Pharmacology Review - Exam 2 PDF

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 m...

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 ③ ① G maximized absorption, simple installation, reduced frequency of administration, compliance, ⑳ 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