Final Pharm Review Exam 1 PDF

Review Exam 1 General Concepts in Pharmacology Muller Muscle involved in id movement Muscle have minimal Lids protect all ocular structures and help in lubrication by distributing the tear lm. They are made up of thin absorptionskin and a tarsal plate. Basic Eye Anatomy for Pharm : es la parte that actually touches the globe Lesta The conjunctiva is a transparent tissue that covers the sclera; it should be clear and glossy. It has a slow penetration rate but it can be sped up when it is compromised. It is made up of the mucus membrane, thin clear membrane, bulbar conjunctiva and palpebral conjunctiva. The structures involved in tear production are: The lacrimal gland is involved inproducing the aqueous phase of tears . ● Tears - wash eyes out and moisturize the cornea (supply oxygen requirements of corneal epithelium), ⑳ tear lm is composed of: produced by accessory glands in eyelids and conjunctiva. The ⑦ ⑤ ● Punctum - absorbs tears ● Canaliculus ● Lacrimal sac - can absorb medication due to a high amount of vessels. ● Lacrimal duct - The tear lm will dilute topical medications. 80% of the medication won’t be absorbed, the remaining 20% will stay in the anterior segment. The sclera is a white brous coat that protects the eye and maintains its shape. For a substance to penetrate it, it has to have special properties. ● Di erent stains can help di erentiate lesions in the conjunctiva and sclera. The cornea is the clear avascular front surface of the eye which provides refractive power. Epithelium -> stroma -> -> contains the The posterior chamber is found between the iris and lens; it contains aqueous humor. The vitreous chamber is lled with vitreous humor and it is very di cult to reach with medication since it is behind the lens. The uvea is composed by the iris, ciliary body and choroid plexus. The lens is found behind the iris and has high protein concentration. ● Layers: Capsule -> Cortex -> Nucleus -> Bowman's Descemet-> Endothelium The anterior chamber is found between the cornea and iris; it contains aqueous humor. ciliary body Basement Dry eye = & absorption The retina covers the posterior part of the eye and gathers information to send to the optic nerve. The macula is the center of visual acuity and is in charge of central vision. Ocular Structures and Pharmacokinetics Pharmacokinetics encompasses drug absorption, distribution, metabolism and elimination. ● Absorption - How will it get in? ● Distribution? - Where will it go? ● Metabolism - How is it broken down? ● Excretion - How does it leave? Medications can be delivered: supply 02 requirements Locally - Solutions, ointments, emulsions, intravitreally, gels, etc ● Systematically - orally, intravenous and intramuscular. the eyer It is the major optical surface (in The tear lm is the rst element ocular drugs interact with; it is made up of a lipid, aqueous and mucus layer. can ● Its volume is around 8-10 microliters and the normal ow (unstimulated) is about 0.5-22 ·2 microliters./min The eye hold up to 3021 ● The main function of the lipid layer is to stabilize the surface and protect the aqueous layer. ● En Oily layer - stabilizes the surface to put o evaporation; it is produced by meibomian glands. outermost layer ● Ene Aqueous phase - comprises 95% of total volume and is inherently unstable ; it is produced by goblet cells and the lacrimal gland. imm thick ○ Its breakup time averages between 25-30 seconds. ● Inner/basal layer - thin hydrophilic coating composed of glycoproteins and secreted by goblet cells. - of corneal epithelium 7 ● pH . . Ene Mucus The cornea is divided into: epithelium N Bowman's X only simple Use diffussion [ ● cleanses tears Epithelium - has tight junctions and resists penetration by hydrophilic drugs (Lipophilic drugs easily cornea epi ● Stroma - made up of collagen bers and makes up 90% of corneal thickness. Allows passage of cornea stroma hydrophilic drugs and is very strong. ● Endothelium - innermost layer, considered a monolayer; maintains osmosis exchanging nutrients from the aqueous chamber to the cornea. ↓ Endothelium , : Lipophilic pass). It is the second element the applied ocular drugs interact with. stroma X Descemet layer ● Has Nalk pump It is the major route for ocular drug absorption. In a healthy cornea there is barely any absorption; however, damage to the cornea can aid in drug absorption. ● The cornea is the major functional barrier to ocular penetration and major site of absorption for topically applied drugs. : hydrophile . For it to absorb medication it must be applied intravitreally or intracameral serves as a depot for superficially drugs . that to tears absorbed are then released er . The sclera is an opaque vascular structure that contains the conjunctiva (connective tissue overlying it) and has a very limited absorption of drugs. ● Sulfonamides and prostaglandins are some of the few drugs absorbed by the sclera. The iris regulates the amount of light reaching the retina and has adrenergic and cholinergic innervation. Miosis : ● Cholinergic Iris Its pigment granules absorb lipophilic drugs and are able to release them over time. They also serve as a barrier. povesto blue eyed individuals