What does ADME mean?
Absorption, distribution, metabolism and elimination (describes the deposition of a pharmaceutical compound in the body)
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What does enteral mean?
Delivered via the GI tract
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What are parenteral mean?
Any route of delivery except via the GI tract
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What is a local effect?
The drug is applied directly to the site of local action e.g. application of creams to the skin in eczema or eye drops in hay fever
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What is systemic therapy?
Treatment is targeted to conditions that affect the body as a whole or organ systems e.g. cardiovascular system (divided into non-invasive and invasive)
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What is non-invasive?
Orally, via the lungs, nasally, rectally, sublingually, transdermally etc.
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What is invasive?
Intravenously, subcutaneously, intra-arterially, intra-muscularly etc.
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What are the different dosage forms for different administration routes (1)?
Oral (tablets, capsules, solutions, syrups, suspensions, emulsions, gels, powders, granules), respiratory (aerosols, inhalations, sprays gases), nasal (solutions, inhalations), eye (solutions, ointments, creams)
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What are the different dosage forms for different administration routes (2)?
Ear (solutions, suspensions, ointment, creams), rectal (suppositories, ointments, creams, powders, solutions, topical (ointments, creams, pastes, lotions, gels, solutions), parenteral (injections - solution, suspension, emulsions - implants)
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What are the three enteral routes of administration?
Buccal/sublingual, oral and rectal
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Describe features of buccal/sublingual ROA
Intended for sustained local delivery or rapid/enhanced systemic delivery. Small hard tablet held in mouth (below lip) to achieve sustained release of drug. Or held under tongue, used for systemic absorption e.g. nitroglycerin for angina
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Describe the components in oral mucosa
Multilayered epithelium, basement membrane, blood supply and submucosa
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What are the advantages of buccal/sublingual ROA?
First pass (liver by-passed, no loss of drug due to first pass effect, high F), rapid absorption (good blood supply to buccal cavity, rapid systemic absorption), drug stability (pH in mouth is neutral ~6.5-6.9, so drug is more stable)
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What are the disadvantages of buccal/sublingual ROA?
Inconvenient (hold dose in mouth, uncomfortable/taste, any portion swallowed is treated as an oral dose and is subject to first pass metabolism), suitable for only low dose drugs
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Describe features of rectal ROA
Most common dosage forms for suppositories (solids/semi-solids) and enemas (solutions), drug absorbed either across rectal and/or colonic mucosa (particularly if applied in liquid dosage form)
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What are the advantages of rectal ROA?
By pass liver (some veins draining rectum/lower rectum lead directly to general circulation and by pass first pass metabolism in the liver), useful (route useful for patients unable to take drugs orally e.g. due to vomiting, irritation or children)
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What are the disadvantages of rectal ROA?
Erratic absorption (incomplete absorption and sometimes erratic/but useful ROA), not well accepted (in the UK)
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Describe features of the pulmonary route
Systemic or local delivery. Attractive target for systemic absorption due to large SA
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What are the advantages of pulmonary delivery?
Large SA, good blood supply, thin cells, avoids first pass hepatic metabolism
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Describe the uses of the pulmonary route for local delivery
Treatment/prevention of local respiratory diseases e.g. asthma, COPD. Designed to target bronchi/large bronchiole regions of conducting airways to treat: cystic fibrosis, bronchiectasis
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Give examples of therapeutics for the pulmonary route in local delivery
Bronchodilators, steroids, anticholinergics, antibiotics and DNase (macromolecule)
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What are the advantages of the pulmonary route for local delivery?
Local targeting of diseased tissue/higher local drug concentration, lower systemic (plasma) concentrations/decreased systemic side effects, rapid onset of action (unlike oral dosage forms - gastric emptying prior absorption and therapeutic response)
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Describe features of the pulmonary route for systemic delivery
Lung considered as a route, no other mucosal route of drug delivery provides F of pulmonary epithelium
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What are the advantages of the pulmonary route for systemic delivery?
Proteins, peptides and antibodies that would be denatured by acid or enzymatic digestion in the stomach can be administered in this route. Fast onset of action
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Give examples of molecules which are delivered via the lung for systemic effect
Small molecules (morphine, dihydroergotamine, fentanyl), protein and peptides (inhaled insulin, inhaled vaccines), gene therapy (to treat cystic fibrosis and cancer)
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What are the limitations of lung delivery?
Reaching site of action/absorption, aerodynamic particle size of aerosol, stability of formulation in aerosol generation process, sufficient and reproducible deposition
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Describe features of the nasal route
Exploited to deliver drugs either locally (e.g. decongestant) or systemically (e.g. triptans for migraine)
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What are the advantages of the nasal route?
