Miderterm #3 Flashcards

Question

Physical Degradation

Answer 1

* Polymorphic Reversion (change in crystal structure) * Tablet becomes friable or discolored; hardening of capsule * Precipitation from solutions * Suspension instabilities * particle growth (dissolution and recrystalize) * deflocculation (caking) * separation of emulsions (creaming, sedimentation, cracking, inversion)

Answer 2

* **degradation of a drug is constant with respect to time** * Rate of degradation is **independent of drug concentration**

Answer 3

* C=C₀-k_ot * k₀=(C₁-C₂)/(t₂-t₁)

Answer 4

* t_90%=(1/10)(C₀/k₀) * **predicted shelf life depends on amount of drug concentration in the formulation **

Answer 5

* degradation of a drug is directly proportional to the concentration of drug remaining

Answer 6

* time required for the concentration to decrease by 50% * t_0.5=(ln2)/k * t_0.5=0.693/k

Answer 7

* t_90%=ln(100/90)/k

Answer 8

* relates temperature and reaction rates

Answer 9

* Step 1: Perform several short-term (brief) accelerated stability studies at different temperature * Estimate a rate constant k for each stability study * **degradation rate increases as temperature increases** * Step 2: Plot the ln or log of the degradation rate constant k as a function of 1/T * Step 3: Use the graph to estimate the rate constant for degradation at lower temperatures by extrapolation * Then calculate t_0.5 and t_90% for room temperature storage from the extrapolated rate constant * Summary: In a few days, have calculated degradation rate constant * can estimate shelf life at room temp. * can estimate rate constant for storage in fridge

Answer 10

* ratio of degradation rate constant for a 10°C elevation above room temperature (25°C) * (fold increase in k for a 10 degree C raise) * Relative change in rate constant stays about the same as you increase the temperature * Most degradation reaction increase by ~3 fold every 10 degrees * For a 20 degree raise: 3^2=9 fold * Q₁₀^t/10

Answer 11

* **Only dissolved drug can effectively penetrate the GI mucosa ** * Mostly by passive diffusion *

Answer 12

* Sufficient water solubility for drug to dissolve readily within fluids of the GI tract (required for all absorptive mechanisms) * Good drug stability in the fluids of the GI tract * Sufficient lipid solubility for drug to partition from solution in the GI fluids (aqueous) into the GI mucosa (lipoidal) * ionization of weakly acidic and basic drugs (as determined by pKa and pH at locations along the GI tract) also play a role * Optimum LogP in range of 1 to 3 * Smaller molecular size * more readily diffuse through the GI mucosa

Answer 13

* disintegration --\>dissolution--\>permeation, one of these processes could become rate-limiting * disintegration rarely rate-limiting * Case A: low lipid solubility (low logP) * dissolution\>\>\>permeation * permeation limits drug absorption rate * **permeation rate limited** * Case B: high lipid solubility (high logP) * dissolution\<\<\<\< li=""\> \<\> * dissolution into fluids limits drug absorption rate * absorbtion highly dependent on formulation * **dissolution rate limited**

Answer 14

Dissolved drug molecules diffuse from the _saturated film_ adjacent to the solid particle surface into the _bulk solution_ (i.e., across the stagnant diffusion layer), thereby establishing a concentration gradient between C_s at the saturating film and C_t in the bulk (well-mixed) medium at time t.

Answer 15

* aqueous solubility (Cs); what affects Cs? * pH * salt form of the drug * buffering agent (maintains favorable pH in diffusion layer) * polymorphic or pseudo-polymorphic form *

Answer 16

* Stomach pH of 1-3, Small intestine pH of 5-7, Large intestine pH of 7-8 * significant ionization may or may not occur, depending upon where the drug is located in the GI tract

Answer 17

* **Ionization of drug increases its solubility in water remarkably ** * **weakly acidic drug**: solubility greater at higher pH * total solubility (C_s) for a weak acid equals the intrinsic solubility of the non-ionized acid HA (C₀) plus the equilibrium concentration of the anion [A

Answer 18

* nonionized into GI mucosa easier * pH effects on dissolution rate is opposite to their effects on permeation rate

Answer 19

* **weakly basic drugs** dissolve readily in the low pH of the stomach, but absorption is more optimal in the small intestine because of improved permeability at higher pH * even though low pH in the stomach affords good permeability of **weakly acidic drugs**, it is poor condition for dissolution. Once the formulation reaches the small intestine, dissolution can proceed more efficiently; however, permeability is less optimal.