can exp greater response with 1st dose . ● - Mydriasis Adrenergic ● The dilator muscle is mainly stimulated by the sympathetic system. The sphincter muscle is stimulated by cholinergic receptors. : -- The aqueous humor is formed by the ciliary body; it exits from the trabecular meshwork or uveoscleral out ow and lls the anterior cavity. The ciliary body produces aqueous humor and is involved in accommodation. It is largely involved in delivering systemic drugs to the anterior chamber. ● It can be a ected by topical and systemic medication. ● It is the major ocular source of drug metabolizing enzymes responsible for the two major phases of reactions that begin the process of drug detoxi cation and removal from the eye. . The crystalline lens is a double-layered structure that grows with age and loses exibility, diminishing accommodation. Capsule - Lipophilic cow molec . cortex - Lipophilic ● ● Weight ● Capsule - provides resistance to hydrophilic drugs with high molecular weight Cortex - has slow lipophilic absorption rate since they can’t easily penetrate because of the capsule. It is a barrier to rapid penetrating drugs. The vitreous is made up of viscoelastic connective tissue and makes up 80% of the ocular mass. ● The retina and optic nerve have a tight junctional complex (zonula occludents) in their epithelium which Retina Optic N Some molecules can be di used but it mainly acts as a reservoir for drugs. . Lipophilic prevents passage of medications both ways. ● It is a barrier for hydrophilic drugs but lipophilic drugs can pass. ● Its capillaries determine molecular selectivity. Systemic Pharmacokinetics Predictors of drug movement and availability at sites of action depend on: molecular size, structure, degree of ionization, solubility and binding. The plasma membrane is a selectively permeable layer. ● It is a phospholipid layer that is hydrophobic outside and hydrophilic inside. . pigment : Lipophilic The most common mode of transport is passive transport. It includes ● Paracellular transport - movement of drug through intercellular gaps ● Di usion - transport due to a concentration gradient; involves the solubility of the lipid bilayer. ● ○ pH: Weak acids and bases (weak electrolytes) pass more easily. ○ pKa: greater di usion when 50% of the drug is ionized. Facilitated di usion - does not require energy; involves carrier mediated transport and highly selective proteins. Depends on physical factors like blood ow, surface and contact time. Acidic drugs release H+ (uncharged) creating charged anions while basic drugs release H+ (charged) with B (uncharged). Active transport has a direct requirement of energy since it moves solutes against electrochemical, saturation, selectivity, and competitive inhibition. Drug absorption refers to the process of drug transfer from its site of administration to the bloodstream. ● Drugs typically enter the body via enteral (per oral, PO), intravenous (IV), intramuscular (IM), intrapulmonary, subcutaneous or topical route and then are absorbed into circulation as a free drug. Bioavailability indicates the fractional extent to which a drug dose reaches its site of action. It is the area under the plasma concentration. 𝑄𝑡𝑦. 𝑜𝑓 𝑑𝑟𝑢𝑔𝑠 𝑟𝑒𝑎𝑐ℎ𝑖𝑛𝑔 𝑠𝑦𝑠𝑡𝑒𝑚𝑖𝑐 𝑐𝑖𝑟𝑐𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑄𝑡𝑦 𝑜𝑓 𝑑𝑟𝑢𝑔𝑠 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 ● 𝐹 = ● Some factors that in uence bioavailability include: rst pass metabolism, drug solubility, chemical instability and nature of the drug formulation. The oral route of administration is the most common method since it is the fastest, convenient and inexpensive. It is absorbed by the GI tract. ● Absorption can be limited by physical characteristics (tablet, capsule, solution), GI mucosa irritation, enzyme destruction, presence of food/other drugs and gastric emptying rate. ● Enteric coat - coat that avoids absorption in the stomach so that it can occur in the colon and ileum. ● Controlled release - allows slow uniform absorption for 8 hours or longer. ● Sublingual - absorption in oral mucosa, it is very fast because of extensive vascularization. Parenteral injections involve the delivery of a drug in their active form (without involving the GI tract) allowing a more rapid, extensive and predictable availability. Routes of parenteral injections include: ● Intravenous - second most common route, it provides the most complete drug availability with a minimal delay; there is complete absorption and fast distribution (100% availability). ○ Advantages - High concentrations rapidly reach the plasma and tissues; it is used for compounds poorly absorbed by the GI system. ○ ● Disadvantages - Requires careful dose and constant monitoring for potential adverse e ects. Intramuscular - depends on the rate of blood ow to the injection site and the fat vs. muscular composition. The deltoid and vastus lateralis muscle o er better absorption for aqueous compounds while the gluteus maximus is better for oil or depot (slow release) formulations. ● Subcutaneous - consists of an injection of a drug in the fatty tissue layer of the subcutaneous tissue under the dermis and epidermis. Provides a prolonged e ect and slower absorption than