Useful for drugs that are not absorbed orally, by pass hepato-GI first pass elimination, ease of administration, rich blood supply in nasal mucosa (drug enters systemic circulation more rapidly than oral), non-invasive/rapid
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Describe features of the nose
Nasal cavity has a volume of 15-20 cm3 and a SA of 150-180 cm2. Each cavity consists of three regions: vestibules, respiratory region (turbinates or chonchae) and olfactory region. Respiratory region responsible for drug absorption
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Describe features of nasal drug delivery
Nasal epithelium, columnar cells (ciliated/non-ciliated), basal cells and goblet cells, ciliate/non-ciliated columnar cells are connected by tight junctions and are covered in microvilli, cilia propel mucus from the anterior to the posterior part
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What are the disadvantages of nasal drug delivery?
Favours passive diffusion, (low Mwt/ for other absorptive surfaces), nasal congestion affects F. Local irritation, mucociliary clearance
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What are the types of formulations for nasal delivery?
Nasal drops (e.g. saline drops) or nasal sprays (e.g. Beconase). Extent/site of deposition of aerosol depends on factors such as particle diameter, charge and velocity. ~40% administered dose is cleared rapidly within 20 minutes
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What are the two ways for administering a drug via the skin?
Local delivery (ketoconazole/antimycotic) and systemic delivery (hormones, fentanyl/opioid based pain killer, nicotine) - local delivery to skin layers may also result in systemic absorption
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Describe the components of the epidermis in the skin
Stratum corneum, granular layer, spinous layer, basal layer and basement membrane
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What is the major barrier to drug permeation?
Stratum corneum - the outermost skin layer
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Describe features of the stratum corneum
A highly hydrophobic layer, composed of dead, flattened corneocytes surrounded by lipid bilayers, brick and mortar structure (corneocytes/lipid bilayer), low permeability (for low Mwt drugs), skin permeation of molecules governed by diffusion
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What are the two pathways of drug absorption through the skin?
Intercellular (between cells, more common) and transcellular (through cells)
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Describe features of oral ROA
Wide variety of oral dosage forms available. Dosage form swallowed and absorbed across GI tract from SI (or sometimes colon, stomach). Most common (98% of all drugs) and preferred route in the UK
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What are the advantages of oral ROA?
Convenient (portable/no pain/easy to take/well accepted), cheap (administration, production/multidose formulations by machines, large quantities, no need to sterilise (must be hygienic), no danger of embolism), variety of dosage forms e.g. enteric
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What are the disadvantages of oral ROA?
Inefficient (high dose/low solubility, poor F/part of dose absorbed across SI membrane), first pass effect (extensively metabolised/need higher doses), slow onset of action, not stable, food, local effect (antibiotics), unconscious patient, palate
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How does gastric emptying affect drug absorption?
Delays drug absorption
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How does gastro-intestinal transit affect drug absorption?
Delays drug absorption
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How does food and fluid affect drug absorption?
Reduces the drug absorption rate to target site
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How do enzymes and pH affect drug absorption?
Degradation of drug before reaching absorption site. pH affects ionisation state of drug (ionised - will not pass biological membrane), drug loss, less effective
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How does first pass metabolism affect drug absorption?
Reduces drug absorption in systemic circulation
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How does enterohepatic re-cycling affect drug absorption?
Absorption from intestinal epithelium and potential transport of drug to liver, recycling, drug cleared, multiple cycles of drug travelling to and from intestines - leads to drug degradation
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Describe the sites of absorption after oral administration
Few (acidic drugs e.g. aspirin) are absorbed in the stomach. Some drugs absorbed in colon (or large intestine). Major site of drug absorption is SI (large SA and potential for large contact time for drug in intestinal mucosa)
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What are the primary functions of the stomach?
Storage/mixing, initiation of digestion (pH 1-3), reducing contents to a slurry (chyme), emptying stomach contents in controlled manner into SI. Stomach has small SA (insignificant to drug absorption except for alcohol, aspirin, glucose, weak acids
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What are the four segments of the large intestine (colon)?
Ascending colon, transverse colon, descending colon and sigmoid colon
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What are the primary functions of the colon?