Answer 20

* small intestine is the major site of absorption (permeation) for most weakly acidic drugs * Small intestine has a much greater absorptive surface area * ionization doesn't completely restrict absorption; ionic equilibrium is reversible * Non-ionized drug is absorbed, ionized drug reacossiate with H+ to form non-ionized drug * ionization affects dissolution more than permeability

Answer 21

* GI motility can affect both the rate and extent of oral drug absorption * Gastric emptying rate: important for how quickly drug to small intestine * Food slows gastric emptying and in turn slows the onset and rate of drug absorption. * slowed by drugs with anticholinergic effect and accelerated by prokinetic agents * Anticholinergic also slows intestinal motility, allows more complete dissolution (opposite for prokinetic agents) * GI content can affect dissolution and gastric emptying rate

Answer 22

* generally, greater solubility of the salt form * drug is initially presented entirely in ionized form into the saturating film, thereby ‘buffering’ the film pH. * sodium or potassium salts of weak acids dissolve much more rapidly than free acids * examples of organic salts that have a lower aqueous solubility than the free acid or base

Answer 23

Salt is more water soluable and less affected by pH As pH incrase, solubilty of weak acid increases, increases in dissolution rate.

Answer 24

* generic hypoglycemic drug used in the treatment of Type II diabetes * Different salt forms of tolbutamide have different solubility and accordingly different dissolution rate. Therefore, their absorption rates will differ leading to significantly different glucose-lowering effects.

Answer 25

* Some salts are deliquescent and would pose a storage problem. * Deliquesce: to dissolve and become liquid by absorbing moisture from the air. * Fix by forming the salt in situ by co-administering a mixture of buffering agent and drug. * increasea solubility (Cs) of drug in the dissolution layer, thereby increasing drug dissolution rate.

Answer 26

* More than one crystal form * same chemical structure, but show different physical properties * **Metastable** polymorphs may have higher aqueous solubility than the stable form * **Metastable polymorphs are useful if they have sufficient stability (conversion to stable polymorph over many months) ** * Polymorphic forms may arise during pharmaceutical manufacturing through: * recrystallization during synthesis of the drug substance * milling and compression

Answer 27

* less soluble palmitate ester of chlorampenicol used because less bitter tasting * hydrolyzed in GI tract and absorbed * absorption rate-limited by dissolution of the palmitate ester * can depend on the chloramphenicol palmitate polymorph selected * **Chloramphenicol palmitate polymorph B is metastable **

Answer 28

* solvent molecules incorporated in the crystal lattice * **pseudo-polymorphism** * Hydrates * Organic solvates: improve dissolution rates, tend to be unstable

Answer 29

* adducted with water * ampicillin, caffeine, theophylline * less water soluble and, therefore, have slower dissolution rates * other sources state that no general rule can be made about comparing the dissolution of solvates vs. non-solvated forms of a drug substance;

Answer 30

* Dry crystals in 65 degree air * tihydrate that is slightly soluable (1/5 solubility) * Dry crystals in vacuum * monohydrate that is sparingly soluable (half the solubility)

Answer 31

* soluble and moderately soluble drugs: 10 to \>100 μm. * Microionization to 5-10 μm or less can improve solubility of drug * timely and expensive, try and avoid *

Answer 32

* powdered form of some **hydrophobic** drugs tends to agglomerate * float on surface * **wetting problem** * reduce contact surface area between particles and dissolution medium * fix by adding surfactant or wetting agent * lowers interfacial tension

Answer 33

* drug powder is mixed with usually **hydrophilic diluents and granulating agents (starches and gelatin)**, which render the surface of hydrophobic drug particles more hydrophilic * gastric fluids have relatively low surface tension due to the presence of conjugated bile acids and lysolecithin

Answer 34

* particle size of an active drug is optimized *

Answer 35

* applicable for drugs whose GI absorption is rate- limited by dissolution * Uses: * rapid in vitro screening procedure during the **development of suspension or solid dosage forms ** * quality control * assure bioequivalency between commercial products of a drug (prove consistency)

