Fraction of activated receptors Mimics regulatory effect of endogenous signaling Agonists Primary agonist: Drug binds to receptor and produces maximal biologic response that mimics response of endogenous ligand When bound to receptor, stabilizing receptor in active state Known as intrinsic activity Phenylephrine is example Allosteric agonist: Group of substances that bind to a receptor to change receptor’s response to stimuli Partial agonists Lower response than a full agonist Have intrinsic activities 0<x<1 Can have affinity greater, less, or equal to a primary agonist WHEN A RECEPTOR IS EXPOSED TO BOTH PARTIAL AND FULL AGONIST, THE PARTIAL AGONIST MAY ACT AS ANTAGONIST Antagonist Bind to receptor with high affinity but possess zero intrinsic activity Has no effect in absence of agonist But can decrease effect of agonist when present Blocks or reduces the action of the agonist Can occur by: Blocking drugs ability to bind to receptor Block drugs ability to activate the receptor Competitive antagonist Prevents agonist from binding to its receptor Maintains the receptor in its INACTIVE state They shift the agonist-dose response curve to the right Noncompetitive antagonist They bind covalently to active sites, reducing # of receptors available for agonist Effects cannot be overcome by adding more agonist Also known as: Irreversible antagonist Allosteric antagonists Difference between competitive and noncompetitive antagonists is that competitive antagonists reduce agonist potency and non-competitive antagonists reduce agonist efficacy Potency Measure of amount of drug needed to produce an effect of a given magnitude A drug producing 50% of the maximum effect is used to determine potency Whichever drug is to the left of a graph, this means it is more potent Because less drug is used to reach 50% effect Potency of drugs can be compared using E50 The smaller E50, more potent drug Efficacy Magnitude of response a drug causes when it interacts with a receptor Dependent on the # of drug-receptor complexes formed Dependent on intrinsic activity of drug This is ability to activate the receptor and cause cellular response Maximal efficacy means all receptors are occupied by the drug MORE CLINCALLY USEFUL THAT POTENCY BECAUSE A DRUG WITH MORE EFFICACY BENEFICIAL THAN A MORE POTENT ONE.