intramuscular routes. Has high bioavailability. ● Intra-arterial- consists of administration directly into an artery. ● Intrathecal - consists of injections into the spinal subarachnoid space producing a local and rapid e ect. The pulmonary route consists of inhaling and absorbing the drug through the pulmonary epithelium and mucous membranes of the respiratory tract. It provides rapid access and absorption into the blood circulation. Topical administration consists of drugs applied to mucus membranes; for example: skin (transdermal), conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra and urinary bladder. The rectal route provides partial avoidance of the rst pass metabolism and is used for large amounts of drugs, drugs with unpleasant taste or in patients with vomits. Systemic Pharmacokinetics: Distribution Drugs are distributed into interstitial and intracellular uids; this distribution is determined by cardiac output, blood ow, capillary permeability and tissue volume. The rst phase of distribution reaches the liver, kidney, brain and other well-perfused organs. The second phase of distribution reaches muscle, viscera, skin or fat. While being distributed, drugs will bind to plasma proteins. ● Albumin - bind to acidic and hydrophobic drugs, serving as a reservoir. Most common and hormone speci c (women tend to have more albumin). ● ⍺1- acid glycoprotein - binds basic drugs The fraction of total drug in plasma is determined by concentration and by a nity and number of binding sites. Unbound drugs are free. There is competition between two types of drugs: ● Class 1 drugs - dose is less than albumin binding capacity ● Class 2 drugs - dose exceeds albumin binding capacity. The volume of distribution (V) relates the amount of drug in the body to the concentration of a drug in plasma. 𝑉𝑑 = 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦 (𝑔𝑚) 𝑃𝑙𝑎𝑠𝑚𝑎 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝑔𝑚/𝐿) The body water compartments are: ● Plasma compartments - traps large molecules. ● Extracellular ﬂuid - traps low molecular weight and hydrophilic drugs; it is a sum of plasma and extracellular. Distribution when elimination is present depends on drug concentration; it is divided into: ● Distribution phase - initial decrease as the drug transfers from plasma. ● Elimination phase - drug leaves the plasma and is lost from the body.\ Tissue binding - drugs accumulate in higher concentrations due to proteins, phospholipids and nuclear proteins; it is reversible, serves as a reserve and can cause toxicity. The central nervous system, blood-brain barrier and cerebrospinal uid have tight junctions, o er transcellular transport and have lipid solubility. In bone, drugs are absorbed by the bone crystal surface and eventually incorporated into the crystal lattice. Fat serves as a reservoir for lipophilic drugs and has low blood ow. Placental transfer of drugs involves a selective barrier since the fetal plasma is more acidic than the mothers and in ux transporters are needed. - Result in activation the of receptor where drugs bind Quantification b of inding W Result in inhibition C arrg-receptor theft are yields as . Pharmacology Review - Exam 2 Ophthalmic Drug Administration: Topical Topical administration includes solutions, gels, emulsions, pellets, etc. ● They are the most common drugs used for anterior segment diseases and the most common type of ocular drug administration overall (80-90%). ③ ② ① Its main goal is ideally to extend contact time, increase trans-corneal absorption, and decrease systemic absorption through the conjunctiva, episcleral vessels and nasal mucosa. ● Chronic topical medication is more likely to cause systemic e ects since the constant application can increase absorption. To reduce confusion in labeling and identiﬁcation, several drugs are packaged with speciﬁc dark colors: 10 eyes . 0 2) Y . (light eyes) -glarcoma ● Gray - NSAIDS <pain dilators ● Yellow or blue - Beta blockers ● Red - Mydriatics and cyclopegics-+ ● Green - Miotics ● Orange - Carbonic anhydrase inhibitors (CAI’s) Pink - Steroids ● Brown - Anti-infectives -glarcoma ● allergy =Inflammation/light pain ● diagnosis + Teal - Prostaglandins ① ungut -glaucoma The ideal characteristics of the topical drug delivery system are: corneal penetration, S C ⑳ ③ ① G maximized absorption, simple installation, reduced frequency of administration, compliance, low toxicity/side e ects and ideal ① concentrations. T Solutions are the most common and commercially available type of topical ocular drugs. ● Up to 80% of it is lost with blinking. ● It is characterized by an initial pulse high (high concentration), followed by a sudden reduction. ● It has short contact time and fast dissolution in the tear ﬁlm. Suspensions have a high partition coe cient with water and contain water insoluble substances. bigger ● It contains solid active drug particles (>10µm) suspended in a transport system. ● It has longer contact time. ● Can have precipitation so it must be shaken well. ● Include steroids like Prednisone. Emulsions are oil-water mixtures. = - Shake Suspensions . EGPC ● The two phases’ liquids are not mutually soluble. ● It contains a dispersed base, a continuous