Answer 36

* **Injection**: Liquid preparation that is a solution of a drug in a liquid vehicle * **For injection**: Dry solids that upon addition of a vehicle become an injection solution * **Injectable emulsion**: Liquid preparation of a drug dissolved or dispersed in an emulsion medium (e.g., propofol iv) * **Injectable suspension**: Liquid preparation of a solid drug suspended in a liquid vehicle (betamethasone sodium phosphate and betamethasone acetate, Celestone Solupan im) * **For injectable suspension:** Dry solid that upon addition of vehicle yields a an injectable suspension (e.g., octreotide acetate, Sandostatin LAR Depot)

Answer 37

* injection rate/volume: * **bolus** in less than a minute or two; small injection volume (1 to 10 mL) * **short-term infusion** from minutes to few hours; decrease peakconcentration; larger injection volume, up to several hundred mL * **long-term infusion** to achieve steady-state plasma drug levels; may need IV bolus loading dose to achieve therapeutic levels sooner * achieve rapid action and allow control of duration * 100% systemic availability of the dose * invasive (risk of infection) * potential for adverse effects; cardiac arrhythmia with rapid injection (e.g., phenytoin) * drugs that are caustic or prone to cause phlebitis require central venous access (internal jugular, subclavian or femoral) via catheter * not suitable for insoluble materials, unless drug particle size is sufficiently small to avoid formation of emboli (e.g., Abraxane ─ nanoparticles of albumin-bound paclitaxel in a injectable suspension) * poorly water soluble drugs may precipitate if injected too rapidly or into a vein with low blood flow; classic examples: diazepam, phenytoin * it can be slowly administered by using short-term infusions of the drug dissolved in a sufficient volume of vehicle and administered immediately to avoid precipitation issue * microemulsions of fat-like or fat-soluble materials (e.g., propofol)

Answer 38

into the bone marrow (as an alternative to intravenous access)

Answer 39

within the cavity of a joint

Answer 40

* Note: all parenteral routes are vulnerable to risk of infection * Any of the above may contain buffers, preservatives, and other excipients.

Answer 41

* primarily used to administer analgesics and anesthetics for regional effects * morphine (or other opioids) by this route * intraoperative or postoperative use * also for the control of chronic pain * activity is through spinal opioid receptors * increased duration of effect, and a lower incidence of respiratory depression and other CNS effects * if respiratory depression is observed by this route, it often is observed hours after the administration of the drug as it spreads rostrally via the CSF or via systemic redistribution to supra- spinal sites

Answer 42

* needle penetrates the epidermal and dermal layer to deposit drug into the loose subcutaneous fatty tissue * usual injection volume of about 0.5 mL; range 0.5 to 1.5 mL, 2 mL injections may cause a feeling of painful pressure * injected formulation volume produces the “drug delivery site” within the interstitial fluid * larger volumes may be administered (over longer time) by SC infusion * large number of potential injection areas on the body to choose from (see accompanying figure) * readily self-administered by patient (and patient acceptance may be increased with prefilled syringe) * good route for multiple dosing or continuous infusion * muscle mass is not an issue in cachectic or elderly patients * risk of infection is present because the needle breaks the protective barrier of the skin * systemic bioavailability for a given drug may be 100% or \< 100%, mainly related to formulation factors and drug stability at the SC injection site * bioavailability information is difficult to find for the SC route

Answer 43

* small molecule drugs are generally rapidly absorbed following SC injection; rate of absorption depends on * drug dissolution if formulation is a suspension or if drug precipitates out of solution at the injection site * absorption involves diffusion through interstitial fluid and tissues, and passage across vascular membranes into surrounding blood capillaries * absorption rate may be influenced by massage, exercise (such as running) and heat (as in a sauna or hot tub), because of the increase in blood flow * vasoconstrictors are used to slow dissipation of local anesthetics; e.g., lidocaine hydrochloride and epinephrine injection for infiltration and nerve block

Answer 44

* protein drugs have the following issues * instability at the sc site; proteolysis * slow absorption depending on size: * small proteins (insulin ~6 kd) are taken up into the interstitial capillaries * larger protein \>16 kd (Mabs ~150 kd) are absorbed indirectly via the lymphatic system (see accompanying figure), which is a slow process occurring over some hours (tmax \>24 hours)

