MD Flashcards

Question

Rate Equation - Summary L2, pg 15

Answer 1

- "order" - here: "apparent order" - Roughly, the ORDER of a reaction is determined by the SHAPE of the CONCENTRATION vs TIME PROFILE wheras the RATE CONSTANT determines the SLOPE

Answer 2

Arrhenius equation - Basisis for drug stability testing ("stress tests")

Answer 3

Note: | - this equation shows the relative change in shelf-life with temperature

Answer 4

Example | - L2, pg 31 & 32 & 33 & 34 & 35 & 36

Answer 5

- Disintegration is a process in which a solid dosage form is broken down into smaller particles thereby increasing its surface area - it refers to the mechanical break up or disaggregation of a COMPRESSED TABLET into SMALL GRANULES upon ingestion, thus enable a faster liberation of the drug particles from the tablet matrix leading to an INCREASE IN SURFACE AREA FOR SUBSEQUENT DISSOLUTION

Answer 6

- Disintegration is an INTEGRAL STEP IN ENSURING, and indeed maximising, THE BIOAVAILABILITY OF THE DRUG from the majority of solid dosage forms - Without disintegration, only the drug near the surface of the tablet would be able to dissolve. Hence the REPRODUCIBLE AND FULL DISINTEGRATION of the tablet upon exposure to the dissolution medium is of CRITICAL IMPORTANCE TO ACHIEVE A RELIABLE CLINICAL PERFORMANCE OF THE DOSAGE FORM

Answer 7

- Given that in immediate-release tablets disintegration is a necessary requirement for dissolution, the disintegration performance has a direct impact on the therapeutic effect of the medication - The surface area available for dissolution, and thereby the dissolution rate, increases with decreasing particle size. Therefore, a fast and thorough disintegration can lead to a quicker absorption of the drug and a faster onset of the desired effect

Answer 8

- Immediate-release tablets: designed to fully disintegrate and dissolve upon exposure to physiological fluids w/in a short period of time (2.5 to 10 mins) - It is particularly important where a rapid onset of action is desired, eg, for analgesics or to enable enhanced bioavailability of a poorly soluble drug

Answer 9

- ORALLY DISPERSIBLE/DISINTEGRATING TABLETS (ODTs) which are designed to disintegrate in the mouth in less than a minute before swallowing. ODTs also have a faster onset of effects than tablets or capsules, and have the convenience of a tablet that can be taken w/out water

Answer 10

(i) facilitate water uptake and transport liquids into the pores of the tablet (surface active agents) or, increase the penetration rate of water into the tablet (wetting agents). Examples: Sodium dodecyl sulphate (SDS) (ii) produce gas in contact with moisture. Examples: mixtures of tartaric acid or citric acid and sodium bicarbonate or calcium carbonate (iii) swell upon contact with water. Examples: Starch (including pregelatinised) (traditional disintegrants) or cross-carmellose sodium (cross-linked sodium carboxymethylcellulose, NaCMC) (superdisintegrants)

Answer 11

- Dissolution is the process by which a chemical or drug passes from a solid into solution * * molecules/ions of a solid becoming dispersed w/in a liquid vehicle

Answer 12

1. Detachment of molecules from the solid surface to form solvated molecules at the solid liquid interface (liberation) 2. Transport from this interface to the bulk solution (diffusion)

Answer 13

- Not in the assessable tasks

Answer 14

- Release from conventional tablets that disintegrate - Release from normal capsules containing solid drug - Release from matrix tablet or pellets: lipid matrix (non-hydrating) and swellable (hydrating) matrix - Release from a coated tablet or coated granules/pellets, where the coat remains intact; liquid & dissolved drug may permeate the film coat

Answer 15

- Continued release from ointments or creams in which drug is present in excess of its solubility - Continued release of drug from an ORAL MIXTURE IN WHICH IT IS SUSPENDED

Answer 16

- Injections; parenteral solutions - Mixtures for oral administration, eg. linctus - Topical applications, eg wart paint - Eye drops - nasal spray

Answer 17

- proposed the basic transport-rate controlled model for solid dissolution. they stated that when SURFACE AREA IS CONSTANT, the dissolution rate (dW/dt or dm/dt) of a drug is proportional to the difference b/w its solubility Cs and its bulk solution concentration Cb: - Where k is constant (the mass transfer coefficient) This equation defines the rate of dissolution of a solid when the process is diffusion controlled and involves no chemical reaction

Answer 18

Nernst & brunner suggested that diffusion occurs across a thin stagnant layer of saturated solution called the difussion layer (or hydrodynamic boundary layer) into the bulk solution This is also called the modified noyes-whitney equation. the equation can also be written - Where D/h can be considered a dissolution constant

Answer 19

- Drug dissolves uniformly from all surfaces of the particles - Particles are spherical - All particles are of the same size - h is constant - both h & Cs are assumed to be independent of particle size - In reality, the particles of a drug are neither spherical nor uniform in size

Answer 20

- parameter - physiochemical characteristics - Physiological variable

Answer 21

- Dissolution profiles of four fractions of ibuprofen

Answer 22

- Food intake triggers many of the secretions in the small intestine. The composition of fed state intestinal fluid can vary greatly from fasted state intestinal fluid - The volume of fluids is higher in fed condition - Changes in upper gastrointestinal (GI) pH - Longer upper GI residence time - Fatty meal increases the presence of lipophilic components and native surfactants

Answer 23

- paddle apparatus

Answer 24

- Since the rate-determining step to the intestinal absorption of poorly soluble drugs is the dissolution in the gastrointestinal (GI) tract, postprandial (=after food intake) changes in GI physiology, in addition to any specific interaction b/w drug and food, are expected to affect the pharmacokinetics and bioavailability of such drugs - The difference in composition can be partially responsible for differences in bioavailability when drug is administered in the fed versus the fasted state

Answer 25

- Poorly soluble compounds are especially prone to higher systemic exposure when given in the fed state with the main effect being faster and more extensive dissolution under fed conditions - The in vivo dissolution behaviour of weak bases is additionally influenced by variations in the UPPER GI pH, making these drugs especially prone to food effects - For some lipophilic drugs, co-administration with a meal has been shown to increase bioavailability compared to fasted state

Answer 26

- L4, pg 16

Answer 27

DISINTEGRATION: tablet disintegration testing is used as a quality assurance measure. It is not a true predictor of how well the dosage form will release its active ingredient in vivo DISSOLUTION: Like the disintegration test the dissolution test does not prove that the dosage form will release the drug in vivo in a specific manner but it is one step closer to the absorption process

Answer 28

Is the relative amount of the administered dose of a drug that reaches systemic circulation from a certain dosage form in comparison to the amount that reaches the systemic circulation by iv administration

Answer 29

is the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability. Dosage forms containing the same drug are said to be bioequivalent if they do not differ significantly in the bioavailability (eg AUC, Cmax, tmax) of the active constituent/ingredient, when administered in the same dose under similar experimental conditions

Answer 30

- Drug products are considered pharmaceutical equivalents if the contain the same ACTIVE INGREDIENT in the same DOSAGE FORM and are IDENTICAL IN STRENGTH or concentration, and generally be labelled for the same conditions of use

Answer 31

- Drug products which are PHARMACEUTICAL EQUIVALENTS and are expected to have the SAME CLINICAL EFFECT and SAFETY PROFILE when administered to patients under conditions specified in the labelling

Answer 32

- Drug products that contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety or are different dosage forms

Answer 33

- Most popular & convenient route - Palatability - Easy to manufacture oral dosage forms

Answer 34

- Muscular tube - Epithelium is protective - Mucus secretion - pH 5-6 - Peristalisis - Oesophageal disorders - Dysphagia - Perforation - adhesion

Answer 35

- Duodenum is the key site for drug absorption

Answer 36

Gastrointestinal pH environment - Relate to drug stability - Drug ionisation & absorption Stomach - Store food - Begin digestion - Delivery food

Answer 37

- Acid secretion (HCI) - Gastric content - eg food increases pH - Acid-lowering drugs - Proton pump inhibitors (eg omeprazole)

Answer 38

Secretions into SI determine the pH - Brunners glands (biocarbonate) - Intestinal goblet cells (mucus)

Answer 39

- L5, pg 11 & 12

Answer 40

- Important parameter controlling the onset of drug action - because it controls the rate of arrival of the drug to the main absorption site (small intestine) - Determines contact time b/w the drug and low pH environment - drug stability?

Answer 41

- phase I - Phase II - Phase III - Phase IV L5, pg 16

Answer 42

Phase of propulsion - rapid flow of liquids with suspended small particles and delayed flow of large particles Phase of emptying - Emptying of liquids with small particles. Large particles are retained in the terminal antrum] Phase of retropulsion - Retropulsion of large particles

Answer 43

- Liver degrades orally administered drugs BEFORE reaching systemic circulation - Consequence is reduced bioavailability

Answer 44

Important for absorption of fats, protein drugs and lipid soluble drugs Lymphatic capillaries and lymphoid tissue (GALT) - Peyers patches (ileum) - M cells - important in immune system. Transport proteins intact across the GIT

Answer 45

- Important for bioavailability - Relatively rapid 3 +/- 1 h - Relatively constant - No discrimination b/w solids and liquids - No difference b/w fed and fasted

Answer 46

- Reabsorption (water & ions) - No villi, but microvilli - Absorptive capacity is minor (ascending) - pH 7 - 8 - Transit is long and variable - Reduced enzymatic barrier compared with the small intestine - Fermentative bacteria

Answer 47

- Stool storage - No villi - Thin epithelia (1 cell thick) - pH 7.5 - Goblet cells - Little free water - Absorption via passive diffusion - Treatment - Local conditions eg haemorrhoids - Systemic effect eg analgesic

Answer 48

Advantages - oral route unavailable - post operative - upper GIT pathology - infants and elderly - Drug unstable in upper GIT Disadvantages - Cultural acceptability - Slow and incomplete absorption - Large-scale production limitations - Limited shelf life - Do not reach further than descending colon

Answer 49

Suppositories - Solid dosage form - Melt upon administration - Vehicle + drug - (i) fatty bases - (ii) water-soluble bases Micoenemas - liquid or gas - Expensive - Difficult to self-administer

Answer 50

Local treatment - candida infections Systemic treatment - No first pass metabolism - Highly vascular - Eg progesterone, Oestriol - Fertility treatment - Hormone replacement

Answer 51

Creams / ointments pessaries - glycerol-gelatin bases - Melt at physiological pH Rings - Impregnated with estradiol - Removed after 3 weeks

Answer 52

Mechanisms of chemical degradation - Hydrolysis (water) - Oxidation (air) - Photolysis - Isomerisation - Polymerisation

Answer 53

pH-rate Profiles - Combination of the two segments - Contribution of water reation - flat part (pH independent) in intermediate range of the curve

Answer 54

Paracetamol: Questions - L6, pg 11 & 12 & 13 & 14 & 15 Example - L6, pg 16 & 17

Answer 55

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Answer 56

Now consider an ionisable drug D subject to: - Specific acid catalysis - Specific base catalysis - Warter reactions ``` Parallel reactions of both, DH and D-: 1. DH + H+ -> P 2. DH + W -> P 3. DH + OH- -> P 4. D- + H+ -> P 5. D- + W -> P 6 D- + OH- -> P ```

Answer 57

With degredation rate constant k relating to the following reactions: - K1: specific acid catalysis of unionised form - K2: Water reaction of unionised form - K3: specific base catalysis of unionised form - K4: specific acid catalysis of ionised form - K5: water reaction of ionised form - K6: Specifice base catalysis of ionised form

Answer 58

experimental method - Carry out a series of experiments at different pH values and get the rate constant at each pH value; keeping the temperature constant Generally: - Ionisation gives rise to more compex pH-rate profiles (not simply V-shaped curve), - But not all reactions are necessarily significant

Answer 59

- Phenolic compounds - Unsaturated compounds - Sulfhydryl groups

Answer 60

- Oxidation is always accompanied by reduction - redox reactions are electrontransfer reactions - L7, pg 4 General - L7, pg 6 Examples - Phenothiazines - Captopril - L7, pg 7 & 8

Answer 61

- Oxidation process involves one electron reaction and free radicals - Hydrolysis: a pair of electrons does a nucleophilic attack - A FREE RADICAL is an atom or a molecule containing one or more UNPAIRED ELECTRONS R* Free radicals take e- from other substances

Answer 62

- Oxidation that takes place spontaneously under mild conditions - Usually involves molecular oxygen and chain reactions

Answer 63

- Initiation - Propagation - termination

Answer 64

1. reduce the rate of initiation: Ki dec. | - Common initiators: Me+

Answer 65

2. reduce the rate of initiation: - Protection from light - If light causes inc Ki then protection from light will be important: PACKAGING - Storage in dark cupboard - Amber glass containers - Opaque containers - Secondary outer packaging

Answer 66

3. Increase the rate of termination: Kt inc - Chain terminators (antioxidants) - Agents which donate a hydrogen to a radical while themselves form radicals that are stable and incapable of continuing the propagation chain cycle or dimerise to form an inert molecule

Answer 67

Chain terminators: oil soluble - Water insoluble chain terminators: - Phenol derivatives L7, pg 23

Answer 68

4. decrease the oxygen concentration: [02] dec -> stability inc. Ampoules - Sealed, inert atmosphere (N2, CO2), flushing Hermetic strip packaging Well filled containers - Reduction of headspace Water de-oxygenation

Answer 69

- Preferentially oxidised substances (higher standard oxidation potential) - Concentration range: 0.1-1% (w/v) - Ascorbic acid - Sodium bisulfite - Sodium sulfite

Answer 70

5. temperature change | a) Arrhenius:

Answer 71

- Oxidation - Due to its sulfhydryl/thiol group, the drug undergoes oxidative degradation in aq. solution - Rate of oxidation depends on pH and oxygen conc. and is catalysed by metal ions - Despite the amide group, hydrolysis is minimal L7, pg 27 & 28 & 29

Answer 72

- Hydrocortisone - Prednisolone - Riboflavin - Ascorbic acid - Folic acid - Chloroquine

Answer 73

usually yeilds numberous products through complex pathways Photodegradation is often accompanied by oxidation in the presence of oxygen

Answer 74

- Storage - Handling - After administration - Sunlight is able to penetrate skin at sufficient depth to cause photodegradation of drugs circulating the surface cappillaries or in the eyes

Answer 75

functional groups expected to introduce photo-reactivity - Aromatic residues - Conjugated double bonds containing nitrogen, sulphur or oxygen

Answer 76

- If the solution is protected from light, it is stable for at least 1 year - If exposed to normal room light, it has a shelf life of only 4 hours

Answer 77

- L7, pg 40

Answer 78

- Coloured glass (amber glass excludes light of wavelength <470 nm) - Stored in the dark - Opaque containers - Coating tablets with a polymer film containing UV absorbers

Answer 79

- isomerisation is the conversion of a drug into its optical or geometric isomers - Adrenaline - Tetracyclines - Pilocarpine - Caphalosporin - Vitamin A

Answer 80

- Conversion of one isomer into another

Answer 81

- Combination of drug molecules into chain - eg concentrated solutions of aminopenicillins 1. Decrease activity 2. Suspected allergic reactions

Answer 82

- Non invasive drug delivery - Avoids 1st pass metabolism - Avoids drug degradation in GI - Good patient compliance - Treat patients with GI disorder - Terminate drug absorption easily