phase and a surfactant for stabilization. ● Advantages - no precipitate, enhances bioavailability and protects ingredients from oxidation. ● Most common mixtures include glycerin, polysorbate 80 and castor oil. ● Include Refresh, Endura and Restasis. OPL Ointments are semisolid and contain solid hydrocarbons (para n). ● They have extended contact time. ● Its most common bases are petrolatum and liquid lanolin. ● Clinical use includes children and ocular injuries like corneal abrasions. ● Di cult to apply and blurs vision. ● Include Erythromycin, Tobramycin and Tobradex. Gels are semisolid; they can have one phase or two phases. ● They are similar to ointments in that they both have extended contact time and blur vision. ● Include Pilocarpine, Timoptic XE, and GenTeal. Sprays are used for mydriatics or cycloplegics; especially for pediatric patients. ● Include Nature's Tears and Tears Again. Lid scrubs are made up of a cotton tip applicator and gauze used as eyelid cleansers (useful for blepharitis). Filter paper strips are commonly used to disclose corneal insults, HSV, DES or DED and even for rigid gas lens ﬁttings. ● Include sodium ﬂuorescein, lissamine green, rose bengal. ● The sterility of NaFl must be ensured due to risk of pseudomonas aeruginosa infections. Contact lenses can be used for treatment such as therapeutic and bandage CL. ● They can absorb water-soluble drugs . ● They are made of a silicone hydrogel material (high DK) with high oxygen transmission. ● Clinically used for corneal erosion, superﬁcial punctate keratitis (SPK), epithelial defects, corneal dystrophies and wound dehiscence after surgery. ● Include: Acuvue Oasys and Air Optix. Corneal shields can be made of collagen and work as a bandage on the cornea. Scleral lenses are large diameter rigid permeable gas lens used in ocular surface disease. Cotton pledges are small cotton pieces soaked in medication. ● They are placed in the conjunctival sac where they have prolonged contact time. ● Clinically used for mydriasis and synechiae. Artiﬁcial tears inserts are rods shaped pellets made up of hydroxypropyl cellulose that are placed in the inferior conjunctival sac. ● They can be made with or without preservatives. ● They release the polymer for 24 hours. ● Clinically used for DES. Solid devices are also available but are not widely used. They can include rings. ● Include Ocusert. Niosomes are bilayered vessels categorized into: ● Nanoparticles - 10µm-1mm, include polymeric colloidal particles. ● Nanosuspension - <100 nm, include submicron colloidal systems. ● Microemulsion - are thermodynamically stable and small (~100 nm). Other methods of topical administration include: ● Iontophoresis - low-density electrical current used to enhance drug transport through the epithelium. Include Eyegate II. ● Sonophoresis - ultrasound at frequencies higher than 20Khz to enhance corneal penetration. Pharmacokinetics: Metabolism and Elimination The metabolism of drugs facilitates the excretion of lipophilic drugs to terminate their action. ● If drugs are too lipophilic, they can’t be excreted and must be transformed. The liver is the major site of drug metabolism but it could occur in other places like the bile or lungs. Metabolism of drugs can be achieved by three main factors: ● First order kinetics - includes most drugs, the amount of drug metabolized is proportional to the plasma concentration (Cp) of a drug; it is constant. mucho sustrate hay por y ans Kidney-Biotransformation la enzima Liver-Metabolism , Excretion gets overwhelmed ○ ● V = Rate of drug metabolism = 𝑉𝑚𝑎𝑥 [𝐶𝑝] 𝐾𝑚 + [𝐶𝑝] Zero order kinetics - the enzyme is saturated by increased free-drug concentration and the rate of metabolism remains constant over time. ○ ● V = Rate of drug metabolism = JAconol 𝑉𝑚𝑎𝑥 [𝐶𝑝] [𝐶𝑝] Biotransformation - occurs primarily in the kidney but can also occur in the kidney, LNOLIVER lungs and bile. ○ Phase 1 reaction - includes oxidation, reduction, hydrolyzing reactions and CYP’s activities. The Cytochrome P-450 system (CYP) has 12 isoforms and are where oxidation occurs when the drugs bind, introducing oxygen. ■ Some drugs that don’t involve P-450 are: catecholamines, histamine, alcohol dehydrogenation and procainamide. ■ ○ CYP3A4 is the most common isoform of the cytochrome P-450 system. Phase 2 reaction - includes conjugation reactions and lipophilic metabolites like the glucuronic acid reaction. Most of the cytochrome isosomes have overlapping capacity: ● Enzyme induction -net increased metabolism of the drug leading to therapeutic failure. ● Enzyme inhibition - when 2 drugs compete for the active site, inhibiting the metabolism of each other. Clinical implications involving metabolism include: ● Liver dysfunction - reduces the clearance of a drug through hepatic enzymes and plasma protein binding. There is a signiﬁcant reduction in ﬁrst pass metabolism but there is increased bioavailability leading to possible overdose and toxicity. Requires dose adjustments. ● Prodrugs - inactive compounds that are activated by metabolism. Drugs are eliminated from the body either unchanged or as metabolites. Excretory organs eliminate polar compounds more e ciently. ● Kidney - eliminates 25-30% of administered drugs. ● Intestines - eliminates unabsorbed drugs and metabolites from bile. ● Breast milk - eliminates a small quantity of drugs but they can a ect the infact. ● Lungs - eliminates anesthetic gasses. Drug elimination by the kidney consists of the following steps: 1. Glomerular ﬁltration - rate and extent of plasma binding; only the unbound drug is 20 % ﬁltered. 