Answer 45

* range of injection volumes: * 0.5 to 2.0 mL for deltoid * 1 to 5 mL for gluteus maximus * 1 to 5 mL for vastus lateralis * as with SC injection, formulation volume that is injected IM produces the “drug delivery site” within the interstitial fluid * drugs irritating to SC tissue may be given IM * risk of infection is present as the protective barrier of the skin is broken * considerations of rate and extent of absorption are generally the same as for SC administration * absorption rate for lipophilic small drug molecules is generally in the order of deltoid \> vastus lateralis \>\> gluteus maximus, because of blood perfusion and amount of fatty tissue at the injection site * poorly soluble small molecule drugs can precipitate on administration and actually form crystals at the site of injection * can cause of pain at the injection site and at times muscle injury * crystals may dissolve very slowly and apparently incompletely, possibly resulting in less than 100% bioavailability; e.g., phenytoin and diazepam * absorption rate for small drug molecules can be decreased or at least compromised when the injection does not actually reach the muscle, but is instead deposited in the subcutaneous fat * lower blood flow in fat * more sequestration and slower release of lipid soluble drug from fat * muscle site, length of needle and angle of injection are important determinants of the likelihood of deposition in fat * deltoid and thigh are less likely to result in this problem, more likely with injection into the buttocks * absorption in infants and young children may be unpredictable due in part to insufficient muscle tone and vascularity of muscle tissue * decreased muscle mass of many older adults may result in faster small drug molecule absorption; approximate 25% decline in muscle strength occurs between the ages of 20 and 60 years, and a decline in muscle strength corresponds with a decrease in muscle mass * protein drugs are usually slowly absorbed (depending on size), again as with SC absorption, because of lymphatic involvement

Answer 46

* process by which drug passes into and/or through the skin after application to the surface of the skin * Other terms * topical drug administration * dermal drug administration * transdermal drug administration

Answer 47

* local effect "dermal drug delivery" * unintentional systemic drug exposure may occur, depending on physicochemical drug properties, dosage formulation design, concentration of drug in formulation, and frequency of application * systemic effect "transdermal drug delivery"

Answer 48

all skin tissues between the surface and the capillaries in the dermis.

Answer 49

* likely both routes are involved * transappendageal route difficult to study and thought to be minor * corticosteroids cross the stratum corneum relatively slowly (polar) so the thought is that the rapid clinical response is due to their passage by diffusion through the pores * evidence of transappendageal route

Answer 50

* Fick's first law of diffusion * assuming sink conditions

Answer 51

* As K_SC increases, P_SC of the drug** increases** * P_SC will be **inversely **related to the molecular weight * P_SCwill vary depending on** ß**, which describes skin variations and temperatures

Answer 52

* Sytemic exposure of drug will depend upons * drug concentration * formulation design (influence of the formulation vehicle and the excipients on the partitioning of drug from formulation into the skin) * change feel and look of skin * area of skin covered * length of exposure * physiochemical properties * skin integrity and hydration * variation in skin permeability * patient's age * site of application * skin temperature * Solvent effects

Answer 53

* molecular size * logP * pKa * peak absorption positvely correlated with logP * more lipid soluable, more systemically absorbed * Protracted absorbtion of estradiol (highest logP) because of aqueous insolubility, slow dissolution

Answer 54

* Higher LogP not necessarily the best * Trend goes backwards at too high of LogP because gets trapped in the SC * Sequestration of the lipophilic fentanil opioids in the epidermis explains the reversal in relationship between flux rate and K_o/w

Answer 55

* drug permeability is high in broken skin, and **polar solutes** are several log orders more permeable when administered over abrasions and cuts * permeability to drugs increases after serious thermal burns and is again altered with debridement/healing

Answer 56

Due to **age** and **site** of application/thickness and **skin temperature**

Answer 57

* premature neonates have inordinately permeables kins *

Answer 58

* varying degrees of drug absorption, which may not be accounted simply by the thickness of stratum corneum * Example: hydrocortisone absorption may vary as much as 42-fold between forearm and scrotum; up to 6-fold higher at forehead than forearm * differences are likely due to a combination of **skin thickness,** **hair follicles**, **density of capillaries** in the skin, **lipid content**, degree of **skin hydration **

Answer 59

* increased temp can increase rate of diffusion through stratum corneum * physiologically by affecting **blood capillary flow**;