Answer 83

Most extensively and readily accessible organ function - Protection (microbiological, radiation, mechanical) - Sensation - Thermoregulation Anatomy - 3 main layers - Appendages - Vasculature

Answer 84

1. Stratum corneum 2. Stratum granulosum 3. Stratum spinosum 4. Stratum basale

Answer 85

Cells are - anucleate - flattened - keratinised - in a lipid matrix (ceramides, fatty acids, cholesterol) 'Brick and mortar' model SC regulates water loss - Barrier function

Answer 86

- 3-5 mm thick - Connective tissue - Nerves and blood vessels - Skin appendeges

Answer 87

Function - Mechanical cushion layer - Thermal barrier - Calories depot Loose connective tissue Thickness varies Vasculature

Answer 88

1. Transappendageal 2. Transcellular 3. intercellular

Answer 89

1. transappendageal (shunt pathway) - hair follicles, sweat ducts - Area available 0.1% - Large polar molecules and ions - Bypass the stratum corneum - Rapid clinical effect

Answer 90

2. Transcellular - Hydrophilic molecules - Through the keratinocyte cells - BUT also the lipid bilayers - Multiple partitioning

Answer 91

3. Intercellular - Only continuous phase in the membrane - Small, uncharged molecules and lipophilic drugs - Diffusion pathway greater than SC thickness

Answer 92

- Systemic treatment via transdermal route | - Ficks first law

Answer 93

- Partition coefficient (K) - Vehicle -> SC -> Dermis -> systemic circulation - Molecular size and shape - Skin hydration - More permeable when hydrated - pH - Unionised molecules absorbed - Diffusion coefficient - Drug concentration - diffusion gradient

Answer 94

Age - elderly skin less hydrated - premature infants Blood flow - Theoretically circulation affects absorption, but clinically relevant? Skin location - Differences in SC thickness across body - Density of appendages differs - Permeability - Genitals > face/neck > trunk > arm > leg - Variability b/w patients at same site Species differences - Human vs laboratory animals Skin condition - Damaged skin (SC) is more permeable - Dermatitis / eczema - Psoriasis - Sunburn - Scar tissue - Callous tissue - Cuts / abrasions Skin hydration - Occlusive dressings

Answer 95

- Water content of SC 15-20% - Increase permeability when hydrated - Soaking, humidity, occlusion - Hydration shell theory - swelling that disrupts lipid layer

Answer 96

i) drug in adhesive reservoir patches ii) drug in matrix (solid) iii) drug in reservoir (liquid)

Answer 97

- Enhance absorption - Protect bioactive - Controlled release

Answer 98

- L8, pg 24

Answer 99

- Partition coefficient - Lipophilic moiety - Esterases - Eg steroid ester - Betamthasone-17-valerate

Answer 100

Should be - Pharmacologically inert - Non-toxic, non-irritant, non-allergic - Reversible effect - Compatible with delivery system - Unidirectional effect - Cosmetically acceptable - (odourless and colourless)

Answer 101

Microneedles - 50 um diameter - Silicon - Painless - Breakage of needle tips - Infection? Iontophoresis - Electrical current - Charged drugs - Current 0.5 m A/cm2

