L33 - Absorption via Different Routes of Drug Delivery

• Enteral vs Parenteral drug delivery

  enteral = via intestineparenteral = other routes that avoid GI tract, eg injections. Good if a drug has poor oral bioavailability
• What are the most common injection routes?

  intramuscular, (IM), intradermal, subcutaneous (SC), intravenous (IV)

  
• What's the main benefit of injections?

  allow us to bypass hepatic first pass - we don't have to get the drug to diffuse past the epithelium itself

  
• What are the main advantages of IV (intravenous) drug delivery?

  - Rapid: near immediate effect- precise dosing, large volumes possible- 100% bioavailability- great if pt needs in systemic circulation urgently

  
• What are some disadvantages of IV?

  - potential toxicity due to rapid increase in drug [plasma] - HCP required- high cost- duration (infusion can extend dosing). Can maintain [plasma] at higher level

  
• What is the speed of diffusion of an injected drug dependent on?

  Diffusion speed depends on Mw of drug.The larger the Mw, the slower the diffusionAlso diffusion of carrier solvent

  
• Intramuscular delivery: what are the advantages?

  - rich capillary bed in muscle: blood flow important (eg more bloof flow in deltoid (shoulder) than buttock- sustained release possible

  
• Intramuscular delivery: what are the disadvantages?

  - HCP required- erratic absorption

  
• Why do HCPs tell you to move your arm after an injection?

  Exercise increases blood flow, so drug can diffuse faster and increase absorption.

  
• Why might your arm hurt after an injection?

  Bc solvent diffuses away more rapidly than the drug.Drug may precipitate.

  
• Subcutaneous delivery: what are the advantages?

  Passive diffusion into capillaries/lymphatics- slow, sustained delivery- self-administration possible- implants for long term delivery

  
• Subcutaneous delivery: what are the disadvantages?

  - small doses- pain from repeated injections- risk of infection w/minor surgery required for implants

  
• What is Tmax?

  Tmax = time at which Cmax occurs (maximum [plasma]

  
• What do you call epithelia with 1 layer/more than 1 layer?

  1 layer = simple epithelium>1 layer = stratified epithelium
• What are the functions of epithelia?

  protection, absorption, gas exchange?

  
• How are epithelia adapted for their function?

  keratinised layers (physical protection), villi (increase SA), cilia, secrete mucus from goblet cells

  
• Nasal drug delivery: advantages?

  - Avoids first pass effect- good if drug has poor oral bioavailability- easy to administer (drops/sprays)- small, lipophilic drugs can enter circulation with 100% bioavailability
• What does passive transcellular diffusion depend on?

  lipophilicity, ionisation, size - Fick's first law

  
• Describe the structure and function of the nasal cavity.


  - large interpatient variability, so variation in drug deposition and absorption- function = air conditioning: tempy, humidity, filtration- hair/mucus/cilia filter particles- Turbinates provide large SA for drug deposition- highly vascularised (short diffusion path)

  
• What are barriers to absorption in the nose?

  - Mucus: secreted by goblet cells. Physical/chemical barrier. -vely charged, so interacts with +vley charged drugs- Cilia: on turbinates. Sweep particles to back of throat where is can be destroyed down GI tracts

  
• Nasal sprays vs drops: which can be considered most effective?

  - drops moved by cilia on turbinates to back of throat, so can be swallowed more quickly- spray droplets distribute more evenly, away form cilia- hence sprays considered more effective

  
• How is Nose to Brain drug delivery possible?

  - NO blood-brain barrier in olfactory region- can deliver drugs to brain by targeting olfactory region- drugs are absorbed through olfactory nerves- paracellular diffusion or axonal transport

  
• What is ocular delivery used for?Why is it not a viable route for systematice delivery?

  local conditions only - not viable route for systematic.- eye is immunologically sealed: hard to get anything into the back of it- back of eye has tiny capillary bed- would need very high doses to reach systematic ciruclation

  
• Define periocular diseases.Eg?

  = diseases at front of eyeEg blepharitis, conjunctivitis, dry eye

  
• Define intraocular diseases.Eg?

  = diseases at the back of the eyeEg AMD, glaucoma, diabetic retinopathy

  
• What are the two main routes of drug absorption in the eye?

  corneal route, and junctival route

  
• Describe the corneal route of drug delivery.What is the cornea?

  cornea = transparent part that covers iris= major route by transcellular (lipophilic) or paracellular (hydrophilic) diffusion- outer cornea constantly produces tear film, wetting front of eye

  
• Describe the conjunctival route of occular drug absorption.


  - drug passes through junctiva and sclera- most of drug lost to systematic circulation (via local capillary bed)

  
• What are the main barriers to lipophilic and hydrophilic drugs in the eye?

  lipohilic = stroma. hydrophilic = epithelium. Drugs must have a mix of hydrophilic and lipophilic properties to permeate the cornea and stroma
• What are some issues with occular drug delivery?

  - DRAINAGE and TEARS- eyedrops flood eye, but only tiny proportion can be held- lots of drug lost to nasolacrimal drainage

  
• How can we improve occular delivery?

  - increase residence time (Eg contact lenses?)- enhance drug penetration

  
• What are some advantages to vaginal drug delivery?

  - avoids hepatic first pass- good for delivery peptides/proteins- lower enzyme activity than GI tract- drug penetration greater post-menopausal as epithelium is thinner

  
• What's normal vaginal pH range?Post-menopause?Pregnancy?

  normal = 4-5post-menopause = 7-7.4 (pH increases)pregnancy = 3 (pH decreases as epithelium thicker)

  
• What influences drug absorption in the vagina?What affects this?

  epithelium thickness - influenced by age, pregancy, menopause, menstrual cycle
• Pulmonary drug delivery: how?What does local delivery require in terms of [drug]?

  - nebulisers (fine droplets), metred-dose inhalers, dry powder inhalers- local dleivery requires smaller [drug] to site. Larger dose would be needed systematically (more ADRs)

  
• Where do we aim to deliver drugs in the lungs for efficient exchange?How are they adapted?

  alveoli = site of gas exchange.Highly vascularised, single epithelial layer (simple spithelium), so short diffusion pathway into bloodstream - potential for systematic effects

  
• What are the three mechanisms of natural defenses in the lungs?

  main defense = mucus1. inertial impaction2. sedimentation3. diffusion

  
• What factors affect pulmonary drug absorption?

  Mucus: - traps drug particles (viscous, humidity aids this)- -vely charged (so +ve interactions)- drug size affects diffusionCoughing:- irritation dislodges mucus to throat (swallowed)Cilia: - more higher up in lungs- sweep drugs to throat- 'mucociliary escalator'Large SA:- increases diffusion rateHighly vascularised:- avoid hepatic first pass

  
• What are some advantages of transdermal drug delivery?

  - fewers ADRs- avoids hepatic first pass/GI metabolism- Reduced dosing frequency: good compliance- large SA to apply- can mediate controlled release

  
• What's a disadvantage to transdermal drug delivery?

  Drug needs to be potent to reach systemic circulation/ have a proper systematic effect