Answer 60

* some chemicals (skin penetration enhancers or absorption promoters) are deliberately added to dermal formulations or transdermal devices to **increase the permeability** of skin and improve drug delivery * unfortunately, many skin penetration enhancer are **irritants or toxic** to the skin and have objectionable odor * Absorption promoters are found in **veterinary pharmaceuticals **

Answer 61

* transdermal “patch” is an alternate strategy to controlled or extended release dosage form * Advantages: * bypassing gastrointestinal incompatibility * bypassing hepatic ‘first pass’ effect * minimization of some inter- and intra-patient variability in gastrointestinal absorption * predictable and extended duration (over days) of activity * reduction of side effects due to a less fluctuating blood drug concentration-time profile * reversibility of drug delivery upon removal of drug source, although absorption does not always cease immediately * enhancing patient compliance * eliminate frequent or daily dosing schedules * better accepted by patients having difficulty swallowing tablets and capsules * avoid irritation of the gastrointestinal mucosa by orally administered drugs

Answer 62

* Limited dose loading per patch (μg to 10-30 mg) * Need drugs that are potent * Drug must have adequate skin permeability and reasonable solubility * recalls because of recrystalization * Manufacturing difficulties (fentanyl patch recall due to membrane breach) * Skin irritation

Answer 63

* drug-in-adhesive * reservoir system * matrix system

Answer 64

* single of multi-layer * multi- layer system: the layer closer to the skin is for immediate release and the outer layer is for controlled release of the drug * Disadvantage: little control over release rate; limited amount of drug can be loaded into the adhesive.

Answer 65

* holds a solution or suspension of the drug in a liquid or gel behind a rate-controlling membrane * release kinetics is usually zero-order * contact adhesive may contain drug for immediate release.

Answer 66

* Newer * semi-solid matrix containing dispersed drug or suspended drug particles * Release rate is governed either by diffusion through the matrix or a rate-controlling membrane separates the matrix from the contact adhesive * contact adhesive may contain drug for immediate release.

Answer 67

* Release of drug from the transdermal system is preferably the rate-limiting step, which minimizes intersubject variations in skin permeability. * Skin enhancer is at times incorporated into the system and delivered along side with the drug to improve skin permeability. * For very lipophilic drugs (e.g., fentanyl), following the initial application of a transdermal patch, the skin underneath the patch absorbs and concentrates the drug to form a depot. The drug then becomes available to the systemic circulation. Hence, blood concentration of the drug continues to rise over the first few applications until a steady-state is reached. * After removal of the patch, continued absorption of the drug from the depot means that it may take some time to clear the drug from the body system.

Answer 68

* Pupil dilation (tropicamide, phenylephrine) * Anesthesia (proparacaine; tetracaine) * Treatment of: * bacterial conjunctivitis (antibiotics) * allergic conjunctivitis (ketorolac, prednisolone) * glaucoma (prostaglandins, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, miotics or cholinergics) * eye inflammation and pain (scopolamine

Answer 69

* intravitreal injection of ranibizumab (Lucentis®) has become common for the treatment of “wet” type age-related macular degeneration.

Answer 70

* Only about 3% (range 1 to 5%) of the drug dose applied topically to the eye by conventional topical dosage forms is taken into the anterior part of the eye * Sterile aqueous solution, aqueous suspension, ointment, or conjunctival inserts are used * Challenging barriers exist for delivery of drugs to the posterior segments of the eye

Answer 71

* **Spillage** during instillation, lacrimal drainage, and tear dilution * **Systemic (non-productive) absorption through the conjunctiva** (leaky, large * area, highly vascularized) * **Corneal barriers** to drug diffusion (corneal epithelium), especially for protein drugs * **Enzymatic breakdown** of drugs (pilocarpine, levobunolol, epinephrine, peptides) * **Binding** of drug by uveal pigment (timolol)

Answer 72

* Typical drop is **20 to 50 μ**L (average about 25-30 μL) in volume * Compared to **precorneal fluid space of only ~7 to 10 μL** * excess tear and eye drop volume rolls down the cheek * or exits through the nasolacrimal duct to the nasopharynx, allowing for systemic drug absorption * Turnover of tears (precorneal) and aqueous humor (anterior chamber); the ocular residence time for topically applied ophthalmic drugs is relatively short * Surface area of the cornea (main portal to aqueous humor) is limited * Therefore, adequate therapy with eye drops usually requires either: * **being able achieve a high initial effect** (i.e., maximize drug dose) to extend drug effect for a sufficient period of time * or, more **frequent applications of a lower dose** ─ compliance issue!