Answer 102

``` Drug in vehicle (+/- dissolution) ↓ Drug partition into stratum corneum ↓ eg estradiol, log P = 2.29 in aqueous vehicle ↓ Movement of drug through vehicle ```

Answer 103

A - nasal vestibule C - respiratory area/turbinate: - C1 - inferior turbinate - C2 - middle turbinate - C3 - superior turbinate D - olfactory region B - Atrium E - nasopharynx

Answer 104

- A non-invasive route - rapid drug absorption - Quick onset of action - Hepatic first - pass metabolism is absent - The bioavailability of LARGER DRUG molecules can be improved by means of ABSORPTION ENHANCER - Better nasal bioavailability for smaller drug molecules - Drugs which can not be absorbed orally may be delivered to the systemic circulation through nasal drug delivery - Convenient route when compared with parenteral route for long term therapy

Answer 105

- Absorption surface area is less when compared to gastrointestinal tract (GIT) - Once the drug administered can not be removed - Nasal irritation - There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa - The absorption enhancers used to improve nasal drug delivery system may have histological toxicity which is not yet clearly established

Answer 106

- L9, pg 10

Answer 107

- rapid onset of action - Similar or superior therapeutic effect at a fraction of the systemic dose: for example, 100-200 ug of salbutamol by inhalation is therapeutically equivalent to 2-4 mg of salbutamol oral dose - reduced systemic side effects - Reduced cost

Answer 108

- Large surface area of absorption (100m2) - Less enzymatic degradation of drug - Avoids first pass metabolism - Rapid action - Some absorption of peptides and proteins - Diseases (eg diabetes)

Answer 109

Mucociliary escalator - Which is composed of a mucus lining layer which covers the surface of the trachea, bronchi & bronchioles, including the terminal bronchioles and which is moved upwards towards the pharynx by the ciliated epithelium where it is generally swallowed Cough response - in the upper airways Phagocytic cells - Which scavenge particulate material which penetrates to the alveolar region of the lung

Answer 110

- Nebulizers - Metered Dose Inhalers (MDI or pMDI) - Dry powder inhalers (DPI)

Answer 111

Formulation: - Vehicle - water for injection - Buffers - pH > 5 - Cosolvents - eg propylene glycol - Tonicity adjusters - NaCl, mannitol - Antioxidants - Usually no preservative

Answer 112

- Jet nebulizers were used traditionally - Used mostly in hospital and ambulatory care settings - Larger and less convenient - The aerosol is delivered continuously over an extended period of time - NOT TYPICALLY used for chronic-disease management - Ultrasonic nebulizers (battery operated, wt 150g) are portable but are generally more expensive

Answer 113

- The propellant is a liquified compressed gas usually having an absolute pressure of 4-5 atmospheres - The drug is expelled from the inhaler by the pressure exerted by the propellant - The propellants in MDIs have traditionally been the chlorofluorocarbons (CFC) - in 1974 it was postulated that CFCs were leading to degradation of the atmospheric ozone layer. It lead to a ban or severe restriction on the use of CFCs. However, 3 propellants (12, 11 & 114) have been specifically exempted for use in specified MDI products

Answer 114

- CFCs are being replaced by HYDROFLUOROALKANES (HFA). HFA containes no chlorine which is the danger atom for adverse effects on the ozone layer

Answer 115

- Allow extra time for propellant evaporation - Reduces droplet velocity (inertia) - Retains large droplets by sedimentation and impaction - Results in greater proportion of dose that enters the mouth to reach the lungs -> reduced side effects (steroids)

Answer 116

Advantages of the Dry Powder Inhaler - Environmental sustainability, propellant-free design - Little or no patient coordination required - Stable formulation inherent to solid form

Answer 117

- The tiny particles are highly cohesive, less flowable and do not disperse after inhalation - Particles which are 1-5 um in size reach lower respiratory tract

Answer 118

Single-dose reusable devices - Have each dose prepared in a separate single unit such as a capsule or blister eg Rotahaler Single-use inhalers - Are suitable for less frequent inhaler therapies or certain infectious or vaccine delivery eg twincaps DPI by hovione Multi dose inhalers - Multi-unti dose inhalers eg DISKUS - Multi dose reservoir eg Turbuhaler

Answer 119

- The dose of the reservoir type is dispensed by a metering valve

Answer 120

1. scelera: no vasculature, tough 2. Choroid: Vascular 3. Retina: light sensitive 4. Cornea: Non-vascular

Answer 121

1. Topical - Conjunctivitis, blepharitis, dry eye, infections 2. Anterior to lens - Corneal infection, iritis, glaucoma, cataracts 3. Posterior lens - Viral retinitis

Answer 122

Active - Eg pilocarpine, naphazoline Vehicles / lubricants - Dextran, gelatin, propylene glycol Preservatives - Benzalkonium chloride, sorbic acid Excipients - Wetting agents, buffers & tonicity adjusters

Answer 123

Advantages - Drug delivered to site of action - Effects are localised - Lower doses required - Convenient, simple & painless - Avoids problems of other routes Disadvantages - Low bioavailability - Ineffective for posterior eye segment

Answer 124

Tears - 7 um - pH 6.9 - 7.4 - Low buffer capacity - Lysozymes

Answer 125

Max volume for eye = 30 uL Exceed volume = spillage - Loss of dose Drug ionization - Ionized drug more easily cleared in tears because more soluble Drainage via nose to GI tract - Systemic side effects - Taste

Answer 126

- Time needed to penetrate and depends on drug characteristics

Answer 127

L10, pg 14

Answer 128

1. conjunctival-scleral absorption - Loss to systemic circulation (conjunctival vasculature and large SA) - Unless targeting conjunctiva (conjunctivitis) - May be important for large, polar compounds - Relatively large SA) - eg gentamycin, prostaglandin

Answer 129

- Short residence time - Clearance of topically instilled medications - 90% of drug lost in 15-30 sec after administration

Answer 130

- Good corneal penetration - Prolonged contact time with the corneal epithelium - Simplicity of instillation for the patient - Non-irritative and comfortable - Appropriate molecular weight and characteristics of active

Answer 131

- Dec. volume of instillation (10 uL) - Formulate so as to minimise irritation - pH - Buffer to 6.0 - 8.0 - Osmolarity - Isotonic - Excipients - Non-irritant Irritant formulations - Inc. lacrimation - Inc. tear turnover - Inc clearance Inc. retention - Viscosity enhancing polymers - Change rheological properties - Gel formation Thixotropic polymers - Viscosity enhancement

Answer 132

- Pilocarpine - Reverse phase gel - Miscible with lacrimal fluid - Bioadhesive

Answer 133

Advantages - Prolonged precorneal contact time - May act as drug reservoir Disadvantages - Now well accepted (discomfort, interference with vision, aesthetic reasons) - Problem of mixing with tears

Answer 134

- Bioerodible insert - Gelling minitablet - Sustained release - Slugs

Answer 135

Idk if need to know

Answer 136

Systemic - High doses - Side effects - Limited value for posterior delivery Topically through cornea - Accessible - Many loss factors - Low bioavailability - Frequent application required

Answer 137

- Topical drops - Intravitreal - trans-scleral diffusion - Target site @ retina

Answer 138

1. intra-ocular - Intra-vitreal injection - Frequent injections (patient compliance) - Retinal and lens damage - Bleeding - Infections may result 2. Periocular - Sub-conjunctival injection - trans-scleral absorption 3. Retro-bulbar injections - Opthalmic local anaesthetics

Answer 139

Intra-vitreal device (drug eluting) - Eg retisert - Tablet-shaped implant, surgically inserted - Prolonged delivery - 5 - 8 months - Ganciclovir for retinitis - Biodegradable polymer

Answer 140

L10, pg 30

Answer 141

- Enteral -> administration via the GI tract | - Parenteral -> "outside the intestine"

Answer 142

- Drug that undergoes substantial FIRST PASS METABOLISM - Drug that are POORLY ABSORBED from the GI tract (low F) - Drug UNSTABLE in the GI tract (eg insulin) - RAPID ONSET of drug action is desired - Ability to immediately STOP DRUG ADMINISTRATION is important - High degree of FLEXIBILITY in dosage adjustment

Answer 143

- Intravenous (IV) - @ vein - Intramuscular (IM) - @ muscle tissue - Intradermal (ID) - @ dermis of the skin - Subcutaneous (subcut; SQ) - @ subcutaneous tissue of the skin

Answer 144

1. Solutions 2. Suspensions 3. Emulsions

Answer 145

Vascular system 1. Arterial circulation 2. Venous (veins) circulation - More superficial and easily accessible - Thin walled than arteries - Low pressure systems compared to arteries - Blood loss in case of accidental venipuncture is less

Answer 146

- Rapid onset of action - Predictable response - Avoid first-pass metabolism - When oral route not an option - Stopped instantly

Answer 147

Bolus: rapid injection into the vein - Single rapid injection lasting 1-2 min - Small volumes (<1 mL) - Rapid onset of drug action

Answer 148

- Slow injection into vein (over several hr) - Large volumes (100 - 1000 mL) - Continuous infusion - large volume of drug at a constant rate - Intermittent infusion - A relatively small volume of drug over a specified amount of time at specified intervals - Sustained level of drug in the blood stream is required over a long period of time (eg pain relief and many antibiotics)

Answer 149

Small volumes - often < 100 mL Large volumes - > 100 mL - Fluid replacement - Calorie replacement

Answer 150

Typically solutions and colloidal dispersions (< 1 um) - Analgesics - General anaesthetics - Antiviral agents - Antibiotics - Immunosuppressive agents - Antifungal agents - Vasodilators - Chemotherapeutic agents - Imaging agents

Answer 151

Instantaneous absorption - Drug properties - Solubility - Degree of ionisation Volume of the injection Osmolarity of the injection

Answer 152

- Controlling solution pH - On injection -> pH shift -> physiological pH -> drug may precipitate - Consequences - Pain - Must re-dissolve before absorption -> absorption is delayed

Answer 153

Typical sites - Upper arm - Upper leg - Abdomen

Answer 154

- Drug that are POORLY ABSORBED from the GI tract (low F) - Drug UNSTABLE in the GI tract - insulin, narcotics, vaccines - Can be solution or suspension (typically not viable for IV administration) - Limited by volume (<2 mL)

Answer 155

Drugs dissolve in the interdtitial fluid and gain entry to the bloodstream 1. Directly (often adipose and poorly perfused) 2. Indirectly by lymphatic capillaries - Relatively slow (c.f. IV & IM) and unpredictable; depends on the local vasculature - Typically 20 - 3- min

Answer 156

Advantages - Perfused with blood supply - Wide range of drugs can be administered in a variety of dosage forms - Provide rapid absorption (~ 20 min) or controlled drug therapy

Answer 157

- IM vs IV: effects are less rapid but generally longer lasting than those obtained from IV administration - May consist of suspensions or sustained-release products - Vaccines - Corticosteroids - Pain killers - Peptide hormones - Antibiotics - IM injections are often painful and non-reversible - requires specially trained personnel

Answer 158

1. Release of the drug from the dosage form into the intercellular fluid (ICF) 2. Absorption from the ICF into the blood & lymphatics 3. Transport from the local blood volume into the general circulation 4. Metabolism

Answer 159

Affects - Conc. of the absorbable species (HA or B) - Drug solubility

Answer 160

Generally: - aq. solutions - Oily solutions - o/w emulsions - w/o emulsions - Oily suspensions - Dispersions in polymer - Solid implants

Answer 161

1. Pharmacokinetics limited by perfusion | 2. Pharmicokinetices limited by the device/depot

Answer 162

regional variations - in general absorption rate: deltoid > vastus lateralis > gluteus maximus - Gender (male > female) Bloodflow - Heat - Massage - Exercise

Answer 163

- Injection < 0.1 mL into the dermal layer or upper layer (only 1.5 to 2 mm deep) of the skin - Requires specially trained personnel and typically achieves inconsistent delivery

Answer 164

- For local not systemic delivery Applications - DIAGNOSTIC: tuberculosis (tuberculin testing) - ALLERGY TESTING: by placing very small amounts of the suspected antigen or allergen in a solution under the skin - VACCINATION: influenza vaccine in Europe (INTANZA) sanofi

Answer 165

IV 1. - 10mL (bolus) and no limit for infusion 2. - Solutions or colloidal dispersions (<1um) 3. - Instantaneous, no absorption phase SC 1. 2mL 2. Solutions, suspensions, oil-based formulations 3. Typically within 20 mins 4. Upper arm, upper leg, abdomen IM 1. 4mL 2. Solutions, suspensions, oil based formulations 3. Less than 20 mins (usually faster than SC) 4. Muscles: Arm, thigh, buttocks ID 1. 0.1 mL 2. Solutions 3. Local action only 4. Dermis

Answer 166

Disadvantages of conventional immediate-release - Sawtooth profile - Repeat administration needed - Patient compliance - Short half-life drugs - Side effects

Answer 167

- Increase the bioavailability of poorly water soluble drugs - griseofulvin, itraconazole, cyclosporin - BSC Class II drugs - 90% of drug candidates are classified as poorly water-soluble Reduce the time for onset of drug acrtion - Analgesics - Dysphagia

Answer 168

- Particulate level - Molecular level - Colloidal level

Answer 169

- If poor water solubility, change to a non-aqueous solvent - Water-miscible organic solvents with an OH- group used - Propylene glycol - Glycerol - ethanol - Dissolve drugs in the co-solvent - Caution drug precipitation may result with dilution in the GIT - Example of propylene glycol and phenytoin solubility in the PHCY211 lab

Answer 170

Salt form of drugs have improved solubility and dissolution - Anions eg hydrochloride*, chloride, sulphate, acetate - Cations eg sodium*, potassium, calcium - Low molecular weight and so do not change overall dose mass Choice of salt depends on drug pKa - Acidic drugs: pKa of counterions should be 2pH units ABOVE drug pKa - basic drugs: pKa of counterion should be 2 pH units below drug pKa

Answer 171

- Cyclic sugars (glucos) - Chiral organic molecules - Hydrophobic cavity and hydrophilic exterior - BSC class II drugs - Improve drug solubility and stability - Incorporatte into tablet dosage forms

Answer 172

Volume of the cavity depends on the number of units in the CD ring

Answer 173

- Colloidal = 10-500 nm - Lipid-based systems - Self emulsifying drug delivery systems - See L DF18 saquinavir - Dilute in water in the GIT - Form spontaneously - Emulsions - two-phase system (w/o or o/w) - Droplet size > 500 nm - Microemulsions - One-phase system - Oil + water + surfactant - Droplet size 20-200 nm

Answer 174

Particle size reduction <1 um) - Inc. surface area - Inc dissolution - Reduce food effects Milling used to reduce particle size Need to avoid aggregation - Use surfactants or polymers to prevent aggregation

Answer 175

- Polymorph = different crystal form of drug - Amorphous form - Absence of long range order - Higher solubility & dissolution rate NOTE: amorphous state is not stable

Answer 176

Solid solute dispersed in a solid solvent - Molecular dispersion - Preparation eg Eutectics - Inc. surface area - Lower melting point

Answer 177

weird shit on L12, pg 20

Answer 178

Disintegration faster than conventional tablets - Improves compliance Effervescent tablets - CO2 liberation facilitates tablet disintegration - Active ingredient available in solution for absorption Chewable tablets - Mechanical disintegration

Answer 179

Orally dissolving tablet (ODT) | - Dissolve on tongue, not swallowed

Answer 180

Pulsatile release | - Lag time and then rapid, complete release of drug

Answer 181

Why and when to use - Acid-labile drug (omeprazole and erythromycin) - Prevent gastric mucosal irritation (NSAIDS) - Target delivery to small intestine - Circadian rhythm to disease state

Answer 182

Enteric coating | - Release delayed until dosage from reaches the small intestine

Answer 183

- L13, pg 8

Answer 184

Eudragit FS - pH distal small intestine 7.5 - pH proximal colon 6 - 7.8 - Copolymer of methacrylic acid, methyl methacrylate and ethyl acrylate - Dissolves slower at higher pH

Answer 185

- Mouth: 1 minute - Esophagus: 4-8 seconds - Stomach: 2-4 hours - Small intestine: 3-5 hours - Colon 10 hours to several days L13, pg 10

Answer 186

- In vitro dissolution | - In vivo plasma conc.

Answer 187

Key components - core - drug + osmotic agent - Semipermeable membrane - Orifice

Answer 188

- Diffusion of FLUID through a SEMI-PERMEABLE membrane from a solution with a low solute conc. to a solution with a higher conc. until there is an equal conc. of solute on both sides of the membrane

Answer 189

1. Water permeates through the rate controlling membrane 2. Inc. osmotic pressure inside the tablet 3. Drug and osmotic agent pumped out through the device orifice

Answer 190

- L13, pg 15

Answer 191

- Delivery orifice - Sem-permeable membrane - osmotic push layer - Barrier inner membrane - Soft gelatin capsule - Liquid drug formation

Answer 192

- Immediate release dose - Drug + osmotice agent 1. Cap dissolves IR (immediate released) 2. Energy sourceactivated by controlled permeation of GI fluid 3. Time-released plug expelled 4. Pulse or sustained release of 2nd dose

Answer 193

- In vitro | - In vivo

Answer 194

Rheumatoid arthritis treatment - Diclofenac - Pulsatile release - Film coat for immediate release - tablet core for later release Coating erodes over time - Independent of pH - Turned lag time before drug release

Answer 195

- Controlled exposure to a vaccine to produce immunity (protection) against the disease - Primes the immune system to generate memory immune responses - Predominantly given by injection - can stimulate steriliizing immunity (pathogen can not establish) or partial protection (pathogen can establish but disease is sub - clinical or very mild)

Answer 196

- L14, pg 1 - L14, pg 2 - L14, pg 3 - L14, pg 3

Answer 197

- Immunological memory is the ability of the immune system to respond more rapidly and effectively to pathogens that have been encountered previously

Answer 198

- Make IgG rather then IgM (isotype switched) - high affinity Ig (affinity matured) - High precursor frequency (clonal expansion) - Already express activation molcules

Answer 199

- high precursor frequency - Already differentiated (Th1, Th2) - Already express activation molecules - High affinity TCR (T cell receptor) ---> infection does not occur, is sub-clinical or mild

Answer 200

- Want to increase the number who survive natural infection (decrease morality) - Reduce the side effects associated with natural infection (decrease morbidity) - While still promting protective memory immune responses

Answer 201

- Safe & effective vaccine - 90-95% uptake (completed immunisations) How? - Safety - Modern vaccines are very safe - Risk vs benefit - actual not perceived - depends on population and disease How? High uptake 1. cost - few cents to hundreds of dollars 2. Stability - is cold chain required? 3. Ease of administration - injection vs oral How? - High uptake - Measles and whooping cough - How can we improve coverage? - Education - Active follow up - national immunisation register (NIR) - Improved access - Traditional site - Expanded delivery - Workplace - Community centres, marae - pharmacies

Answer 202

- Free influenza immunisation to > 65's | - Non-subsidised immunisations with age restrictions

Answer 203

- Drug solubility - Product stability (particularly biopharmaceuticals) - rate of release (sustained/controlled ie after IM or SC) - Sterility - Manufacturability

Answer 204

Extravasation - Leakage of the injection from the vein into the surrounding tissue Air embolism - Injection of air into a vessel Thrombosis - Formation of a clot in a blood vessel Haemolysis - Breakdown of red cells with the release of haemoglobin Phlebitis - Inflamation of the vein wall due to irritation from the formulation Pain

Answer 205

Drugs which are irritating or very viscous suspensions -> abscess tissue formation -> hydrostatic pressure on the surrounding tissue - -> pain - -> necrosis

Answer 206

- Vehicle (aqueous vs non-aqueous) - Buffering agents - Tonicity adjusters - Solubilizer - Wetting agents, suspending agents, emulsifying agents - Preservatives

Answer 207

Ideally: formulated as close to the physiological pH - pH 7.4 (7.35 - 7.45) - Resting muscle pH 7.15 - Active muscle pH 6 Reality: IV or IM administration (pH range from 2 to 12) - pH is dependent - Injection volume - Rate of administration - Buffer capacity of the product

Answer 208

Can occur if drug is solubilised at concentrations above its solubility in blood (IV injections) Influenced by injection rate Potential consequences of precipitation: - Delayed and possibly incomplete absorption - Crystalline precipitates can be abrasive to the blood vessel wall --> phlebitis

Answer 209

Tonicity - How an extracellular solution can change the volume of a cell by affecting osmosis - Modifications of the "tone" of the cells Osmosis (revision): - Process by which molecules of a solvent tend to pass through a semipermeable membrane from a less concentrated solution into a more concentrated one Osmolarity (revision): - Osmotic conc. of a solution, (expressed as osmoles of solute pr litre of solution)

Answer 210

Hypertonic - [solute] high Isotonic Hypotonic - [solute] low

Answer 211

Hypotonic formulation - hypotonic plume - [solute] dec. - RBC lysis - renal failure - Water enters blood cell Hypertonic formulation - hypertonic plume - [solute] inc. - RBS shrinks - Water exits RBC - haemoglobin

Answer 212

- Formulation plume - RBC lysis - Renal failure

Answer 213

Not always feasible due to - High drug conc. - Low injection volumes - stability considerations May look at slightly hypertonic preparations as cells tolerate this better than slightly hypotonic preparations Drug products may be mixed with a sufficient amount of isotonic diluent May look at alternative route administration

Answer 214

Electrolytes - Sodium chloride - Potassium chloride Mono- or Disaccharides - Dextrose - Lactose - Sucrose - Trehalose Others - Glycerine - Mannitol - Glycine

Answer 215

Inflammation of the vein wall - Precipitation of a poorly soluble drug - Extreme local pH effects of vehicle - Particulate matter

Answer 216

- Precipitated drug @ injection site - Precipitated drug downstream of injection site - Formulation plume

Answer 217

Slow injection - Plume (critical conc. for hemolysis or precipitation) Fast injection - Bigger plume more interaction with RBCs, drug @ higher conc. for longer (large interface high pH of plume and biological fluid)

Answer 218

- minimise hemolysis or ppt < EC - Effective concentration (EC) of a drug: concentration in the injected vein at the site of the injection at the time of he injection

Answer 219

Precipitation -> phlebitis - Infusion in-line membrane filters 0.2 mm)

Answer 220

- The cause of pain during IV is less well understood - Phlebitis is often associated with pain while haemolysis is not - Often occurs in parenteral suspensions (high amount of solids) - Pain may occur immediately or delayed - Pain on injection - IV administration of pain relief drug either prior or co-administered with drug (limited sucess)

Answer 221

Advantages - Vs. oral or parenteral dosage form - Site specific drug administration (eg implants for treatment of tumours or cancer) - Significantly lower doeses of the drug used -> dec. side effects - Controlled delivery of a therapeutic(s) - Improved patient compiance

Answer 222

A. Peak and trough - Profile from conventional dosage forms that result from regular and frequent administration of the drug ie daily injections B. Typical controlled release - Profile following single dose administration and sustained release of drug at a constant rate over a period of time

Answer 223

- IDDS require minor surgery - Cost/benefit ratio - Maybe specialized training - Regulatory path for approval longer - Pain and discomfort

Answer 224