Absorption of water and electrolytes, storage/elimination of faecal materials, large intestine has small SA (despite large diameter), minor site of drug absorption (except for propanolol)
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Describe features of the structure of SI
Longest section of GIT, large SA, runs from pyloric sphincter to ileo-caceal junctions, comprised of three regions, duodenum, jejunum and ileum. Structured to increase SA over that of cylinder equivalent dimensions
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Describe features of the cross-section of SI
Serosa (outermost layer, connective tissue), muscularis (longitudinal/externa circular muscle, mixing/propelling gastric contents along SI), submucosa (connective tissue, blood, lymph vessels), mucous membrane (epithelium/absorption, close to blood)
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Describe the 1st level of specialisation to increase SA of SI
Convoluted spiral (circular) folds of submucosa covered by mucosa. More dense in jejunum than ileum, folds serve to give 3-fold increase in luminal SA (folds of Kerckring at organelle level)
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Describe the 2nd level of specialisation to increase SA of SI
Finger like protrusions of mucosa, more dense in jejunum than ileum, close proximity to blood and lymph supplies, countercurrent flow (enhance absorptive capacity), increase in SA of 30-fold
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Describe the 3rd level of specialisation to increase SA of SI
Thousands of small extensions on each epithelial cell (project into lumen). Microvilli. Each microvillus has a dense bundle of actin filaments (extended shape). Contract (move fluid in contact with surface). Increase SA up to 40-fold (overall 200 m2)
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Describe features of SI epithelium
Epithelium is one cell thick. Crypts at base of villi contain stem cells and divide by mitosis to produce more stem cells and cells that migrate up the surface of the villus while differentiating into 4 main cells
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What are the four main cell types?
Enterocytes (columnar epithelial/tight junctions between cells), goblet cells, endocrine cells, paneth
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What are the functions of the SI epithelia cells?
Paneth cells (secretes antimicrobial peptides), endocrine cells (secrete hormones), goblet cells (secrete mucus), enterocytes (absorptive cells) - short lifespan of 2-3 days, cells die by apoptosis, endothelium renewed every 36-72 h
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Describe features of enterocytes
Predominant cell type, tall, thin cell, nucleus at base, microvilli in apical side (BBM), absorptive cell, tight junctions (preserve cell polarity/limit paracellular permeability). Channels between cells water filtered (low Mwt molecules pass), BM
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Describe features of the epithelial membrane
Both microvillus membrane and basement membrane contains extrinsic and intrinsic proteins, digestive enzymes and transport proteins (half the weight of membrane is protein but number of lipid greater), Mwt of lipid < Mwt of protein
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Describe the composition of the GI fluid
Made up of saliva, gastric secretions, dietary food/liquid, refluxed liquid from duodenum, composition changes when fluid is mixed/delivered
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What are the major components important for drug deposition?
Hydrogen ion concentration (affects pH and dissolution of ionisable drugs), bile salts (combines with lipids to form mixed micelles, enhance drug solubility), lipase (affects drug release from lipid-based dosage forms), pepsin (affects stability)
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What are the steps involved in the release and absorption of a drug from a tablet?
Dosage form, inflow, drug particles, dissolution/transit, drug in solution, uptake, outflow
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What dictates drug absorption?
Drug factors, physiological/anatomical factors and disease factors
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What are the main drug and patient factors that many influence drug absorption?
Physicochemical characteristics of the drug, patient characteristics, PK characteristics of drug
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Describe features of GI transit time
Absorption determined by residence time/absorption. GI transit time impacts systemic exposure of rapidly/absorbed drugs. Influence with limited mucosal permeability, carrier mediated uptake, intestinal degradation, dissolution (rate limiting)
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Is gastric emptying a simple exponential/square root function of the volume of a meal?
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Describe features of gastric emptying
Stomach empties liquid faster than solids, food affects pH and transit, rate of transfer is controlled by activity of receptors, formulation of drug influence drug absorption through indirect effect on gastric emptying
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Describe features of intestinal transit time
Independent of feeding conditions and the physical composition of intestinal contents. Gradient of velocity where SI transit in proximal intestine is faster compared to distal intestine
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Describe features of bacterial miroflora and oral drug absorption
Bacterial microflora in human distal small/large intestines, no bacterial microflora in stomach and upper SI (due to low pH of human gastric content)
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Describe features of gut bacterial microflora
Involved in hydrolysis, dehydroxylation, deamidation, decarboxylation, reduction of azides, pharmacomicrobiomics (variation on drug deposition/response)
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Outline the role of gut microbiota on drug metabolism
Direct mechanisms, indirect mechanisms, first pass metabolism, activation, deactivation, toxicity, reduction, hydrolysis
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Other cards in this set
What does enteral mean?
Delivered via the GI tract
What are parenteral mean?
What is a local effect?
What is systemic therapy?