2. Tubular secretion - active, adds drugs to the tubular ﬂuid. proximal 3. Tubular reabsorption - passive, moves weak acids and bases but depends on pH. scretion [ Distal Drugs that are modiﬁed in the liver by conjugation with bile salts are secreted into the small intestine and may be involved in the enterohepatic circulation. ● Biliary excretions and unabsorbed drugs are excreted in the feces. Drug excretion by other routes are relatively unimportant but may have forensic signiﬁcance. Some clinical considerations involved with drug elimination include; reduced renal plasma ﬂow, displacement of other drugs and decreased extraction fraction. Ophthalmic Drug Administration: Ocular Injections and Oral Medications Medication can reach ocular structures via systemic administration (oral/IV), intravitreal injection, periocular injection and topical administration. Ocular injection methods include: ● Subconjunctival - pierce Bulbar conjunctiva ● Sub-Tenon’s - goes under Tenon’s capsule ● Retrobulbar - behind the globe ● Peribulbar - around the globe Subconjunctival injections - since the outer sclera is covered by the conjunctival membrane, this technique is less invasive than others. There is better di usion to the conjunctiva, sub conjunctiva and sclera. It can administer 200-300µl of drug solution but cannot exceed 0.5mL. ● Clinically used for antibiotics in cases of corneal/intraocular infections; mainly corticosteroids and triamcinolone acetonide. Sub-Tenon’s injections - Sub-Tenon’s capsule is between the conjunctiva and episcleral plexus where there is connective tissue; however the posterior capsule degenerates with age. It has longer drug action but di cult molecular penetration and could even penetrate the globe if performed by someone not well-trained. ● Clinically used in the anterior segment for bacterial infections and iridocyclitis. ● Clinically used in the posterior segment for choroiditis, post-cataract cystoid macula edema (CME) and for ocular anesthetics. Retrobulbar injections - involve the deposition of drug solution into the retrobulbar space within the muscle cone; there is fast drug movement with high concentrations. Could cause serious complications such as retrobulbar hemes, globe puncture, retinal detachment and vitreous hemes. ● Clinically used for anesthesia, macular region and inﬂammation. Peribulbar injections - have lower risk of injury since they don’t reach the muscle cone but are less e ective for anesthesia. Can cause serious complications such as diplopia, orbital heme, artery occlusion, brainstem anesthesia and optic nerve head trauma. Intracameral injections - administers the drug directly into the anterior chamber but can only administer small quantities of drugs. Commonly used for the application of viscoelastic during cataract surgery. ● Clinically used for bacterial infections and iridocyclitis. Intravitreal injections - administers drugs to the vitreous, route direct pars plana and used for treatment of endophthalmitis and vitreoretinopathy. ● Clinically used with liquid silicone for retinal detachment, ganciclovir for cytomegalovirus retinitis, steroids (Retisert) and for wet ARMD (Macugen). Systemic Drug Administration Systemic administration involves the delivery to vascularized ocular tissues in the: ● Anterior Segment - via the conjunctiva and episcleral vessels ● Posterior Segment - via the retinal and choroidal circulation. Systemic administration eventually delivers a lower drug dose due to the multiple barriers. Oral administration - is the most commonly used method. It had several dosage forms such as tablets, capsules, liquids, suspensions, enteric coating, XR. ● Clinically used for infections/inﬂammation of the eye’s internal structures/adnexa and ocular pain but is less e ective for ocular surface diseases. ● Advantages - Cost e ective, variety of forms and reduced contamination. ● Disadvantages - patients with dysphagia, absorption by GI contents, systemic toxicity. Parenteral administration ● IV - has high serum concentration and is used for several ocular infections and endophthalmitis. Two types: ○ Continuous infusion - patient is hospitalized so there is a slow and prolonged administration. ○ Single intravenous pulse - require tourniquet of upper arm which is released after administration. ● Intramuscular - could be injected in the ventral/dorsal aspect of the gluteus muscle (contraindicated in children under 3), deltoid or quadriceps muscle. ○ Clinically used for hyperacute bacterial conjunctivitis caused by N. gonorrhea. Metabolism of Ophthalmic Drugs Compared to the liver, the metabolic capabilities of the eye are minimal but biotransformation metabolic activities have been detected in various ocular structures. Ocular tissue metabolic processes within the eye have important implications like: controlling the detoxiﬁcation of therapeutic agents, providing the potential for site-speciﬁc bio-activation of certain drugs, molecules to improve drug e cacy and minimize SE, development of prodrugs/codrugs and protecting for xenobiotics/foreign compounds. The eye is well protected against absorption of drugs and xenobiotics: ● Anterior barriers - tears, cornea and conjunctiva ● Posterior barriers - retinal vessels, RPE, Bruch’s membrane and choroid ● Additional barriers - vitreous, iris, lens, ciliary body Phase I: Metabolic activity in the eye - metabolic activities in ocular structures adjacent to regions of highest uveal blood ﬂow, cytochrome P-450 activity has been identiﬁed, cytochrome P-450-dependent metabolism of endogenous substances (arachidonic acid, prostaglandin, steroids) was found to primarily occur in the corneal epithelium. Cytochrome P-45o-dependent activities in ocular tissues are inducible by the classical P-450 inducers. ● RPE and ciliary body Phase II: Metabolic activity in the eye - several studies have shown that various tissues of the eye of conjugation activity and transport of endogenous substance by way of transferases (Phase II enzymes), the catalytic activity in the process induces the biotransformation of metabolites which are eventually removed by eye circulation. ● Iris and ciliary body -seem to have the highest glutathione-S-transferase activity. ● Cornea - exhibited highest speciﬁc activities for N-acetyl, sulfo- and UDP-glucuronosyl-transferases. ● This fact and the exposure to exogenous substrates at the eye supports the hypothesis that the eye must possess the capacity for metabolism of drugs and detoxiﬁcation biotransformation. ● The metabolic activity present in the lens is not surprising, given the limited blood supply to this tissue. Elimination In elimination studies, several drugs have been shown to clear more slowly from the eye compared to other tissues, The iris, retina, choroid, and uveal tract are the tissues that result in most drug accumulation. Slow elimination has been associated with drugs binding to melanin in the pigmented epithelium.x GCP0 FINAL EXAM REVIEW: Clinical Pharmacokinetics • Clinical Pharmacokinetics: Pharmacological effects of a drug and concentration of the drug in an accessible body compartment like blood or plasma, as these change in time. Provides: o Quantitative relationship between dose and effect o Drug concentration in body fluids and their adjustments o Therapeutic efficacy and avoidance of unwanted effects o How these doses can be modified and adjusted to provide even doses • Parameters of drug disposition o Bioavailability: fraction of drug into the systemic circulation o Volume of distribution: Measure of the drug into the available space in the body and what is found in systemic circulation. o Clearance: Measure of body efficiency to eliminate the drug of the system o Elimination: Measure of the rate of the removal of the drug from the systemic relation • Bioavailability: Indicates the fractional (F) extent to which a drug dose reaches its site of action #$% '( )*+, *-./ℎ12, 3%3$-41/ /1*/+5.$1'2 != #$% '( )*+,3 .)41213$-*-) o The uncharged drug is going to have the therapeutic action. o Area under the plasma concentration o The concentration of the drug in the plasma over time. These doses and the plasma concentration is going to be reduced over time (IDEAL) until the drug is not in the system. o Intramuscular and intravenous skip a lot of the absorption process and it is going to reach to site with more medication. o The more quantity of medication absorbed the more it must be eliminated. • • • Lymphatic elimination of drug intravenously is going to be large and is going to be excreted in comparison with a drug with less dosage. Parameters of Drug Distribution: Apparent volume of distribution: Volume into a drug distributes. Related to the quantity of drug and plasma concentration and how it is influenced in the system. The distribution of a drug is different depending on the medication, the person and even liver/kidney disease. 74'+2$ '( )*+, 12 $ℎ- 8')% (,4) 6! = ,4 ;5.34. )*+, /'2/-2$*.$1'2 ( < ) • Clearance: If bioavailability is complete, steady-state concentration of a drug will be achieved when the rate of elimination equals the rate of drug administration. o Rate of elimination to the plasma concentration >.$- '( -51412.$1'2 '( . )*+, =< = (?21$3 = 6'5 @-* +21$ $14-) ;5.34. )*+, /'2/-2$*.