Controlled delivery of a therapeutics achieved with polymers - Ease of fabrication - Tunability of degradation kinetics - Biocompatibility (degradation products)

Answer 225

- Difficult because there will be exceptions - 'implants and implantable pumps that contain and deliver drug' Non-degradable - Matrix controlled system - Membrane enclosed reservoir Degradable

Answer 226

- Matrix (diffusion) controlled system - Uniform volume expansion of the bulk material causing the opening of pores of the matrix structure Membrane enclosed reservoir - Swelling of permeable polymer is a non-uniform volume expansion allowing for water permeability and diffusion of internal components out of the system - Permeable non-degradable membrane - Thickness and permeability properties can control diffusion into the body

Answer 227

Membrane enclosed reservoir - Birth control - Vascular disease - Occular treatment

Answer 228

Jadelle - - Silastic medical adhesive - Silastic tubing - LNg 75mg crystals embedded in copolymer Jadell levonorgestrel (LNg) implants for female contracteption

Answer 229

Intraocular - Ocusert Pilocarpine (dec. intraocular pressure) - 7-day delivery vs 6 hrly

Answer 230

Drug eluting stent eg coronary artery disease a) plaque, artery, stent, ballon b) expanded stent, inflated balloon c) stenting

Answer 231

- Hydrolysis of the polymer (tissue fluid at the implantation site) -> drug release - Rate of drug releaser is determined by th - rate of biodegradation; polymer composition molecular weight, drug loading, and the drug polymer interactions - Controlled release of the drug is achieved by the combination of polymer erosion (by hydrolysis) and diffusion of the drug through the polymer matrix

Answer 232

Surface erosion - Degrades from the outer surface inward, uniformly Bulk erosion - Degrades or deforms uniformly throughout the bulk of the material

Answer 233

Cancer treatment - Gliadel wafer - Zoladex (advanced prostate and breast cancer)

Answer 234

- Biodegradable polyanhydride copolymer - Newly diagnosed high grade malignant glioma as an adjunct to surgery and radiation - Diffusion based

Answer 235

- Analogue of luteinizing hormone-releasing hormone (LH-RH) for advanced prostate and breast cancer - Polymers: PLGA or PLA as a carrier (drug is dispersed in the polymer matrix in the form of a prefilled syringe) - Injected S.C and continuosly releases over a period of 1 or 3 months

Answer 236

- Medtronics MiniMed 670G ('Artificial Pancreas') - Cannula is implanted s.c - Pump is worn outside the body

Answer 237

Prophylactic vaccines - Traditional childhood vaccines - Stimulate a memory immune response w/out subjecting a person to the actual infection - important if the infection has a high morality or morbidity rate - Protect against the development of serious clinical disease via herd immunity Therapeutic vaccines - Stimulate an effector immune response, either antibody and cellular, in order to treat a disease - Provide immediate therapeutic benefit - New and evolving - eg cancer vaccines, asthma vaccines, addiction vaccines, hypertension vaccines, alzheimer vaccines

Answer 238

* Antigen - provides disease specificity * Adjuvant - provides potency * Formulation / delivery system - does everything else

Answer 239

- Whole pathogens - highly (too?) immunogenic | - Subunit antigens - few to many defined T cell and B cell epitopes eg proteins, peptides, DNA, sugars, vesicles

Answer 240

Function to: - Enhance immune responses - Increase immunogenicity of weak antigens - Decrease amount of antigen required - Modulate type of response - Th1, Th2, CD8

Answer 241

Types of adjuvants 1. Mineral salts eg alum 2. Bacterial products - Bacterial toxins (de-toxified) - eg cholera toxin - mucosal vaccines,, IgA - Pathogen-associated molecular patterns (PAMP) eg MPL

Answer 242

Types of adjuvants 3. Natural products / mediators Heterologous - Plants/animals - triterpenoid glycosides (saponins, QS21), a-galactosylceramide Autologous - Immune regulatory cytokines/chemokines eg IL-2, IL-12, IFN - > Increase ability of immunocompromised individuals to respond to vaccine - > Systemic toxicity, short half-life, expensive - > incorporate into a delivery system?

Answer 243

Biological - Living and dead - GE vector bacteria, viruses - VLP, bacterial ghosts Synthetic - Lipid based (liposomes, emulsions) - Polymer based (natural & synthetic)

Answer 244

- Alum - non-crystalline gels, safe, not suitable for stimulating cellular (CD8) responses - Emulsions - oil & water (o/w, w/o, w/o/w) & can include nanoparticles - Hydrogels - network of cross linked polymers (natural eg chitosan or synthetic eg poloxamer) & can include nanoparticles

Answer 245

Challenges: - Physical barriers - Anti-microbial defenses - Tolerogenic immune processes - Poor bioavailability

Answer 246

- infectious organism - Live vaccine - attenuation - Inactivation - inactivated vaccine - Toxoid vaccine - Purify toxin

Answer 247

- Clinical isolated or animal isolates - Attenuated by serial culture/passage or targeted mutation Advantages - Excellent immune response, robust - can be given orally Disadvantages - Reversion - Disease in immunocompromised individuals

Answer 248

- Heat, formalin inactivated - Advantage - safe - Disadvantage - variable efficacy - require boosting - reaction to formalin - weaker/no cellular response

Answer 249

- Used where disease pathology is due to a powerful exotoxin or enterotoxin - Stimulate a protective Ig response Advantages - Excellent vaccines, good efficacy, safe Disadvantages - Impurities

Answer 250

1. Identify protective antigens 2. Clone into bacterial plasmid 3. either - Purification - DNA vaccination - Transfection - Vector vaccine - Expression - Sub-unit vaccine

Answer 251

- Part of the organism - proteins/peptides, vesicles etc - Natural or recombinant, highly purified = safe - Can be purified from actual organism, expressed in bacterial, yeast, insect cells or mammalian cells or chemically synthesised - Stimulate a specific immune response - Can be conjugated to carriers to increase immunogenicity

Answer 252

- Common bacterial pathogens have polysaccharide capsules - Bind to B cells - stimulate mainly IgM, short lived protection (sometimes) & no memory - Conjugate to a T cell stimulating protein eg tetanus toxoid (TT), diphtheria toxoid (DT) - protective immunity & memory

Answer 253

Advantages - Safe, defined, potential for transdermal delivery? Disadvantages - Cost - Efficacy variable - proteins and peptides are not immunogenic - no danger signals - Soluble - Small

Answer 254

- DNA for vacine antigen carried by a non/lowly - pathogenic organism - virus or bacteria - Vectors must be attenuated sufficiently so will not cause disease but will still induce an immune response - Vaccines still experimental

Answer 255

Advantages - Vaccine consists of infectious organism - CD8, CD4 & Ig - Polyvalent vaccines - Include genes for immune mediators (cytokines) - Antigen is protected (oral delivery) Disadvantages - Vector may recombine with wild type organism "super bug" - Reversion to wild type - Disease in immunocompromised individuals - Pre-existing immunity to vector organism - Cost, fear of genetically modified organisms

Answer 256

Advantage - easy to make, polyvalent vaccine Disadvantage - Limited efficacy in primate trials (adjuvants, electroporation) - Safety (integration, induction of tolerance, genetically modified organism)

Answer 257

- Zero-order | - Square-root time

Answer 258

A) Lipid matrix - Drug in hydrophobic matrix (solid at room and body temperature) - Diffusion driven - HIguchi release

Answer 259

B) Insoluble polymer matrix - Drug in inert polymer (dissolved or dispersed) - Polymer not soluble in GIT - Eg ferro-Grad - Residual matrix - Drug release by porosity

Answer 260

C) Hydrophilic matrix - Water soluble drug and a swellable polymer - 2 diffusion steps (water in and drug out) - Gel formation, then gel erosion - Eg alginates, xanthan gum, carbopol

Answer 261

Drug resevoir - Liquid (solution, suspension) - Semi-solid - Solid Polymer coating - Specific permeability - Non-porous or microporous

Answer 262

1) Water permeates through the rate controlling membrane 2) Dissolution of the drug in the reservoir 3) Drug release

Answer 263

- Single unit (coated tablet) | - Multi-unit (particulats in a capsule)

Answer 264

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Answer 265

Nanoformulations - <1000 nm size Advantages - Entrap and protect bioactive - Controlled release kinetics - Can attach ligands for selective cell uptake - eg PEG Dox liposomes

Answer 266

- trojan peptides - Surface decorate polymeric nanoparticles with CPPs - Different CPP architecture

Answer 267

Bioadhesion - When two materials, one is biological, are held together for an extended time by interfacial forces Mucoadhesion - Attachment to the mucin layer of biological membranes Principle - To maximize exposure to the absorptive site and so prolong contact time with the GIT

Answer 268

- Moist epithelia - Mucus is a network of glycoproteins - 95% water by weight - Protection and lubrication - Forms a continuous layer - Thickness varies - -ve charge at physiological pH - Mucus turnover 50 - 250 min

Answer 269

Check out the pics

Answer 270

Influence charge on the mucin and the polymer - Mucin has a -ve charge at physiological pH - Eg polycarbophil pKa = 4.75 and rabbit gastric mucosa

Answer 271

Why and when? - Narrow therapeutic window - Poor stability in some parts of GIT - To treat local conditions Gastric retentive - Size Colon targeted - Pro-drugs

Answer 272

Size - Human pyloris 12 +/- 7 mm - Open in fasted state - Evacuation by MCC - < 7 mm evacuated - > 15 mm prolong retention - Site specific for delivery to SI - Local treatment of H. pylori

Answer 273

Swellable system - Fast swelling (1 min in water) - Superswelling - Mechanically strong - eg polyvinylpyrrolidone (PVP) hydrogels

Answer 274

A = erodable polymer containing drug B = backing sheet C = gelatin strips

Answer 275

Why? - Colon cancer - Crohn's disease - Ulcerative colitis

Answer 276

Surface area = 0.2 m2 - No villi, mucosal surface is flat with deep crypts - Wider lumen Access via the oral route - require a delayed release system - or coated system that is only soluble in the colon Limited water content of the transverse and descending proportions of the colon First pass metabolism

Answer 277

- Prolonged residence time - Reduced enzyme secretions - Responsive to absorption enhancers

Answer 278

- Many and diverse bacteria - Anaerobic - Fermentation - SCFA production) - Bacterial enzymes - Eg 5-aminosalicylic acid - Caution with the concomitant use of antibiotics - Disrupt colonic microflora

Answer 279

- Sulphasalazine prodrug | - L18, pg 32

Answer 280

- See Lecture MD17 - Poly(methacrylate) polymers - Coatings for dosage forms - Polymer solubility is pH dependent

Answer 281

- Treating a disease/condition by generating or augmenting an immune response against it = Active Immunotherapy - Using a components of the immune system to treat disease = Passive immunotherapy

Answer 282

Pros - Targeted and specific - Effective - Less toxic - Different and complementary mechanisms of action Cons - Expensive - Complex - large molecules, cell based therapies, bioavailability - Off target effects

Answer 283

INAPPROPRIATE immune responses - Exogenous substances/antigens - eg allergies/atopy (asthma, food allergies, dermatitis), celiac disease - Endogenous substances/antigens = autoimmune or inflammatory diseases - eg rheumatoid arthritis, inflammatory bowel diseases, psoriasis, type 1 diabetes, multiple sclerosis, gout, heart disease

Answer 284

FAILED immune responses - Cancer - Infection

Answer 285

NON-IMMUNOLOGICAL diseases - Diseases where pathology is mediated by a specific substance can be treated with antibodies - eg addiction, high blood pressure (STILL EXPERIMENTAL)

Answer 286

Addiction therapy

Answer 287

Have a wee look @ L31, pg 2 - Passive - Active

Answer 288

Used to treat - Haematological conditions - deficiencies (SCID, aplastic anemia) and malignancies (cancer - CML, AML, ALL< NHL, HD) - Non-haematological conditions - Alzeimers disease, burns, stroke, solid tumors, osteoarthritis, diabetes - MHC matching required on transplants will be acutely rejected - Chronic rejection common, patients on life long anti-rejection therapy

Answer 289

Sources of stem cells 1) Bone marrow (BMT) - cells taken from hip, general anaesthesia required 2) Peripheral blood stem cells (PBSC) - cells taken by leukapheresis, pre-treatment with cytokine required 3) Cord blood - waste product, taken from umbilical cord after delivery, fewer cells, very naive, less risk from infection

Answer 290

- Has both elements of private and public banking - Several; models available - All retain part of the blood sample for family use (new/experimental ex vivo expansion techniques now mean this is viable) - Rest is searchable for public use - Variable requirement for consent to be sought from family if the CB is matched to a patient - Costs to families reduced

Answer 291

Advantages - Personalised - Little toxicity - Ability to genetically engineer cells ex vivo Disadvantages - Complex - Autoimmunity - Expensive - Complex

Answer 292

- Genetically engineered T cells - have an antibody-like receptor (more specific, readily activated) - Can be very effective - Expensive - Immune related adverse events (IRAEs) common

Answer 293

- 53 adults - 83% complete remission - Median overall survival of 12.9 months - Low disease burden median survival 20 months & less toxicity - Severe adverse effects - 26% patients

Answer 294

- Antibodies and cytokines that modify (amplify or downregulate) immune responses - Vaccines that modify immune responses

Answer 295

Antibodies - Modify (amplify or downregulate) immune responses) - Approved for use in inflammation, cancer, autoimmunity - Latest in cancer is checkpoint blockade inhibitors, highly promising - but issues with cost, toxicities, size

Answer 296

- Common with checkpoint blocking antibodies, CAR T cells - AEs were reported - fatigue, chills, rashes, diarrhea/colitis, pancreatitis, perforation, hepatitis, tumor liquefaction - Several large studies reported increased efficacy in patients affected by irAEs

Answer 297

Adalimumab (humira) - Anti-TNF - #2 of the top drugs by $$$ in NZ in 2017 - Supplied as pre-filled syringes for s.c. injection - used in treatment of - arthritis (rheumatoid, juvenile, psoriatic), ankylosing spondylitis, Crohns disease, Ulcerative colitis, Psoriasis - Side effects - increased risk of serious infection, increased risk of some skin cancers, reduced risk of heart disease

Answer 298

Vaccines - All types from whole cells, lysates, peptides - Limited benefit in cancer due to immune-supressive effects of tumor, better vaccine & combination therapy required

Answer 299

- Targeted delivery - Combination therapies with drugs to reduce tumor immunesuppression & T cell exhaustion - eg checkpoint inhibitors, chemo-drugs & anti-inflammatories

Answer 300

Cytokines - Delivered by i.v or s.c injection/infusion - Issues with short half life and systemic toxicities

Answer 301

Could be important for drugs which - Have a time-dependent mechanism of action eg some cytotoxic drugs, antibiotics - Are unstable (short half life) - Need continuous exposure - need multiple short periods of exposure

Answer 302

Could be important for drugs which are: - Highly toxic, narrow therapeutic window - Readily metabolized - Readily excreted - Concentration-dependent mechanism of action

Answer 303

- Amount of time above the therapeutic level more important than peak drug concentration - eg. some classes of antibiotics and cycle specific cytotoxic cancer drugs

Answer 304

- Peak concentration is more important than time above therapeutic level - Non-cycle specific cytotoxic drugs (chemotherapy) & concentration-dependent killing antibiotics - 'Log kill' agents

Answer 305

When would you want to control release in vivo? | - some graphs on L19, pg 2

Answer 306

using nano-scale materials for therapeutic benefit to modify: - Kinetics of release (temporal control) - Sustained, pulsatile - Location of release (spatial control) - crossing barriers (eg BBB, c)ell membrane, nuclear membrane), tissue site (eg tumor) To inc. therapy efficacy and decrease side effects (drug toxicity, antibiotic resistance

Answer 307

- increase solubility - Protect active(s) - Co-delivery of multiple drugs - To control time of release (temporal) - To control location of release (spatial)

Answer 308

- Size - EPR effect - Shape - Chemistry - hydrophilic or hydrophobic (increased cell uptake), charge (+ve charge increases cell uptake)

Answer 309

- The immune system has evolved to recognise and take up nm-um complexes - Bad for drugs, good for vaccines - Commonly use 'stealth' technologies eg coating with poly (ethylene glycol) = PEGylation

Answer 310

- But does depend on pressure inside tumor - may get leakage back out of the tumor into the blood vessel

Answer 311

- Half life of Peg-Dox is 55 hours compared to 10 min for Dox, so does not need to be given by continuous infusion (CI)

Answer 312

- Patients treated with Peg-Dox arm experienced fewer infectious and cardiac events than patients in the CI-Dox arm - Hematologic toxicity was moderate and reduced in the Peg-Dox arm

Answer 313

- Peg-Dox was associated with lower toxicity but did not improve survival due to a higher rate of induction failure and higher cumulative incidence of relapse - Still room for improvement ..... active targeting, controlling release

Answer 314

- Antibodies - high selectivity and binding affinity - Aptamers (short single-stranded DNA or RNA) - selectivity & binding similar to antibody (newer) - Ligands - peptides & small molecules, must have high selectivity & avidity

Answer 315

- Delivering drug in a nanoformulations can increase circulation time and sustain release, if can avoid uptake by the immune system - Release will depend on particle composition & stability can be via - Diffusion - Osmotic pumping - erosion

Answer 316

1. Burst of drug at/near surface 2. Slow release by diffusion 3. Burst due to erosion, breakdown, degradation

Answer 317

- Stimuli responsive nanoformulations - Release drug upon exposure to an endogenous or exogenous stimuli - eg thermodox

Answer 318

- eg H2S triggered release of DOX from polymeric responsive nanoparticles

Answer 319

- A drug administered to the body will be absorbed from the input site and then distribute around the body and finally be eliminated by (usually) the kidneys or liver

Answer 320

- Absorption - Distribution - Metabolism - Excretion

Answer 321

Warfarin conc.-time data - L20, pg 7 ADME over time - L20, pg 8 Clinical Pharmacology - Pharmacokinetics - Pharmacodynamics - Diagram - L20, pg 10

Answer 322

- The oft quoted raison d'etre of "clinical" pharmacy is to ensure that the RIGHT PATIENT receives the RIGHT DOSE of the RIGHT DRUG by the RIGHT ROUTE using the RIGHT FORMULATION at the RIGHT TIME - CLinical pharmacokinetics is all about determining the right dose rate

Answer 323

- The most important aspect from a dosing viewpoint is to achieve a desired concentration at the site of action for the desired period of time - However since the concentration of drug at the site o action is often unknown or theoretical it is usual to measure the plasma (or blood or serum) concentration of drug as a surrogate of this effect-site concentration

Answer 324

- Most drug movement processes are due to passive diffusion, therefore the driving factor is concentration - This means that the higher the concentration the greater the amount that crosses the membrane - until equilibrium is reached - This concentration-dependent process is termed first-order (most drugs) - if the movement was active, eg independent of concentration, then it would be other than first-order (eg Michaelis-Menten or Zero-order)

Answer 325

- The higher the concentration the faster the rate of elimination (slope) - Lower concs have slower rate of elimination (slope)

Answer 326

- The rate of elimination is independent of the concentration

Answer 327

- In the simplest model we describe the body as a box (compartment) into which all drug is administered and from which drug is eliminated

Answer 328

Dose -> Absorption -> distribution -> Elimination

Answer 329

- If the elimination rate of a drug is dependent on the conc. and is always changing

Answer 330

The slope of the straight line (on log scale) is the elimination rate constant - The slope of the log transformed data is the elimination rate constant (k)

Answer 331

L20, pg 23 &24

Answer 332

- The elimination rate constant is constant | - The rate of elimination is almost never constant

Answer 333

- The rate of elimination [RE] (mg/h) is a variable that, for drugs that display first-order PK, constantly changes over time - the elimination rate constant [K] (/h) is a constant that describes the relationship b/w the amount of drug in the body [A] and the rate of elimination for drugs that display a first order process therefore, RE = A x k

Answer 334

- The rate constant of elimination can be used to determine the half-life of the drug

Answer 335

- Clearance is a CONSTANT that describes the relationship b/w the plasma drug concentration (C) and rate of elimination (RE) - C has units of Mass/volume (eg mg/L) - RE has units of mass/time (eg mg/h) - CL is the ratio of RE to C ie - CL = L/h

Answer 336

A constant relating the rate of elimination to the plasma conc. (C) - RE (mg/h) = CL (L/h) x C (mg/L)

Answer 337

- Dose rate (mg/h) = water from tap - plasma conc. (mg/L) = volume of water in bath - Clearance (L/h) = size of plug hole - Rate of elimination (mg/h) = water draining from bath

Answer 338

- the driving force for drug elimination is the concentration in the plasma - The rate that water can drain from the bath at any time is the product of the volume of water and the size of the plug hole: - rate of elimination from bath = volume x plug hole size in PK terms RE = C x CL

Answer 339

hence RE = MD (maintenance dose rate) therefore: - MD (mg/h) = CL (L/h) x Css,ave (mg/L)

Answer 340

- for any drug dosed to steady state the only PK parameter that is needed to describe the relationship b/w dose rate and average plasma conc. is clearance - Since most drugs are dosed on multiple occasions (ie to steady state) then CL is the most important PK parameter - But CL has weird units volume per time (L/h)

Answer 341

The most common definition of CL is: - "the volume of blood cleared of drug per unit time" averys drug treatment pp9 In essence this is meaningless by virtue that it is impossible to completely clear a portion of blood completely of drug - However, this description does show the units are volume per time (eg L/h)

Answer 342

- Measure the conc. from the afferent artery | - Measure the conc. from the efferent artery

Answer 343

- Extraction is the fraction of drug that is removed from a single pass through the organ (eg liver) - To compute clearance we need to consider how much drug gets to the organ - Since drug is carried in the blood then this can be done by considering the perfusion of the organ (Q) hence - CL = Q (L/h) x E (no units) - ie clearance is the product of the perfusion and the intrinsic ability of the organ to eliminate the drug

Answer 344

- Equations in L21, pg 19

Answer 345

L21, pg 20

Answer 346

- This is the theoretical maximum rate at which a drug can be cleared if all the drug were present in the liver (ie if QH = infinite) - it is proportional to the maximum rate at which the drug can be metabolised (Vmax) and inversely proportional to the affinity of the drug for the enzyme (Km)

Answer 347

High CL is defined as CL >/= 1/2Q Low CL is defined as CL < 1/2 Q

Answer 348

This is the most meaningful physiological relationship since: - Any pathology that reduces organ perfusion (eg heart failure) will reduce clearance - Any pathology that reduces organ function (eg acute tubular necrosis) will reduce clearance

Answer 349

- Most organ systems in the body run in parallel - this means that the overall clearance is additive - Hence: CL (total) = CL(renal) + CL(liver) + CL(lung) + CL(bile) + ...