Answer 73

* adequate ocular bioavailability * comfort and safety

Answer 74

* adequate drug **solubility** (required dose in small drop volume) * optimization of **pH** (avoid lacrimation response, optimize absorption) * **osmolarity** (minimize irritation) * **preservative** effectiveness (multidose formulations) * drug **stability** in solution

Answer 75

* The usual physicochemical considerations apply to ocular drug absorption: corneal permeability is related to drug lipophilicity and ionization * Eye inflammation could alter corneal permeability depending on the drug molecule * pH probably governs the diffusion of weak acids and bases across the cornea into aqueous humor. Studies in the rabbit eye showed * absorption of pilocarpine into aqueous humor increased (\>2-fold) as **pH is raised from pH 5 to pH 8** * pilocarpine is a cholinergic agonist used to control intraocular pressure in glaucoma; a weak base with **pKa = 6.78** (some sources pKa = 7.1), log P = 0.12, water solubility 31.2 mg/mL; **higher nonionized fraction is achieved as pH rise above pKa** * **parallel increase in absorption of a nonionized marker, glycerin** * later study showed that **lacrimation response decreases over this pH range**, which may have resulted in a slower turnover of precorneal fluid volume and contribute to the pH effect

Answer 76

* Animal studies have suggested that instillation of **smaller eye drop volumes** of somewhat **higher drug concentration** might be more effective (leading to more drug absorption) * Instillation of **10 μL** of a 2% epinephrine solution (20 mg/mL x 0.01 mL = 0.2 mg) to rabbits gave the same pupillary response as did **50 μL** of a 1% solution (10 mg/mL x 0.05 mL = 0.5 mg), and 10 μL produced less pain and lacrimation * Unfortunately, **conventional eye drop bottles cannot dispense volumes \<20 μL accurately**; **also patients cannot feel the tiny drop!** * In addition, drug absorption is altered by adding a saline drop either 30 seconds later or 2 minutes later * An **interval of at least 2 to 5 min between ophthalmic dosing** appears to be required for effective absorption due to volume effects * This argues for a combination ophthalmic product, where possible, rather than separate solutions

Answer 77

* NLO can be achieved by pressing a fingertip on the inside corner of the eye (**punctual occlusion**) after application of the drop; simple **eyelid closure achieves the same effect** • NLO decreases lacrimal drainage and increases drug residence time in the precorneal fluid, thereby increasing drug absorption into anterior chamber

Answer 78

* Therefore, **unintended** and “unwanted” **systemic absorption of ophthalmic non-selective beta-blockers** could affect pulmonary or cardiac function. FDA has required timolol ophthalmic products to carry warning of the potential of aggravating broncospasm in asthmatic patients or provoking cardiac failure in patients with preexisting cardiac dysfunction.

Answer 79

* Comparison of solution and suspension formulation of flurometholone, an ophthalmic anti-inflammatory agent * Concentrated solution has a longer effect

Answer 80

* Drugs are administered intra-nasally for the alleviation of local symptoms as well as for systemic effects; examples for * local delivery includes decongestants, antihistamines, and corticosteroids * systemic delivery includes nicotine, desmopressin, oxytocin, salmon calcitonin, LHRH agonists (buserelin, nafarelin)

Answer 81

* Human nasal cavity has a **5-10 mL total volume** and a total surface area of 150 cm²; however, the effective delivery volume for conventional nasal spray is **limited to 100-150 μL because of the labyrinth** of the nasal passage * Drug **absorption** occurs mainly **across the mucosa in the respiratory region**, which is constituted by the epithelium, basement membrane, and lamina propia (vascularized by fenestrated capillaries, lymphatic drainage) * Drug diffusion barrier includes the respiratory nasal epithelium and its 5- μm thick mucus covering * Nasally absorbed small molecule drug **directly enters the systemic circulation, thereby avoiding hepatic first-pass metabolism**

Answer 82

* Propranolol is a high hepatic clearance drug **subject to significant first-pass hepatic metabolism.** Comparison of plasma propanolol AUC after PO, IV and intranasal routes of administration; n = 6 male subjects * Nasal about as good as IV * Examples of other high first-pass drugs delivered by nasal spray: butorphanol (Stadol NS), fentanyl (Lazanda)

