Routes Flashcards
What are the benefits of nasal drug administration? [9]
- Avoidance of 1st pass
- Can be used to administer drugs that are sensitive to intestinal metabolism.
- Can be used for acid-sensitive drugs (e.g. peptides)
- Can be used for polar compounds with poor oral absorption.
- Drops and sprays are easy for young and elderly to use.
- Small, lipophilic drugs can diffuse through nasal epithelium and enter systemic circulation. BA up to 100%.
- Large surface area and highly vascularised
- Rapid delivery possible.
- CNS delivery possible.
What are the disadvantages to nasal drug administration? [4]
- Mucus barrier present, contains enzymes which may degrade drugs.
- Rapid mucociliary clearance - drug ends up being swallowed.
- Poor absorption of drugs >500 Da, so delivery of large molecules is limited to potent drugs.
- Variability and adverse reactions.
How can we improve nasal delivery of drugs? (particularly peptides) [3]
- Alter the mucus layer - surfactants and bile salts decrease mucus viscosity and have been shown to increase the absorption of drugs.
- Increase contact time with the nasal epithelium - delivery to different areas of the nasal epithelium, the use of mucoadhesives.
- Penetration enhancers - reversed micelle formation (bile salts), lipid extraction (surfactants), tight junction modification (EDTA, bile salts).
How can we alter the mucus layer in the nasal cavity to improve drug delivery? [2]
Use surfactants and bile salts to decrease mucus viscosity.
How can we increase the contact time of drugs delivered nasally with the nasal epithelium?
Use mucoadhesives such as Alginate, PLGA, Sephadex, Lactose. Target delivery to certain areas of nasal epithelium.
How can drugs enter the CNS from nasal delivery?
Olfactory epithelium, small SA but effectively an area where the BBB is not present.
Drugs can enter brain directly via paracellular diffusion of axonal transport through olfactory nerves, e.g. dopamine and cocaine.
Why does the presence of mucus present a barrier to nasal drug delivery?
- Acts as physical barrier drugs must cross.
- Can bind drugs - electrostatic interactions or H-bonding.
- Contains enzymes which may actually degrade drugs: neutral endopeptidase, carboxypeptidase N.
Which factors promote the clearance of nasal mucus and thus increases nasally delivered drug clearance? [6]
- Common cold.
- Rhinitis
- Asthma
- Hayfever
- B-Adrenergics
- Cholinergics
What factors inhibit mucus clearance in the nasal cavity? What effect does this have on nasal drug delivery?
- Anaesthetics
- Antihistamines
- Propranolol
- Bile salts.
These factors could cause increased nasal absorption of drug by increasing residence time. Clearance in obstructed nostrils is significantly reduced.
What is TJM?
Tight Junction Modifying peptide which can significantly improve intranasal absorption of human peptides.
How can devices be used to increase nasal absorption?
The ViaNase system disrupts normal airflow via a vortex and maximise nasal deposition of particles leading to increased residence time and minimisation of lung deposition. Also OptiNose Delivery System.
How does the ViaNase system increase nasal absorption of a drug?
The ViaNase system disrupts normal airflow via a vortex and maximise nasal deposition of particles leading to increased residence time and minimisation of lung deposition. Also OptiNose Delivery System.
What are the advantages of pulmonary drug delivery? [6]
- Rapid onset (esp. local)
- Large SA.
- High blood flow.
- High permeability (one cell thick barrier between blood and air)
- Low metabolism of drugs
- Avoidance of first pass metabolism.
What are the disadvantages of pulmonary drug delivery? [4]
- Complex delivery devices are needed.
- Reproducibility - patients cannot into respiring properly.
- Mucus.
- Clearance.
How does the Technosphere device improve pulmonary drug delivery?
- Small particle size.
2. High surface area.
By which routes can drugs be absorbed from pulmonary delivery?
- Transcellular pathway.
2. Paracellular pathway.
What is the transcellular pathway?
Passive diffusion of small, lipophilic drugs through the epithelium down a concentration gradient.
What type of drugs are absorbed via the transcellular pathway?
Small, lipophilic drugs.
What types of drugs are absorbed via the paracellular pathway?
Small, hydrophilic drugs.
What is the paracellular pathway for drug absorption?
Involves the passive diffusion of small, hydrophilic drugs down a concentration gradient between the cells of the epithelium. Slower than transcellular route but tight junctions are looser than other mucosal barriers.
Which route is faster for drug absorption, transcellular or paracellular?
Transcellular. Paracellular is slow.
What are the main factors affecting drug absorption via the pulmonary route? [5]
- Mucus
- Surface area
- Blood supply
- Epithelial thickness
- Enzymatic activity
How does the presence of mucus influence drug absorption from the pulmonary route?
Mucus provides a viscous barrier to absorption.
The thickness varies throughout the lungs.
The size of a drug can affect the diffusion through mucus and the mucociliary escalator can result in clearance of trapped drug particles.
How does the epithelial thickness in the lungs affect pulmonary drug delivery?
The thicker the epithelium the harder it will be for drugs to diffuse across/through. Thickness varies throughout the lungs.
How can enzymatic activity in the lungs influence drug absorption? Which enzymes are present?
Enzymes can deactivate drugs: CYP isoenzymes, esterases, peptidases, monoxygenases, transferases.
What is the initial hurdle in nasal drug delivery?
Deposition in the nasal cavity. Liquid drops are spread throughout the cavity, aerosols or powders are distributed according to particle size.
What is Fick’s 1st law?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
What does ‘h’ represent in the equation for maximum flux/Fick’s 1st law in general?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
What does ‘D’ represent n the equation for maximum flux/Fick’s 1st law in general?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
What does ‘K’ represent n the equation for maximum flux/Fick’s 1st law in general?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
How does mucus influence the terms in Fick’s 1st law equation?
Thickness varies so influences ‘h’ the diffusion path-length across the barrier.
Solubility/diffusivity of drug can change depending on the composition of the mucus so also ‘D’.
Also the partition coefficient K is influenced.