$1'2 o A rational regiment for a long-term drug administration. In ocular diseases we do not deal with this since topical drugs hydrolyze easily and it is going to be neutralized. On the other hand, when you prescribe oral medications, you have to consider clearance especially with long term medication. Ex: A physician may check every 6 months to see if a drug has caused toxicity. Another example can be the usage of steroids for 14 days or more. o Clearance should have a steady state concentration with a therapeutic window (therapeutic window is associated with efficacy and minimal toxicity) o Each drug is going to have a limit of concentration that will be saved for a patient. After X or Y that patient will achieve toxicity, that’s why you need to respect the therapeutic window, especially with patients with liver disease. o Clearance must remain constant in a medically stable patient. When clearance is constant the rate of drug elimination is directly proportional to the drug concentration. o Plasma clearance will vary from a thinner to an obese person. o The rate of clearance is limited, it can be influenced by a target disease that has dramatic effect in clearance. Drugs eliminated in Zero Order kinetics is not going to be constant. It is going to be constant in first order kinetics. o Total clearance Volume of biological fluid from which drugs have completely removed. =5"#"$% = =5&'($% + =5)'*$"+, + =5#")'& Most common is renal clearance. • Half-life (B.0 ): The time it takes plasma concentration to be reduced to 50%. Constant / for drugs that follow first order kinetics. 0.693 × I! $10 = = (?21$3 = $14-) 2 =< • Steady rate o The rate of elimination is balanced with the rate of administration. o Usually at 4$10 time frame 2 o Achieved by first order kinetics. • Dose regimen: Plan of administration over a period. Optimal dose for a patient to be treated in a specific period of time. You always prescribe a medication that is inside the therapeutic window. If you go over the window, you will cause toxicity. Therapeutic window: Concentration range that provides efficacy without toxicity. Important in long term therapy. You can go to the minimal effective concentration but if you go to low it will not cause any effect, so try to go to the adequate concentration because it is effective in long term therapy conditions. o The dose that increases in the body it will be eliminated in the minimum effective concentration. • Ocular Bioavailability • • • Bioavailability: Fraction of administered drug gain access to systemic circulation chemically unchanged o FDA: “Rate and extent to which the active ingredient or inactive is mostly absorbed from a drug product and becomes available at the site of action. In ocular therapy, bioavailability is used to measure the side effects and toxicities and not an indication of therapeutic efficacy. Topical ocular delivery o Low bioavailability o Less toxicity o Low local and systemic effects -Since cornea is a barrier, when the drug is absorbed in the punctum and goes to the nasolacrimal drug it is not going to be enough to create a systemic side effect o Physiological protective mechanisms from the eye o Absorption of an ophthalmic drug is going to be minimal when applied topically. It is going diluted when in contact with tear film, so the remnant in anterior segment is going to be less. • • Physiological factors affecting ocular drug bioavailability. o Pre-corneal clearance (when the drug is administered): 1st element that the drug is going to encounter including the tear film and blinking mechanism. -Poor bioavailability less 5% because of: -Tear turnover and drainage: because of the anterior segment is already occupied with tear film and the cavities of the eye can hold certain amounts of liquid. -Dilution by tear flow: -Reflex blinking: normal action of external reflex -Drug induced lacrimation: If drug do not have adequate pH or preservatives that can trigger dry eye, irritation and lacrimation by sending a message to the lacrimal gland for it to lubricate the eye more. It can be affected by an altered lipid phase and aqueous phase o Low corneal permeability: Layers of the cornea to allow the passage of medication or not. o Blood ocular barrier: Contain tight junctions that does not allow passage of medication. o Cornea as a barrier: Main barrier of the eye -Mayor route for absorption -Corneal epithelium permeability is thanks to tight intercellular junctions. -Molecules such as hydrophilic (paracellular route) and lipophilic drugs (transcellular route: across the cell) cross by simple diffusion (most common mechanism of the eye). For the drug to pass through transcellular route, the cell must have lipids in the membrane for lipophilic drug to pass. -The first barrier that drug will encounter will be the corneal epithelium, then stroma and lastly endothelium. The endothelium does not have affinity, the drug can pass easily. Physicochemical factors affecting ocular drug bioavailability. o Molecular solubility -Max amount of solute dissolved in an event solvent under standard conditions of temperature (body or room temperature to prevent burning in cornea) , pressure (ambient pressure), and pH(too acidic or too basic will burn cornea, but basic will be worse since its more soapy and will be more difficult to take out of anterior segment). -Topical ophthalmic drugs mainly absorbed by cornea, some through conjunctiva and sclera -Differential solubility dictates type of molecules -comprimer Intracellular (inside cells) Intercellular (between cells) o Molecular size and shape -Determinant in ocular permeation -Epithelium diameter (2nm): Molecules bigger than 2nm will not enter -Large molecules (Fluorescein): When epithelium tight junctions are compromised, the large molecules will enter. This is called superficial epithelium punctate. -Determinant rate of diffusion: The bigger the molecule the more difficult to enter the rate of diffusion o pH and dissociation -Aqueous solubility depends on: Solution pH, pka, pkb and tear pH (7.4). The tear pH is marinated by a bicarbonate buffer system, there will be continue regeneration of tear film. The pH should be similar as the anterior chamber. Low or high pH will cause ionization on medication preventing the therapeutic action. Remember that ionized medications cause therapeutic action. -Ophthalmic solutions: The chemical equilibrium: state in which the nonionized (more lipophilic) portion is in balance with ionized (more hydrophilic) portion. Weak acid or bases Non-ionized form -pH is indispensable for the chemical and physical stability -Buffers in formulations counteract shift in pH. Buffers maintain the pH and preservation of drugs in bottles to protect it from oxidation. -In addition, buffer systems may momentarily alter the pH of tears after instillation -Irritation: Buffers regulate irritation in the eye *Inadequate storage of drugs can also cause irritation in the eye* o Formulation factors Instilled volume 1 drop=30microliters Tear volume=11microliters -Types of instillations: Bottle tip or dropper design (to achieve the 30 microliters), Dispensing rate(slow enough for patient to have adequate flow in the eye), Angle of the bottle(45 degrees angle smaller than vertical position so you can have a smaller quantity of drug to have the minimal effective concentration) Nasolacrimal Drainage Area : 80% of drug is released by blinking 1. Anterior segment 2. Conjunctiva 3. Punctum: Inferior absorbs mostly 4. Canaliculi: Minimum amount of remnant 5. Lacrimal sac 6. Nasolacrimal duct and then bloodstream Viscosity: Crucial to increase retention in anterior segment (emulsions, gels) -Drug retention cul de sac -Increase contact time -Cohesiveness with the ocular surface tends to increase trans corneal penetration 15 to 30 cps optimal viscosity (centistokes) (greater viscosity slower velocity of flow displacement) Too viscous will not allow penetration in cornea Osmolarity: Measure of solute concentration. Medication need to mimic the isotonic formulation to not alter the osmolarity in the eye and tear film -Hypertonic solutions with a tonicity greater than the equivalent to 5% saline solution concentration: usually cause decrease drug concentration at the corneal surface -Hypotonic formulations with a tonicity under the equivalent 5% solution undergo rapid dissolution upon instillation, thus offsetting adverse symptoms *Isotonic formulation less irritating to eyes do not alter osmolarity, 290 osmol (0.9% saline sol, because this is the normal osmolarity in our bodies) * A Systemic Pharmacodynamics • • • Studies drugs biochemical, cellular, and physiological effects and their mechanisms of action. Interactions with macromolecules (receptors or drug targets) All drugs have specific mechanism of action. Nature of drugs o Inorganic ions o Nonpeptide organic molecules o Small peptides and protein o Nucleic acids o Lipids and carbohydrates Some of these drugs are found in plants, animals but most of them are synthetic Most endogenous and exogenous drugs are optical active and may contain one or two asymmetric centers known as enantiomers (same molecule but different shape). Size and molecular weight of drugs o From 7 to 50,000 (MW) o Most common between 100 and 1,000 • • If molecule is too small, they are going to selective in their action. Ex: hematologic drugs Receptors and their sites o Specialized cell surface molecule targeted by a drug that mediates its pharmacologic actions. o Large molecules of biochemical processes Types: -Ligand-gated ion -G proteins: Cholinergic drugs, dilated fundus examination, meds for glaucoma -Enzyme linked -Intracellular: For steroids and to reduce inflammation Physiological Receptors o Agonist: Mimic regulatory effect of endogenous signaling. Dilators have adrenergic(sympathetic) system, when you stimulate this system, you are going to have vasoconstriction, pupil dilation, flushing. In agonist receptors, they mimic the organism’s system. Ex: If you apply a adrenergic agonist drug, you are going to add more receptors that are going to increase the blood pressure -Primary Agonist: Going to attach to the receptors of cell -Allosteric Agonist: Increase the endogenous signaling but is going to be attached in other areas of the cell. o Partial Agonist: Lower response than a full agonist, is going to mimic signaling but in a lower extent. o Antagonist: Block or reduce the action of the agonist (block up that receptor) o Competitive antagonist: Competes with agonists for the receptor site and the response is going to be lower than a full antagonist. o Noncompetitive antagonists: Prevents response of an agonist without competing with the agonist. It goes directly to the specific receptor. *Depending of the receptor it will be the response of the drug.* • • Potency o An expression of the activity of a drug in terms of the concentration or amount needed to produce a defined effect. o Maximum effect of concentration: JK34 o Same drug can have the same effect in different potency o Medication does not compete with receptor Efficacy o Maximal response produced by a drug.

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