Answer 350

- We know from the equation MD = CL x Css,ave - Css,ave is the steady state average concentration (average over a dose interval) - We can know Css,ave exactly if we give a continuous infusion

Answer 351

- Most drugs are administered orally... | - Graph on L21, pg 29

Answer 352

- the average steady state concentration (mg/L) when multiplied by the dose interval (t) is the same as the area under the concentration-time curve (AUC) for the dose interval (0 - t)

Answer 353

- AUC is the area under the concentration-time curve - It represents the total systemic exposure of the body to a dose of drug - It may be estimated - L21, pg 31

Answer 354

- Forst lets compute the AUC - Divide the curve into trapezoids with area = base x average height - Add up the area within each trapezoid - The sum of the areas = the AUC

Answer 355

- The area in the trapezoid = the area in the rectangle | - Where the height is the average height of he trapezoid

Answer 356

L21, pg 36

Answer 357

Therefore if we can estimate AUC by doing an intensive PK study then we can get an estimate of CL - From an estimate of CL we can determine the best dosing regimen for an individual - From estimates of AUC from lots of individuals we can get estimates of CL and therefore estimate the variability in CL

Answer 358

- Volume of distribution is the APPARENT VOLUME into which a drug distributes with a concentration equal to that of plasma

Answer 359

Write this equation V = ammount added / Conc. = 10g / 1g/L - Consider repeating the experiment with charcoal in the container - L22, pg 10, pic

Answer 360

V = amount added / conc. = 10g / 0.01g/l - The apparent V is larger than the volume of the container since the drug is concentrated in the charcoal

Answer 361

You cannot tell from just knowing V whether it is evenly distributed throughout the body or concentrated in a small area

Answer 362

V = amount in body / Conc. = A(mg) / C(mg/L)

Answer 363

- idk bout this but - L22, pg 14 & 15 & 16 For digoxin - Digoxin concentrates in the myocardium and also distributes into striated muscle

Answer 364

- To estimate V requires knowledge of both A and C - The only time that A is known exactly is at time zero after an iv bolus injection A = dose ∴ V = dose / Co

Answer 365

- The amount od drug in the plasma C is a function of dose and time and V - C(t) = dose / v x e(-kxt)

Answer 366

- At time = 0 there is no concentration - The concentration and the amount in the body are both constantly changing - It is now much more difficult to estimate V

Answer 367

- if we know the volume of distribution of a drug then we can work out the dose needed to "fill-up" the body to achieve the desired target conc. - If we recall V is the ratio of the amount in the body to the plasma conc. - So if we needed a conc. of 10mg/L and we knew the volume of distribution was 20L then we know the dose must be 200 mg

Answer 368

Based on the previous calculation: - LD(mg) = V(L) x Ctarget(mg/L) Giving a LD will help achieve the target concentration quiker

Answer 369

- CL relates to the function of the body | - V related to the structure of the body

Answer 370

YES: for drugs that require rapid attainment of steady state (eg phenytoin, most antibiotics) NO: Loading doses should not be used for drugs that may cause toxicity associated with high Cmax concentrations (eg antidepressants, carbamazepine) - The pharmacology of the drug and patients clinical condition will dictate the need for a loading dose

Answer 371

Bioavailability - Relative amount of the administered dose of a drug that reaches systemic circulation from a certain dosage form in comparison to the amount that reaches the systemic circulation by iv administration Systemic availability Oral availability - For the oral route

Answer 372

"relationship b/w two preparations of the same drug in the same dosage form that have similar bioavailability - Not siscussed further here

Answer 373

EXTENT of drug reaching the systemic circulation - Cmax - Maximum observed conc. - AUC - Area under the conc.time curve RATE that drug reached the systemic circulation - Tmax - Time that maximum conc. (Cmax) is observed - Ka - Absorption rate constant

Answer 374

Oral administration - the same drug given as an oral tablet - Graph on L23, pg 9 (Absolute) bioavailability (F) - F = AUCoral/AUCiv - L23, pg 10

Answer 375

'Relative bioavailability' refers to a case where the intravenous dose is not the comparator Examples - comparing oral and rectal administrations - Comparing 2 formulations for the same drug given by the same route Requirements for a comparison of AUC's - Same drug and dose - Clearance must not change b/w the comparators - Linear pharmacokinetics (AUC is proportional to dose) - No other factors alter drug bioavailability (food, drug interactions)

Answer 376

1. Disintegration of the dosage form and dissolution of the drug 2. Absorption across the membranes in the gut wall 3. Pre-systemic metabolism (or ;first-pass') and elimination

Answer 377

F = fa x fh - L23, pg 14

Answer 378

- The ability of a drug to pass through a biological membrane - Drug factors that influence absorption from the gut may inlcude; - Lipophilicity - Solubility - Ionisation - pH of the gut - Patient factors that influence absorption from the gut may include; - Gastric emptying time and intestinal mobility - Food and drug interactions

Answer 379

- The metabolism or efflux of a drug prior to reaching the systemic circulation - Some drugs undergo a high first pass, so have a low F - Some are virtually eliminated before reaching the systemic circulation - eg glyceryl trinitrate (F <1%) - therefore not used orally

Answer 380

- Metabolism in the gut wall (eg oestrogens, atorvastatin) - Efflux from the gut wall (eg dabigatran) - Esterase metabolism in the plasma of the portal circulation (eg aspirin) - Metabolism in the liver (most common)

Answer 381

- Inactive metabolites inc. bioavailability | - This dramatic inc. in drug exposure, in some cases, causes toxicity

Answer 382

Graphs on grapfruit juice and felodipine L23, pg 21 Note: - Presystemic interactions occur because of enzyme inhibition in the gut wall. Therefore, drug interactions impact peak plasma conc. (Cmax) not clearance

Answer 383

Assuming complete absorption of intact drug into the portal circulation; - F = fh = 1 - hapatic extraction ratio (EH) - Recall; CL = Q(L/h) x EH - High EH means low F L23, pg 23

Answer 384

- Pharmaceutical product development - Different formulations - Generics (bioequivalence) - Different routes of administration - Clinical relevance - Explaining variability in drug response b/w people - Drug interactions - Food effects

Answer 385

- Variability in PK b/w people ↑↑ for high CL (low F) drugs - Recall; F = 1-hepatic extraction ratio (EH) - High CL (low F) drug; - A ~10% change in EH from 0.9 to 0.8, will double F - F = 1 - 0.9 = 0.1 - F = 1 - o.8 = 0.2 - Low CL (high F) drug; - A ~10 change in EH from 0.1 to 0.09, will have little impact on F - F = 1 - 0.1 = 0.9 - F = 1 - 0.09 = 0.91

Answer 386

- The time that it takes for the drug conc. (or the amount of drug in the body) to decrease by half - It is the most widely used and misused PK parameter

Answer 387

- recall that the elimination rate for a drug with first-order PK is 1. Dependent on the concentration, so is constantly changing 2. Is the tangent of the curve

Answer 388

- When logged the exponential decay curve becomes a straight line - The slope of this line is the elimination rate constant (k or sometimes ke) - We can use k to determine the half-life

Answer 389

- k = Cp1 - Cp2 / Δt

Answer 390

t1/2 = 0.693 x V / CL - half life will inc w/ V - Half-loife will decrease with CL

Answer 391

- easily confused, but they tell us different things Elimination rate is the AMOUNT of drug eliminated per unit time - Units: mass/time, eg mg/h - Not a constant for first-order drugs The elimination rate constant (k) is the APPROXIMATE FRACTION of drug eliminated per unit time, - Units: per time e.g. h-1 - k = 0.33 h-1 (ligocaine) can be interpreted as a (very) rough estimate of the percent of drug eliminated per hour, ie 33% of the drug is eliminated per hour

Answer 392

Tells us about - The time-coarse of elimination - The time-course and magnitude of drug accumulation (how long to reach steady-state?) - Choice of dose interval - Duration of action

Answer 393

- After 1 half-life, 50% of the drug has been eliminated - by 4 half-lives >90% of the drug has been eliminated - 10 half-lives is considered sufficient for wash-out

Answer 394

After 4 half-lives the drug will be approaching a steady-state - This is true when starting drug therapy, and when changing the dose - After 4 doses (4 half-lives), the drug has accumulated to 93.8% of steady-state

Answer 395

- The magnitude of drug accumulation is determined by the dose interval (tau) and half-life

Answer 396

Accumulation Index = 1 / (1 - e-k x tau) Given that Tau = 24 h and half-life of 336 h; Accumulation Index = (1 / 1 - e-(0.693/t1/2) x 24) Accumulation Index = 20

Answer 397

- Accumulation Index (nth dose) - Accumulation Index (3rd dose) L24, pg 16

Answer 398

- Dosing interval is a function of the dose, half-life, and EC50 (potency of the drug) - Dose interval CANNOT be determined using half-life alone - however, if there is a target concentration range then it is possible to determine the appropriate dosing interval to maintain concentrations in the range based on the half-life alone (this is not common)

Answer 399

- After a single dose, the longer the half-life the longer the concentration will remain in the target range - Increasing the dose is one way to extend the duration of action (eg anaesthetic induction) - Rule of thumb: doubling the dose will extend the duration of action by one half-life

Answer 400

1. Disintegration and dissolution of the drug 2. Physiology of gastrointestinal tract 3. Food or drug interactions in the gut lumen 4. Passage through the gut wall

Answer 401

Only dissolved drug can readily traverse the gut wall Will depend on; - The release characteristics of dosage form - Excipients, special dosage forms (enteric coated, slow-release) - Physiochemical properties of the drug - Partition coefficient (water or lipid solubility) - Particle size - Ionisation - Crystal form

Answer 402

Gastric emptying - highly variable b/w people - Fasting: ~1hr - Drugs in solution: 10 - 20 min - After eating: much slower (> 7 h in some cases) Small intestine transit time - much less variability - Often ~ 3hrs Gastric emptying time may impact absorption rate for drugs that readily dissolve in the stomach (paracetamol) or enteric coated drugs Insoluble drugs may have enhanced absorption if transit time is slow

Answer 403

Altered pH - Food alters stomach pH - Altered solubility, eg acid suppressants (PPIs) & dabigatran (dec absorption by about 30%) Complexation - With di- and trivalent ions (Ca2+, Mg2+) in antacids (eg interactions with alendronate, quinolone antibiotics)

Answer 404

- Passive diffusion - Paracellular - Convective (pore) transport - Carrier-mediated transport - Facilitated transport - Active transport - Ion-pair transport - Endocytosis

Answer 405

- The primary absorption process for most drugs - The driving force is a conc. gradient across the membrane - Drug diffuses from high conc. to low conc. - After oral drug administration, when drug is reaching the gut lumen, the conc. in the gut will be much higher than in the plasma

Answer 406

rate of flux = f (D,SA,K,h,(C1-C2) D = diffusion coefficient SA = surface area K = Partition coefficient h = membrane thickness C2 = conc. gradient

Answer 407

Drug properties that determine permeability; - Molecular size - Small ions (eg urea, K+) can cross membranes paracellularly - Proteins do not readily cross cell membranes (so protein bound drug will not cross membranes - see L() - Lipophilicity - Determined by the n-octanol/water partition coefficient - Charge (ionisation) - Determined by pH, pKa etc

Answer 408

- Gaps b/w cells in the gut wall are very tight - A very small surface area (0.01% of the absorptive area) - Small polar drugs, eg alcohol

Answer 409

- no input of energy required - Movement is down a concentration gradient - Transporters involved are highly selective - Many endogenous compounds (eg glucose) - Example; gut absorption of vitamin b12

Answer 410

- May be AGAINST a concentration gradient - Energy is required - transporters are saturable and can be competitively inhibited (drug interactions) - include efflux transporters (eg P-glycoprotein) that limit drug absorption from the gut

Answer 411

- Oral absorption often approximates first order PK behaviour - ka is the first-order absorption rate constant - ka is similar in concept to the elimination rate constant (k) - A ka of 0.5 has units h-1 and indicates that 50% of the remaining drug in the gut will be absorbed every hour The absorption half-life = t1/2 = 0.693/ka

Answer 412

L25, pg 23

Answer 413

- If the drug is absorbed across the gut at a constant rate, then it will follow zero order absorption - The rate of absorption will be INDEPENDENT of the amount of drug remaining in the gut lumen - Similar to an IV infusion (see tutorial 1) - May occur because of saturable transporter process or due to slow release from the dosage form (eg sustained release tablet)

Answer 414

First order - Tmax is determined by ka Zero order - Tmax is determined by the input rate and duration

Answer 415

- Occurs when the half-life of absorption is longer than the elimination half-life - or more corectly; ka << k

Answer 416

- The REVERSIBLE interaction of a drug with protein in plasma - Almost all drugs are bound to plasma proteins to some extent - Drug-protein complexes are large and do not readily cross membranes therefore only the unbound drug is available to interact with receptors or can be eliminated - Rate of drug binding are very rapid (milliseconds)

Answer 417

Albumin - quantitatively most important a1-acid-glycoprotein - acute phase reaction protein Lipoproteins Specific protein types (eg thyroxine binding globulin etc

Answer 418

- Generally acidic drugs bind more avidly to albumin - There are two main binding sites on albumin (sites I and II) - substrates include - Type I: Warfarin, sulphonamides, NSAIDs, valproate - Type II: penicillins, benzodiazepines, probenecid - Drugs that bind to the same site might be expected to competitively displace each other

Answer 419

- Binding to this protein is quantitatively less important - the concentrations are typically 1/100th that of albumin - This is a reactive protein that may increase several fold in the presence of acute inflammatory conditions (eg myocardial infraction) - It mostly binds basic drugs (eg lignocaine)

Answer 420

- Most drugs reversibly bind to proteins via electrostatic forces - Irreversible binding is much less common and results in inactivation of the drug, eg cisplatin

Answer 421

- Often used interchangeably. They are not the same

Answer 422

- Binding to protein is theoretically a saturable process governed by mass action (as with ligand binding to receptors) - Drug binding to albumin is rarely saturated - albumin conc. are much higher than the drug conc. (exceptions L26, pg 10)

Answer 423

For a few drugs the clinically used doses may be sufficiently large to saturate the protein binding sites for the drug - Some beta-lactam antibiotics (eg ceftriaxone) - Corticosteroids (eg prednisolone) - Valproate The upshot is that the free concentration for these drugs may be much greater than expected

Answer 424

* Decreased number of binding sites - Due to reduced protein conc. - Occurs because of; 1. Decreased dietary protein intake (malnutrition, cachexia) 2. Decreased protein production (liver failure, ageing) 3. Increased protein elimination (eg loss via the kidneys in nephrotic syndrome) * Decreased apparent binding affinity - This may be caused by a competitive reversible drug interaction where one drug displaces another from its binding site

Answer 425

graph on L26, pg 12

Answer 426

- Clinically irrelevant in most cases - May alter volume somewhat - The problem of drug interactions and displacement of drug from binding sites has been grossly overstated

Answer 427

- In the 1960's, reports of bleeding when warfarin was used with the NSAID, phenylbutazone - In vitro studies showed that phenylbutazone displaced warfarin from its protein binding site - Conclusion: increased FREE FRACTION of warfarin = increased anticoagulant effect Three problems 1. A test-tube is not a dynamic system - does not reflect biology 2. Phenylbutazone actually inhibits warfarin metabolism (real mechanism of the interaction) 3. Free Fraction is irrelevant (it is the free concentration we are interested in)

Answer 428

Results in - Increased free fraction - Unchanged free concentration - reduced total concentration - Clinically IRRELEVANT in most cases except when interpreting plasma concentrations (eg therapeutic drug monitoring)

Answer 429

What we assume happens - Proteinbinding displacement or reduced availability of albumin - This is what happens in a test-tube What actually happens - No Δ Cpfree

Answer 430

L26, pg 20 & 21

Answer 431

- IV-Bolus | - Extravascular administration

Answer 432

- Drugs are often given in multiple doses to treat short-term and chronic illnesses - Multiple dosing help maintain the drug conc. within a target conc. range (therapeutic window) - Therapeutic window is the drug conc. range above the minimum effective conc. (MEC) and below the minimum toxic conc. (MTC)

Answer 433

- Cp - Onset of effect - Lag period - Peak effect - Duration of action - MEC adverse - MECdesired

Answer 434

- Faster absorption - Larger dose - Control curve from panel A - Faster elimination

Answer 435

- Drug exposure metrics are parameters that describe various measures of drug concentration in th body (eg blood, plasma, serum) - Commonly used exposure metrics include Cmax, Cmin, Css, Css,avg, & AUC

Answer 436

- Clinically, multiple doses are referred to as maintenance doses - At steady state - the rate of drug elimination = the rate of drug dose - So to maintain a target conc. at steady state you need to account for drug clearance so that MD = CL x Css,avg mg/h = L/h x mg/l

Answer 437

Accumulation | - Graph on L27, pg 15

Answer 438

- Drug conc. after multiple doses can be calculated by adding together the concentrations from each dose (each previous dose and the current dose) - Also, doubling the dose will result in the concentrations at each time doubling - Assuming linear pharmacokinetics

Answer 439

- AUC is a useful drug exposure metric and can be used to adjust doses in order to meet a desired target exposure (eg target AUC of 85 mg.h/L for gentamicin) - Following a single dose, AUC0-infinite can be calculated using the trapezoidal method (and is a function of dose and CL) - Following multiple dosing, AUC0-infinite after the first dose equals AUC0-t at steady state

Answer 440

- So we can use the AUC0-infinite after first dose to estimate steady state AUC and thus the Css,avg - Also, Css,avg is the same whether a dose is given every dosing interval or subdivided into shorter dosing intervals - Eg 300 mg q12h and 100 mg q4h will result in the same Css,avg

Answer 441

- You may recall that dosing interval is a function of the dose, half-life, and C50 (drug potency) - However, if there is a target exposure metric then it is possible to determine the appropriate dosing interval to maintain concentrations in the target range based on dose and half-life alone

Answer 442

- if we know the volume of distribution of a drug then we can work out the dose needed to 'fill-up' the body to achieve the desired target concentration - So to achieve the target quickly we can give a loading dose ``` LD = V x Ctarget mg = L x mg/L ```

Answer 443

It depends - The pharmacology of the drug and the clinical pictures will dictate the need for, amount, and schedule of a loading dose - If you need FIRST dose to reach steady state - First dose = MD / 1 - e-kxt) - If you need FIRST dose to only "load" the body: - LD = V x Ctarget

Answer 444

Clinical Scenario 2: Loading dose (vacomycin) - So here the MD is given one dosing interval (ie 6 hours) after the LD - A large first dose is not needed and will potentially result in toxic effects - L27, pg 26

Answer 445

- The dosing frequency will depend on both the half-life and the therapeutic window - This is the dosing frequency required to control the conc. peak-trough ratio during dosing - half-lives explain this - Card L27, pg 28 & 29 & 30

Answer 446

These drugs can be given every half-life (t = t1/2) - Eg ocycodon - opiod, half-life ~6h, given q6h (SR formulation given less frequently) If immediate achievement of steady state is needed then first dose should be double the MD First dose = MD/0.5 = 2 x MD

Answer 447

- These drugs can be given once daily (eg azithromycin or sirolimus) - Others with very long half-lives can be given once weekly (eg mefloquine) - Sometimes a loading dose (or doses) may be clinically indicated (eg amiodarone)

Answer 448

- 'Linear' in PK refers to first-order processes - Although the parameters are non-linear, the change in C is proportional to a change in Dose linear - Dose adjustments are proportional to the target exposure

Answer 449

- Cam, a child with cystic fibrosis, is to receive once daily gentamicin for a chest infection. His first dose was calculated to be 100 mg (5 mg/kg). - His AUC after the first dose was estimated to be 60 mg.h/L - ie 100 mg AUC of 60 mg.h/L - How much should his next dose be?

Answer 450

- The change in C is 'not' proportional to a change in dose = Non-linear behaviour occurs usually because of saturation of carrier-mediated processes, eg rate and/or extent of metabolism

Answer 451

- AUC is disproportional to dose - (in linear PK, Dose = CL x AUC) - Steady-state concentration is disproportional to dosing rate - (in linear PK), MD = CL x Css) - Estimated PK parameters (eg t1/2, CL) are different at different doses and/or plasma drug conc. - (in linear PK, CL, V, ka are constant)

Answer 452

- Refers to non-linear metabolism/elimination - Describes drug concentration when the enzymes responsible for drug metabolism/elimination become saturated and the maximum rate of metabolism (Vmax) for the drug is approached - The serum concentration at which the rate of metabolism equals Vmax/2 is km

Answer 453

- the M-M function specifies the rate of an enzymatic reaction as a function of the substrate concentration - Vmax is the maximum possible reaction rate that can be achieved - Km is the value of C at which half the Vmax is achieved - The value of km is useful because non-linearity is usually 'visible' when C is >> km - The M-M parameters (ie constants) Vmax and km help determine the dose rate needed to maintain a target Css or AUC.

Answer 454

- Some drugs have 'time-dependent' non-linear metabolism - Instead of CL changing with a change in dose or conc., CL changes w/ time - Notable example is carbazepine which undergoes auto-induction - Clinical implications: starting with the MD will result in toxic conc. (drowsiness, tachycardia, coma). - Need to start low and go slow

Answer 455

L28, pg 22 & 23

Answer 456

- Some drugs require transporters to carry drug molecules from the lumen of the gastrointestinal tract to the portal circulation - eg amoxicillin, vitamin B12 - Some drugs have dissolution limitations. As the dose increases, less of the dose can dissolve sufficiently to be absorbed - eg steroids - Some drugs that are metabolised by a first-pass effect in the gut wall display non-linear absorption. As the dose increases, the enzymes responsible for the first-pass affect are saturated leading to higher systemic bioavailability

Answer 457

- Glomerular filtration is essentially "capacity-unlimited", that is first-order (linear) elimination - However, tubular secretion is saturable because the carrier systems are capacity-limited and can be competitively inhibited - eg probenecid used to reduce renal CL and increase blood conc. of penicillin (which has a short half-life)

Answer 458