Answer 83

These data explain the relative lack of success of nicotine gum for smoking cessation

Answer 84

* The usual physicochemical variables, i.e., molecular size, lipid solubility, and ionization of weak acids and weak bases, apply to nasal absorption * Drugs with MW larger than **1000**, e.g., polypeptides, **exhibit poor nasal bioavailability**, a MW threshold higher than that of GI mucosa (~500) * However, the relationship of MW or molecular size and nasal bioavailability is curvilinear and varies across species

Answer 85

* Drugs with poor nasal bioavailability could be formulated with permeation enhancers (absorption promoters) to improve absorption * Surface active agents (bile acids) are effective enhancers; however, there is concern of tolerability and safety over their long-term application to the nasal mucosa * Nasal cilia functions to propel overlying mucus containing trapped dust, allergens and bacteria to the back of the throat; some drugs and enhancers are known to suppress nasal cilia movement

Answer 86

* The **alveolar epithelium** allows remarkably efficient exchange of gases and volatile compounds, as well as absorption of drugs due to its * high permeability * rich vascular supply * large absorptive surface * (~75 to 100 m2, compared to ~200 m2 for small intestine) * However, **delivery of aerosolized drug to the distal portion of the bronchial structure poses a challenge.** Drug deposition along the pulmonary tract is governed by: * **physical properties** of the droplets (liquid) and/or particles (solid) being delivered * mechanical aspects of aerosol dispersion from the delivery device aerosol = a gaseous dispersion of fine solid or liquid particles * individual’s **respiratory function **

Answer 87

* delivers high drug concentrations directly to the disease site * minimizes risk of systemic side-effects * produces rapid clinical response * bypasses the barriers to oral delivery, such as poor gastrointestinal absorption and first-pass metabolism in the liver * achieves a similar or superior therapeutic effect at a fraction of the oral dose * for example, oral salbutamol 2 to 4 mg is therapeutically equivalent to 100 to 200 μg by MDI for treatment of asthma and COPD

Answer 88

* a noninvasive ‘needle-free’ delivery system * no gut and hepatic first-pass metabolism that occurs with oral administration * suitable for a wide range of substances from small molecules to very large proteins * There are few examples of drugs delivered by inhalation for systemic use (withdrawal of Exubera – inhaled insulin). Reasons being: * use of inhalation device is a challenge for a significant segment of patients * many protein pharmaceuticals are difficult to deliver in inhaled form * lung toxicity from long-term, high drug exposure is a concern (lung cancer with Exubera)

Answer 89

* Physical properties of delivered aerosol droplets and particles influence their fate during transit through (into or out of) the airways of the lungs * Aerosol droplet or particle “diameter” is important in determining their deposition site * Density and shape may also be important (most pharmaceutical aerosol particles are symmetrical and behave as if they are spheres)

Answer 90

* thought to be ~1 to 5 μm, depending on particle shape and delivery mechanism * **Large particles** (\>5 μm) are quickly cleared by **impaction** in the mouth, throat, and upper airway * Some **intermediate** size particles (3-5 μm) are filtered out by **gravitational sedimentation** in the upper and mid portions of the bronchial tree, where absorption is minimal because of limited epithelial surface area * Most **small particles (\<3 μm) reaches the alveoli**. However, retention is limited to particles \>1 μm; **particles \<1 μm are exhaled**. * Delivering the appropriate aerosol droplet or particle size is challenging, but it is critical in determining the efficacy of the inhaled drug

Answer 91

* **Nebulizer** which uses compressed air or ultrasonication to create aerosol droplets from a drug solution or suspension, administered through a mouth piece; unsuitable for widespread use in ambulatory setting, hard to carry around * Propellant-driven or pressurized aerosol inhaler (**metered dose inhaler**); aerosol solutions and powders * **Dry powder inhalers** (e.g., Diskus

Answer 92

* Advantages: * delivers large doses * suitable for infants/sick people physically unable to use other devices * Disadvantages: * Bulky * Nonportable * Contents easily contaminated

Answer 93

* Advantages: * Compact * Portable * Multidose * sealed environment (no drug degradation) * Disadvantages: * inhalation technique and coordination required * High oral deposition

Answer 94

* Advantages: * Breath actuated * No hand-mouth coordination required * Disadvantages * Respirable dose dependent on inspiratory flow rate * Humidity may cause drug aggregation