``` Chemical influence on cells to produce a response # cellular molecules > # drug molecules ``` Non-uniform distribution of drug molecules "Corpora non agunt nisi fixata" - A drug will not work unless it is bound

Answer 459

most drug targets are proteins - Receptors: Classical site of action - Enzymes - Carrier molecules (transporters) - Ion channels Exceptions - Antitumor and antimicrobial drugs (DNA) - Bisphophonates (bone calcium)

Answer 460

- Part of communication system to coordinate activities of cells - Recognise specific drugs (ligands) and cause an effect

Answer 461

Drugs that bind to physiological receptors mimic endogenous signalling molecules - eg opiates (like morphine) mimic endorphins - Occupation governed by AFFINITY AGONISTS have affinity & efficacy ("copies") - Activation governed by EFFICACY ANTAGONISTS have affinity but no efficacy ("prevents")

Answer 462

- For a drug to be useful it must act selectively on cells and tissues - High degree of binding site specificity - Specificity is reciprocal Eg angiotensin - Vascular smooth muscle and kidney - No effect on other smooth muscle - Small chemical change (single AA) can inactivate the molecule (R cant bind altered form)

Answer 463

- Complementary specificity is central to explaining many events in pharmacology - BUT: No drug acts with complete specificity - Tricyclic antidepressants (TCAs) - Block monoamine transporters - Lower potency -> higher [drug] - -> off target effects (= side effects)

Answer 464

- Potency is DIFFERENT from efficacy | - Graph on L29, pg 15

Answer 465

The effect of a drug can gradually diminish when it is given repeatedly - Occurs in minutes (tolerance occurs over days or weeks) Due to: - Exhaustion of mediators - Change or loss of Rs - Increased metabolic degradation - Physiological adaptation

Answer 466

Many drugs alter - Neurotransmitter synthesis - Storage in vesicles - Release into the synaptic cleft/removal - Transport into pre/post synaptic neurons Enhance or diminish neurotransmitter effects -> therapeutic effect

Answer 467

- Lil diagram on L29, pg 20

Answer 468

A small number of drugs: - Affect ionic environment of blood, urine, GI tract - Act via ion pumps, transporters (specialized cells in kidney, GI tract) - -> effects throught body (Δ blood electrolytes, pH)

Answer 469

Therapeutically important target - Gastric parietal cells eg omeprazole (Losec) - Irreversible inhibitor - dec. gastric acid secretion by 80-95% - Peptic ulcer disease

Answer 470

- Alterations in Rs and signalling effectors -> disease - Loss of R in a specialized signalling system - dec. androgen R -> testicular feminization syndrome - Loss of widely employed signalling pathways - eg autoimmune depletion of N2AChRs in myasthenia gravis

Answer 471

- eg bronchodilator drugs for asthma | - Eg antidepressants

Answer 472

rapid - Change in heart function Slow (mins-hours) - Change in functional state of Rs (desensitisation) Slower (hours-days) - Changes in gene expression - > Long term changes in cardiac structure and function (hypertrophy)

Answer 473

- Drugs act on cellular targets to produce effects at different functional levels (biochemical, cellular, physiological and structural) - The direct effect of the drug on its target produces acute responses - Prolonged R activation leads to delayed long term effects - Long term delayed responses result from changes in gene expression - Therapeutic effects can be based on acute responses or delayed responses

Answer 474

Depends on components which regulate or are regulated by a [Ca2+] free cytosolic 1. Ion channels/transporters 2. Storage and release by organelles 3. Ca2+ dependent regulation by enzymes, contractile proteins, vesicle proteins

Answer 475

- Ca2+ sequestered in organelles - Free Ca2+ concentration, [Ca2+]i = 10-7M Ca2+ in tissue fluid, [Ca2+]0 = 24 mM - Gradient favours Ca2+ ENTRY Regulation 1. Control of entry 2. Control of extrusion 3. Exchange between cytosol and i.c. stores

Answer 476

Voltage gated Ca2+ channels (L, T, N, P, R) - Allow Ca2+ entry when cell is depolarize - L: cardiac muscle contraction, N, P: neurotransmitter release - eg Nifedipine, verapamil, diltiazem (CV), gabapentin (epilepsy, pain) Ligand gated channels - Non selective - eg NMDA type glutamate R -> excitotoxicity SOCs (Transient Receptor Potential channel family) - Open when ER stores are depleted - Linkage unknown - No current drugs: potential as smooth muscle relaxants

Answer 477

- Energy for Ca2+ extrusion comes from electrochemical gradient for Na+ - dec. gradient (dec Na+ in) = dec Ca2+ extrusion = 2* rise in [Ca2+] - Important in cardiac muscle eg digoxin

Answer 478

1. Inositol triphosphate receptor (IP3R) - Activated by IP3 (2nd messenger produced by activation of GPCRs) This is how GPCRs inc [Ca2+] 2. Ca2+ -induced Ca2+ release - Ca2+ ions also released by Ca2+ itself acting on ryanodine Rs (RyRs)

Answer 479

Neurons and muscle cells - Propagation -> long distance, high speed communication Cardiac/smooth muscle: - Spontaneous, rhythmic activity Gland cells - Amplify signal that causes call to secrete Ion channels are important drug targets

Answer 480

Disorder: Type II diabetes - Pancrease can't produce enough insulin to control blood glucose levels Treatment: Oral hypoglycaemics (sulphonylureas) - eg glibenclamide, glipizide Promote insulin secretion from B cells

Answer 481

Sulphonylureas - Bind to and block ATP-sensitive K+ channels - Depolarisation (no K+ exiting) - Opens voltage gated Ca2+ channels - inc [Ca2+]i --> insulin secretion Then what happens? - Insulin binds to R (1); - Protein activation cascade initiated (2); - Glut4 translocated to membrane, glucose influx (3); - Glycogen synthesis (4) - Glycolysis (5) - Fatty acid synthesis (6)

Answer 482

Molecular basis of contraction is similar - Interaction between actin and myosin - Fueled by ATP - Initiation by inc. [Ca2+] Differences in skeletal, cardiac & smooth muscle - a. Linkage between membrane event and inc. Ca2+ - b. Mechs by which Ca2+ regulates contraction - -> different responsiveness to drugs

Answer 483

- Disorder: Atrial Fibrillation ``` - Treatment: Calcium channel blockers (non-dihydropyridines) eg verapamil, diltiazem (class IV) ``` - Slow conduction through AV node --> ventricular rate control

Answer 484

Class IV agents - Bind to L-type (slow) Ca2+ channels - Dec. frequency of opening - No Ca2+ release from internal stores - No stimulus for contraction coupling - Slow AP conduction in AV node - Reduce ventricular contractility

Answer 485

Much of pharmacology based on interference with - Neurotransmitters - Hormones - Inflammatory mediators Ca2+ plays a central role in release mechanism - Drugs affecting control mechanisms that regulate [Ca2+] ---> affect mediator release

Answer 486

- L30, pg 24

Answer 487

- SNARE proteins (synaptobrevin) essential for docking and fusion of vesicles - Ca2+ necessary for neurotransmitter release

Answer 488

Disorder: Epilepsy - Sudden abnormal and excessive firing of neurons --> seizures (Excitatory neurotransmission . inhibitory) Treatment: Gabapentinoids eg gabapentin, pregabalin - Modulates release of excitatory neurotransmitters

Answer 489

Gabapentin structurally related to GABA But doesent bind to GABA Rs --> no effect on GABA transmission - Binds to voltage gated Ca2+ channels - Less available for vesicle docking - dec release of excitatory neurotransmitters Less propagation, prevents seizures (also effective for neuropathic pain)

Answer 490

- [Ca2+]ic is a critical regulator of cell function - Link between drug interacting with a molecular target and its physiological response - Excitable cells generate APs in response to membrane depolarisation - Drugs that inhibit Ca2+ channel function reduce excitability - Muscle contraction occurs in response to a rise in [Ca2+] - Drugs that inhibit Ca2+ channel function reduce contractility - Exocytosis (principal mechanism of neurotransmitter release) occurs in response to inc. [Ca2+] Drugs that inhibit Ca2+ channel function reduce NT release

Answer 491

- Over 100 billion NEURONS and 10-50 times that number of support cells (called NEUROGLIA) are organized into two main subdivisions: The central nervous system (CNS) The peripheral nervous system (PNS)

Answer 492

- A somatic nervous system (SNS) - An autonomic nervous system (ANS) - An enteric nervous system (ENS)

Answer 493

- The ANS controls involuntary functions that are critical for survival eg. regulates heart rate, digestion, respiratory rate, pupil dilation, and sexual arousal - ANS is located in the medulla oblongata - The hypothalamus acts to integrate autonomic functions and receives feedback from the limbic system to do so (hypothalamus)

Answer 494

Sympathetic nervous system - General action is to mobilise the bodys nervous system fight or flight response; it is also constantly active at a basal level to maintain homeostasis Parasympathetic nervous system - Regulates organ and gland functions during rest and is considered a slowly activated, dampening system. (rest and digest or feed and breed) - As a rule, the SNS functions in actions that require quick responses, while the PSNS is initiated in actions that don't require immediate response

Answer 495

1. A SENSORY function detects internal and external stimuli 2. An INTERCEPTION is made (analysis) 3. A motor RESPONSE occurs (reaction)

Answer 496

NEURONS - Are the real 'functional unit' of the nervous system, forming complex processing networks within the brain and spinal cord that bring all regions of the body under CNS control NEUROGLIA - Though smaller than neurons, greatly outnumber them. They are the "glue" that supports and maintains the neuronal networks

Answer 497

- A neuron, also know as a neurone and nerve cell, is an electrically excitable cell that receives, processes and transmits information through electrical and chemical signals

Answer 498

Target cells = 1. Muscles cells 2. Glands 3. Other neurons

Answer 499

SENSORY NEURONS - Carry signals from the outer parts of your body (periphery) into the central nervous system INTERNEURONS - Connect various neurons within the brain and spinal cord (entirely within the CNS) MOTOR NEURONS - Carry signals from the central nervous system to the outer parts (muscles, skin, glands) of your body

Answer 500

- Stimulus - Sensor/receptor - Integrating center - Efferent pathway - Effector

Answer 501

- An action potential is the nervous impulse or signal for long distance communication. Each action potential is generated at the cells trigger zone - Action potentials are considered an all-or-nothing phenomena because they are either generated or not - The generation of an action potential is dependent on the strength of its stimulus

Answer 502

An AP has two main phases: - A depolarizing phase - A repolarizing phase - Refactory period, cant re-stimulate

Answer 503

- Synapse is the connection region between two neurons which spreads the action potential - Synapse facilitates the signal transmission from the axon of a presynaptic neuron to dendrites of the post synaptic neuron or the target neuron - Signal occurs via chemical messengers called neurotransmitters

Answer 504

1. AP reaches the end bulb of axon terminals 2. Voltage-gated Ca2+ channels open and Ca2+ flows inward 3. Ca2+ influx triggers release of the neurotransmitter 4. the neurotransmitter crosses the synaptic cleft and binds to receptors 5. Ligand-gated receptors on the postsynaptic membrane

Answer 505

1. Both excitatory and inhibitory neurotransmitters are present in the CNS and PNS 2. The same neurotransmitter may be excitatory in some locations and inhibitory in others 3. Neurotransmitter effects can be modified in many ways

Answer 506

- A ganglion is a collection of cell bodies in the peripheral nervous system - There are millions of synapses located in a ganglion - Ganglia are connected with each other and form a complex of ganglia known as plexus - Ganglia provide relay points and intermediary connections between neurons of the nervous system

Answer 507

DORSAL ROOT GANGLIA - (also known as the spinal ganglia) contain the cell bodies of sensory (afferent) neurons CRANIAL NERVE GANGLIA - Contain the cell bodies of cranial nerve neurons AUTONOMIC GANGLIA - Contain the cell bodies of autonomic nerves

Answer 508

table on L32, pg 22 - Maybe read over

Answer 509

- Both the parasympathetic and sympathetic divisions are TWO-NEURON systems with the first neuron named either PRESYNAPTIC or PREGANGLIONIC and the second nerve called POSTSYNAPTIC or POSTGANGLIONIC - The organs innervated by the autonomic nervous systems are called EFFECTOR organs

Answer 510

If cholinergic - Muscarinic receptors - Nicotinic recceptors If Adrenergic - Alpha receptors - Beta receptors

Answer 511

Adrenalin, Noradrenalin | - Adrenergic receptors

Answer 512

Acetylcholine | - Cholinergic receptors

Answer 513

Ligand | - Cholinergic receptors

Answer 514

Adrenergic Receptors 1. Adrenergic receptors are autonomic receptors that bind to adrenalin and noradrenaline 2. Sympathetic nervous system 3. Adrenalin and noradrenaline 4. Alpha and beta receptors Cholinergic Receptors 1. Cholinergic receptors are autonomic receptors that bind to acetylcholine 2. Parasympathetic nervous system 3. Acetylecholine 4. Nicotinic and Muscarinic receptors

Answer 515

2 types: - a (a1, a2) - B (B1, B2) Catecholamines act on several R types : NA: a1, B1 : A: a1, a2, B1, B2 HIGH stress --> SNS releases catecholamines --> a/B Rs ---> Physiological response

Answer 516

Excitatory action - Heart - Blood vessels supplying skin, kidneys, mucous membranes (constriction) - Salivary and sweat glands Inhibitory action - Gut - Bronchial tree - Blood vessels supplying skeletal muscle - (dilation/relaxation) Metabolic action - Increased glycogenolysis in liver and muscle Endocrine actions - Modulation of the secretion of insulin, renin, and pituitary hormones

Answer 517

Heart - B1R stimulation - Inc. heart rate, contractility - Inc. AV node conduction - Inc. cardiac output Lungs - B2R stimulation - Relax bronchial muscle - Dec. secretions - Inc. airway diameter Bladder - Relaxation (BR) - Contract sphincter (a2R) - Prevents urination

Answer 518

Blood vessels - Express a, B, DA, Histamine, M R's - SNS activation releases NA, A and DA - a1 vasoconstricts vessels (arterioles) - dec. blood flow to unneccessary organs, shunted to where needed - B2 vasodilates skeletal muscle beds - Dec. overall vascular resistance, Inc. blood floow to muscles

Answer 519

Remeber - Other organs have edrenoreceptors Drugs that activate the SNS - Dec. motility of large intestine (--> Constipation) - Causes pupillary dilation (--> blurred vission) - Cause piloerection (goose bumps) - Cause perspiration (sweating)

Answer 520

- Drugs that mimic the action of the sympathetic nervous system - Inc. availability of NA or A to stimulate adrenoreceptors

Answer 521

What is the effect of salbutamol (a B2 agonist) On the lung On the heart

Answer 522

- Many drugs interfere with the function of the SNS - Affect the physiology of sympathetically innervated organs - Several are important for the treatment of cardiovascular disease - metaprolol

Answer 523

On the lung? On the heart?

Answer 524

SNS activation - Accelerates heart rate - Widens bronchial passages - Slows down digestive system - Constricts arterioles and dilates skeletal muscle beds By knowing what Rs drugs interact with: - Predict effect of drugs enhancing or blocking SNS activity on organs - Extend this to predict unwanted effects (in other organs)

Answer 525

What is the effect of phenylephrine an a1 agonist on the - Nasal mucosa? - Lungs? - Heart? What effect does propranolol, a non-selective B blocker have on - Lungs? - Heart? - Eye?

Answer 526

Parasympathetic system - Oculomotor (III) - Facial (VIII) - Glossopharyngeal (IV) - vagus (X)

Answer 527

Parasympathetic PRE ganglionic nerve endings release ACh --> NICOTINIC receptors POST ganglionic nerve endings release ACh --> MUSCARANIC receptors - Lying on the couch (= rest and digest) - LOW stress --> PNS is active --> Muscaranic Rs --> Physiological response

Answer 528

M1 1. 'Neural' 2. Autonomic and enteric ganglia, gastric cells, Cerebral cortex 3. Inc. IP3 = excitation 4. Gastric secretion - CNS excitation M2 1. 'Cardiac' 2. SA node, AV node 3. Inc. [K]i, dec. cAMP = inhibition 4. bradycardia M3 1. 'Glandular/smooth muscle' 2. Exocrine glands, Smooth muscle (GIT, eye, airways, bladder) Blood vessels (indirect) 3. Inc IP3 = stimulation 4. Exocrine secretion (salvia, sweat) bronchoconstriction - vasodilation via NO M4 2. CNS 3. Inc. [K]i, dec. cAMP = inhibition M5 2. CNS 3. Inc. IP3 = excitation

Answer 529

HEART - M2 Stimulation - Dec. SA node firing - Dec. AV node conduction - Dec. heart rate, contractility - Dec. cardiac output Lungs - M3 stimulation - Constrict bronchial muscle - Inc. secretions - Dec. airway diameter Bladder - M3 (M2) Stimulation - Contraction of detrusor - Relax sphincter - Micturition reflex

Answer 530

I dont really get it buuut - Agonists at both N and M Rs, more potent at M - Few important clinical uses

Answer 531

Pupil dilation impedes drainage M agonists --> constriction - Better drainage - Dec. pressure - Cholinergics Contract Circular (Constrictor) muscle - Contract Ciliary muscle)

Answer 532

On the lung? - On the heart? - On the blood vessels

Answer 533

Muascarinic antagonist - Atropine - Hyoscine - Ipratropium - Cyclopentolate All muscarinic antagonists show similar peripheral effects - Degree of specificity depending on subtypes

Answer 534

- On the eye? - On the heart? - On the CNS?

Answer 535

reactions that occur at a therapeutic dose that are - Unrelated to the therapeutic aim - Related to the mechanism of action If we know how each class of drug interacts with Rs in each organ --> Correctly predict side effects of each drug

Answer 536

some weird shit on L34, pg 22

Answer 537

Excitatory action - Ciliary muscle (for near vision) - Salivary glands, pancreas, gall bladder - Gut - Bronchial tree (constriction, secretion) Inhibitory action - Heart - Blood vessels supplying skeletal muscle

Answer 538

- Big summary on L34, pg 25

Answer 539

- Defined as maintenance of a relatively stable internal environment - Homeostasis is essential for survival and function of all cells - Is any self-regulating process by which an organism tends to maintain stability while adjusting to conditions that are best for its survival

Answer 540

- Sensing and responding to changes in surrounding environment - Control exchange of materials between cell and its surrounding environment eg Co2 and O2 or nutrients and waste - Perform chemical reactions that provide energy for the cell - Synthesize cellular components

Answer 541

Extracellular fluid (ECF) - Fluid environment in which the cells live (fluid outside the cells) which has 2 components - Plasma - Interstitial fluid Intracellular fluid (ICF) - Fluid contained within all body cells

Answer 542

- The intracellular fluid is 'conditioned by' - The interstitial fluid, is 'conditioned by' - The plasma 'conditioned by) - The organ system it passes through

Answer 543

- Homeostasis involves dynamic mechanisms that detect and respond to deviations in physiological variables from their "set point" values by initiating effector responses that restore the variables to the optimal physiological range

Answer 544

1. Nervous system - Controls and coordinates bodily activities that require rapid responses - Detects and initiates reactions to changes in external environment 2. Endocrine system - Secreting glands of endocrine regulate activities that require duration rather than speed - Controls concentration of nutrients by adjusting kidney function, controls internal environments volume and electrolyte composition

Answer 545

- Concentration of nutrient molecules - Concentration of water, salt, and other electrolytes - Concentration of waste products - Concentration of O2 = 100mmHg and C02 = 40 mmHg - pH = 7.35 - Blood volume 4-6L and pressure 120/80 - Temperature = 37*C

Answer 546

1. External stimuli - Heat, cold, lack of oxygen, pathogens, toxins 2. Internal stimuli - Body temp - Blood pressure - Conc. of water, glucose, salts, oxygen, etc - Physical and psychological distresses

Answer 547

- Detect deviations from normal in the internal environment that need to be held within narrow limits (SENSOR) - Integrate this information with other relevant information (CONTROL CENTRE) - Make appropriate adjustments in order to restore factor to its desired value (EFFECTOR)

Answer 548

1. Intrinsic controls - Local controls that are inherent in an organ 2. Extrinsic controls - Regulatory mechanisms initiated outside an organ - Accomplished by nervous and endocrine systems