Answer 95

* Canister * Actuator (mouth piece) * metered valve * surfactants to stop clumping * lubricants to get drug through valves * shake well to mix ingredients * shearing forces break droplets into aresol * Formulation for a propellant-driven MDI consists of propellant(s), drug in cosolvents, and surfactants. Used to be CFC, had to change to HFA. Costly change. * accurate metering of small doses of drug is achieved by a small but complex metering valve (dependable and reproducible)

Answer 96

* Drug particles deposited on the surface of the trachea and bronchi and left unabsorbed are **swept retrograde by ciliary movements into the oropharynx and swallowed**

Answer 97

* Synchronization of the release of metered dose (actuation) with the beginning of a deep inspiration (**hand-lung coordination**) is needed * 1/2 to 2/3 of patients use improper techniques of inhalation * **~15% or more of patients unable to coordinate even after instruction **

Answer 98

* designed to help individuals with coordination problems for MDI * slow the aerosol jet stream and thereby **reduce impact in the oropharynx** * introduce a time delay between actuation and inspiration (**improve hand-lung coordination)** * studies have shown that spacers are best indicated for patients with coordination problems (e.g., children) or who develop oral candidiasis (thrush fungus) with inhaled corticosteroids and topical side effects

Answer 99

circumventing hand-lung coordination challenge (3M Autohaler

Answer 100

* All are **breath-actuated**; circumvents the hand-lung coordination problem * Some patients find that the fine powder **irritates their upper airway** * Patients suffering from a **severe asthmatic attack** or patients with s**evere chronic obstructive pulmonary diseases** might have **trouble taking a deep enough inspiration to deliver the dose fully **

Answer 101

* recommended following each use of inhaled corticosteroids delivered either by MDIs or dry powder inhalers to avoid oral oral candidiasis from local immunosuppression.

Answer 102

* Oral drug dosing is not feasible (e.g., patient nauseous or vomiting) and/or for local effect * Suppositories are used more frequently in children than in adults * Rectal route is far more popular outside of the United States

Answer 103

* Antipyretics and analgesics ─ aspirin, acetaminophen * Anticonvulsants ─ **diazepam**, paraldehyde * diazepam can be a prefilled rectal syringe that needs to be set by the pharmacist * Antiemetics ─ prochlorperazine, cyclizine * Antipsychotics ─ chlorpromazine * Corticosteroids ─ hydrocortisone

Answer 104

* Retention enema (solution) * Suppositories * oleaginous base (theobroma oil or cocoa butter) * water soluble polymer base (mixed polyethylene glycols)

Answer 105

* Length of human rectum 10 to 15 cm; circumference 15 to 35 cm (distended); diameter 2.5 to 5 cm; total surface area of **200 to 400 cm²** * Mucosa is **devoid of villi**; therefore limited absorbing surface area, compared to small intestine * Richly vascularized ─ lower, middle, and upper hemorrhoidal veins; **only the upper vein drains into portal blood supply **

Answer 106

* Rectal drug absorption is **more variable than oral drug absorption** * Volume of fluid in the rectum is about 1-3 ml and fluid is rather viscous, so drug dissolution is a problem * Presence of fecal matter can further decrease drug dissolution rate, or retard diffusion to the absorbing surface; predose cleansing enema can improve drug absorption * **Retention of drug suppository in rectum** is a critical factor for drug bioavailability, therefore evacuation or urge to evacuate bowel is a problem * High MW PEG is irritating and can cause evacuation * Vehicles or formulation components that are irritating to the rectum are generally avoided * There are notorious examples of poor absorption from badly formulated rectal suppositories (_especially extemporaneous preparations_)

Answer 107

* _middle and inferior rectal veins_ drain the lower part of the rectum and enter into the inferior vena cava; hence, by-passing the liver, avoid first-pass metabolism, and increased systemic availability * blood from the _superior rectal vein_ flows through the _portal circulation_ into the liver, and some hepatic first pass drug metabolism can occur * Plasma concentrations of lidocaine following 200 mg IV infusion, 300 mg rectal and 300 mg oral administration. * Lidocaine subjected to extensive first-pass in the liver, such that its oral bioavailability = 35%. In comparison, rectal bioavailability ~100%!

Miderterm #3 Flashcards

(140 cards)