Answer 549

Negative feedback loop - Original stimulus reversed - Most feedback systems in the body are negative - used for conditions that need frequent adjustment Positive feedback loop - Original stimulus intensified - Seen during normal childbirth, blood clotting

Answer 550

- Baroreceptors in walls of blood vessels detect an increase in BP - Brain receives input and signals blood vessels and heart - Blood vessels dilate, HR decreases - BP decrease

Answer 551

- Strength receptors in walls of uterus/cervix send signals to the brain - Brain induces release of hormone (oxytocin) into bloodstream - Uterine smooth muscle contracts more forcefully - More stretch, more hormone, more contraction - Cycle ends with birth of the baby & decrease in stretch

Answer 552

- Electrolytes help regulate myocardial and neurological functions, fluid balance, oxygen delivery, acid-base balance, and much more - The most serious electrolyte disturbances involve abnormalities in the levels of sodium, potassium, and/or calcium - Kidneys work to keep the electrolyte concentrations in the blood constant despite changes in the body

Answer 553

There are three types of dehydration 1. Hypotonic of hyponatremic (primarily a loss of electrolytes, sodium in particular) 2. Hypertonic or hypernatremic (primarily a loss of water) 3. Isotonic or isonatremic (an equal loss of water and electrolytes)

Answer 554

- The kidneys can only conserve fluid. - They cannot restore lost volume - If volume drops too low, Glomerular filtration rate (GFR) stops

Answer 555

Proximal tubule 1. - Fluid is isosmotic to ECF Loop of Henle - Hyperosmotic fluid 2. Active transport of solute creates hyposmotic fluid 3. Urine osmolarity depends on permeability of the collecting duct 4. Urea transport helps keep interstitial osmolarity high

Answer 556

- With maximal vasopressin, the collecting duct is freely permeable to water. Water leaves by osmosis and is carried away by the vasa recta capillaries. Urine is concentrated - In the absence of vasopressin, the collecting duct is impermeable to water and the urine is dilute

Answer 557

---> Hypothalamic neurons that synthesize vasopressin - Integrating system - Vasopressin (released from posterior pituitary) - efferent pathway - Collecting duct epithelium - effector - insertion of water pores in apical membrane - tissue response - Increased water reabsorption to conserve water - Systemic response

Answer 558

- Vassopressin and thirst; both decrease OsM, but raise blood pressure - To lower blood pressure our kidneys excrete sodium

Answer 559

diagram on L35, pg 25

Answer 560

- The body has a potent sodium - retaining mechanism: the rennin-angiotensin system - Sodium levels effect blood pressure - lots of sodium = higher blood pressure - Instates of sodium depletion, aldosterone levels increase; in states of sodium excess, aldosterone levels decrease - The major physiological controller of aldosterone secretion is the plasma angiotensin II level that increases aldosterone secretion

Answer 561

- To gain approval for general medical use, the quality, safety and efficacy of any product must be demonstrated - Demonstrate particular safety and efficacy - Preliminary data, especially safety data, must be obtained prior to drugs administration to human volunteers - Regulatory approval to commence in clinical trials is based upon pre-clinical pharmacological and toxicological assessment of the potential new drug in animals

Answer 562

- Less than 1% of compounds in research make it to market approval - Reasons fail: safety, efficacy, time, cost - Biopharmaceuticals: peptides, proteins, antibodies, oligonucleotides

Answer 563

- Prevent bleeding in leukaemic patients - Blood platelets via transfusion > $1 billion sales - 6% of platelets used daily to repair blood vessels

Answer 564

- Designed to prevent localised bleeding - Ultra-rapid clotting action - Ready-to-use formulations - Blood-free component

Answer 565

- The boundary between preclinical development and clinical trials is sharply defined by the filing of an investigational new drug application (IND), which is required prior to initiation of the clinical trial. - At the end of the pre-clinical studies the sponsor submits the IND application to the regulatory agency - The regulatory agency will review the IND for safety to assure that research subjects will not be subjected to unreasonable risk

Answer 566

- Preclinical studies have to comply with the guidelines dictated by Good Laboratory Practice (GLP) to ensure reliable results

Answer 567

- How is the drug manufactured - Information on drug appearance - How drug is formulated (tablets, liquid, suspension etc) - How the drug will be analysed for purity, concentration and stability - How the drug will be tested for its safety and efficacy

Answer 568

Animal pharmacology and toxicology - Pre-clinical studies (PD/PK/Tox) Manufacturing information - Process development - Assay development - GMP manufacturing - GMP testing - Stability testing

Answer 569

- Pharmacodynamics - Pharmcokinetics - Toxicology

Answer 570

- Pharmacodynamics describes the relationship between the concentration of a drug in the body and its biological effect (dose response) - How potent and efficacious the drug is with regard to its desired pharmacological effect, including safety aspects and efficacy - Pharmacodynamics establishes the therapeutic index of a drug, describing the ratio of the dose causing toxicity and the dose eliciting a therapeutic effect - Ideally, the therapeutic index is large to indicate a wide therapeutic window

Answer 571

- The effect of a drug is determined by the amount of active drug present in the body particularly at the target site - Depends on absorption, distribution, metabolism, and excretion (ADME) of the compound - Pharmacokinetics describes changes in plasma concentrations over time as a consequence of ADME - ADME profiling is critical for establishing dose range an administration schedule for subsequent phases of the clinical trial

Answer 572

- To determine whether a drug is safe for testing in human subjects - Preclinical toxicology studies are performed to identify the treatment regimen for the least degree of toxicity - Determine a suitable and safe starting dose for clinical trials - Starting with single-dose studies to identify organs that might be subject to drug toxicity, preclinical in vivo studies continue with repeated-dose approaches - The treatment regimen ideally mimics the intended clinical design with respect to treatment duration, schedule, and route of administration - Other studies evaluate carcinogenicity, genotoxicity, and reproductive toxicity

Answer 573

- Obtaining relevant results from preclinical studies with a high degree of predictability requires appropriate preclinical models that are as comparable to the target population as possible - Typically, this involves a series of experiments using vitro, in vivo, and more recently, also in silico models - In silico: expression meaning "performed on computer or via computer simulation" in reference to biological experiments

Answer 574

- In vitro studies are a relatively fast, simple, and cost efficient way of preclinical testing - Studies utilise cell, tissue, and organ cultures, or focus on particular cell components such as proteins or other biological macromolecules - In vitro studies often provide mechanistic evidence for the investigational compound's mode of action and toxicity - Limitation: isolated cells may not behave in a petri dish as they would within the body where they partake in crosstalk and interaction with millions of other cells

Answer 575

- In vivo studies consider the complete organism based on various animal models - A with studies in humans, animal testing is tightly regulated in most countries and permission from local ethical review boards is required to ensure that no unnecessary harm is done to the experimental subjects - The ideal preclinical model-accurately mimics human disease - Typically, in vivo studies are performed in a rodent (eg, mouse, guinea pig, hamster) and non-rodent model to comply with FDA requirements

Answer 576

- Mouse - Rat - rabbit - Dog - Pig - Monkey

Answer 577

Mouse model - The genomes of mouse and man are highly similar: 99% of all mouse genes overlap with those of humans - Additionally, genomic manipulation in this organism has become fairly simple. Genetic engineering has given rise to humanised mouse models and provides valuable tools for translational research - Limitations: species-specific differences in host immune response, drug metabolism, and tumors heterogeneity affect therapeutic out - comes - Differences in pharmacokinetics and pharmacodynamics among species are different and thus, mouse models often suffer from poor predictive power regarding clinical efficacy

Answer 578

- The information is collected from these studies is vital so that safe human testing begin - The choice of species is based on which will give the best correlation to human trials - Can reproduce the disease in the animals and measure treatment: introducing a gene or cells (cancer cells) - Observe changes at the macroscopic, microscopic and biochemical changes for PK, PD and toxicology studies

Answer 579

- Animal testing in the research-based pharmaceutical industry has been reduced recently both for ethical and cost reasons, also its continuous - Antivivisectionist: a person who is opposed to vivisection - Vivisection is the practice of using live animals for scientific experiments

Answer 580

- Preclinical testing entails the use of thousands of animals - This is costly and in many cases continuous - Attempts around development of alternatives to animals to toxicity testing and are centred around animal cell culture systems - Range of animal and human cell lines that can be cultured - Measure live - dead cells - Regulatory authorities are slow to allow replacement of animal-based testing protocols until replacement systems has been shown to be reliable and is fully validated

Answer 581

- A 'clinical trial' is specifically defined as any investigation in human subjects

Answer 582

1) To discover or verify the clinical, pharmacological or other pharmacodynamic effects of the drug 2) Identify any adverse reactions to the drug 3) Study absorption, distribution, metabolism and excretion of the drug with the object of determining the safety or efficacy of the drug

Answer 583

Clinical trials Preclinical - Drug approved fo testing in humans Phase 1 - 20-80 participants Phase 2 - 100-300 participants Phase 3 - 1000-3000 participants - Drug submitted for FDA Aproval FDA Review - Drug approved) Phase 4 - 1000+ participants

Answer 584

- Clinical trials consist of testing the drug on healthy volunteers and/or volunteer patients - The testing must meet ethical standards - Volunteers must give consent - The testing also must be in compliance with the formal rules of clinical trials according Good Clinical Practice

Answer 585

- Good Clinical Practice 'GCP' is a set of rules and regulations which clinical trials must be conducted - GCP is guided by regulatory agencies (eg. FDA) - The main principle is that 'the rights, safety and wellbeing of the trial subjects are the most important considerations and should prevail over the interest of society

Answer 586

- Post-war era when sleepness was prevalent, thalidomide was marketed initially as sedative - Dr. William McBride discovered that the drug also alleviated morning sickness, recommending this off-label use of the drug to his pregnant patients, setting a worldwide trend - In 1961, Dr McBride began to associate this so-called harmless compound with severe birth defects in the babies delivered - Many of them to be born with shortened, absent, or flipper-like limbs - Thalidomide, which worldwide maimed an estimated 20,000 babies and killed 80,000 - Lack of data indicating whether the drug could cross the placenta, which provides nourishment to a developing fetus - Prompted international regulatory agencies to develop systematic toxicity testing protocols; - Secret files revealed a thalidomide cover up by the German company that made the drug - German medical professionals had been telling the pharmaceutical giant of their concerns about the link between thalidomide and childrens deformities for up to two years before the drug was banned in 1961 - 21 New Zealanders affected by the drug - ten New Zealanders who have endured a lifetime after being born thalidomide babies are to get a share of 3.5 million

Answer 587

- A clinical study is conducted according to a research plan known as the protocol - The protocol is designed to answer specific research questions and safeguard the health of participants

Answer 588

- The reason for conducting the study - Who may participate in the study (the eligibility criteria) - The number of participants needed - The schedule of tests, procedures, or drugs and their dosages - The length of the study - What information will be gathered about the participants

Answer 589

- New drugs are mostly evaluated by way of Randomized Controlled Trials (RCT) - The participants of the trial are randomly assigned to either a group receiving the new substance or to a control group that is being given standard or placebo treatment - Generally, the experiment is a double-blind - Randomization reduces bias, while the existence of different comparison groups allows to determine any effects of the treatment in relation to the control group

Answer 590

- The potential drug is used for the first time by humans - They are normally carried out on healthy volunteers - Purpose: determine the toxicity level of the drug in the human body - Initial dosing schemes based on animal data (pre-clinical data) - Normally takes place in a hospital - Can last from 2-8 weeks

Answer 591

- If the drug is potentially toxic but it can be used to save lives, for example, in diseases such as cancer or aids, the volunteers are patients - These studies also provide basic pharmacokinetic data concerning liberation, absorption, distribution, metabolism and excretion - Volunteers commit to not taking other medication, drinking coffee and alcohol and smoking. This pre-cautions allow to exclude other factors that may cause side-effects

Answer 592

- London on March 13, 2006 - In a phase I study, on March 13, 2006, 6 volunteers at Northwick Park Hospital in London aministered the monoclonal antibody TGN1412 (TeGenero from Wurzburg) - Treatment of oncological and autoimmune diseases - Phase I resulted in a catastophic life-threatening adverse event for subjects induced by an unpredictable cytokine storm - Within 90 minutes all the healthy volunteers suffered headache, dizziness, diarrhea, some grotesque swelling of the head and neck, low blood pressure, later unconsciousness and finally (after 12-16h) multiple organ failure - All 6 volunteers were in intensive care - All patients survived but had toes and parts of fingers amputated - Easy money $2000!?

Answer 593

- Phase II trials are performed on larger groups (100-500) - Designed to access how well the drug works (efficacy), as well as to continue Phase I safety assessments in a larger group of volunteers and patients - Phase II studies are sometimes divided into Phase IIA and Phase IIB. There is no formal definition for these 2 sub-categories, but generally - Phase IIA studies are usually pilot studies designed to demonstrate clinical - Phase II B studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects ('definite dose-finding' studies)

Answer 594

- Side effect is a secondary unwanted effect that occurs due to drug therapy - A side effect is an undesired effect that occurs when the medication is administered regardless of the dose - Side effects are mostly forseen by the physician and the patient is told to be aware of the effects that could happen while on the therapy - Side effect are tracked and investigated extensively during clinical trials before entering the market, mainly phase II

Answer 595

- Will only be started once it is established in phase II studies that drug is reasonably effective and is safe and well tolerated - Purpose: to test and observe the drug on a much longer time scale, and much larger patient population. Measuring efficacy and looking for adverse effects - Can last 8 months - 4 years - Can enrol up to 3000 patients worldwide

Answer 596

- An adverse event is an undesired occurrence that results from taking a medication correctly - The event is not expected by either the doctor or the patient and the effects can be reduced by lowering the dose or just stopping the medication all together - Adverse events require interventions wheras most side effects spontaneously resolve with time

Answer 597

- Phase III is the last trial a sponsor conducts before submitting an NDA, new drug application to the regulatory agency (eg FDA) - The NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the US. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA - It is an application which is filed with regulatory agency to market a new drug for sale in region

Answer 598

1) They approve the drug 2) They reject the drug 3) They tell the sponsor to re-do phase III study, often changing a few testing parameters to make the phase III trials more reliable

Answer 599

- Even during this stage, grave side-effects may be observed - if so, the drug does not go to market - A prime example of such event is Pfizer's Torcetrapib - After 16 years of development at a cost of US $800 million, further work on it was terminated because there was a statistically increased risk of death associated with its use

Answer 600

- Post-marketing surveillance - Purpose: additional testing should the pharmaceutical company decide to market the drug as a treatment to a slightly different condition than was previously planned or to gain more information on the warnings and side-effects of the drug - Gives the pharmaceutical company chance to really test the drug for long term side-effects, in order to better understand how it reacts and better market the drug to its consumers

Answer 601

- Phase IV are often conducted on specific demographics: the elderly, children, pregnant women and people taking other medication - The research allows identifying and measuring unique and long-term effects - Additionally, during phase IV research it is possible to discover new activity - This procedure allows the discovery of serious side-effects that were not evident earlier - Occurs after drug approval and may last 1-8 years

Answer 602

- An example of a Phase IV termination is that of practolol - A selective beta blocker (beta-1 blocker) that has been used in the emergency treatment of cardiac arrhythmias - Referred to as a 'wonder drug' - This was withdrawn from the market after few years of being available, because some patients lost sight - the cause of blindness is still unknown

Answer 603

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