Pharmacokinetics - Absorption Flashcards
- PR_BK_18 Administration and absorption: routes of administration; first-pass metabolism and bioavailability. Selection of appropriate route. Drug delivery systems: e.g. sustained release, enteric coated, transdermal patch and iontophoretic systems - PR_BK_19 Oral administration: Time-course for systemic appearance; factors e.g. pKa, lipid solubility, active transport. Bioavailability of drugs given orally and its measurement (11 cards)
What factors affect movement of a drug across a membrane?
GRAPH FOR PKA & ionisation
Size
Graham’s law - passive diffusion inversely proportional to square root of molecular size - sevoflurane and propofol diffuse very quickly
Lipid solubility & partition coefficients
Lipid soluble molecules cross membranes more readily - Fentanyl’s lipid solubility allows use in transdermal patches.
Diamorphine has higher lipid solubility than morphine, diffusing into white matter more quickly - reducing risk of cranial spread.
Ionisation
Only the unionised fraction can cross cell membranes - determined by pKa.
Eg Lidocaine (pKa 7.9) vs bupivacaine (pKa 8.1) - so despite bupivacaine being more fat-soluble, much is unionised at physiological pH (7.4), so therefore less is available to cross the membrane to act on sodium channels.
Concentration gradient
Fick’s law - Rate of transfer across a membrane is proportional to the concentration gradient across the membrane
Bowman’s principle - A high dose of a less potent neuromuscular blocking agent will have faster onset of action due to a higher concentration gradient
Protein binding
Only the free fraction of a drug is available for physiological processes - if over 90% protein bound, then this plays a significant role in clinical effect.
For instance phenytoin easily saturates metabolic pathways, and zero-order kinetics can develop with small increases in plasma concentration.
Presence of carrier processes
Acrive transport, faciliated diffusion, pinocytosis
This applies to any phospholipid bilayer - and therefore applies to questions about gut absorption, placental transfer, or a specific cell.
Cardiac output and regional blood supply will always be key factors
Why is alfentanil faster than fentanyl, despite being less lipid soluble?
Alfentanil is 7x less fat soluble, but has faster onset for 3 reasons
Both agents are weak bases (ionised below their pKa).
Alfentanil’s pKa is 6.5, and fentanyl’s is 8.4. Therefore more alfentanil is unionised at phyisiological pH
Alfentanil is 10x less potent than fentanyl, so a much greater dose is given, creating a bigger concentration gradient
Alfentanil has a smaller volume of distribution, creating an even greater concentration gradient.
It is cleared more quickly than fentanyl, so has a shorter duration of action.
What is first pass metabolism and when is it useful? What routes avoid it?
When an orally administered drug is metabolised prior to entering the systemic circulation, usually by the liver or intestinal wall.
Morphine and midazolam both have significant first-pass metabolism.
It is clinically useful for pro-drugs - inactive molecules which are metabolised to the active compound.
Eg Codeine (CYP2D6) metabolised to morphine, Enalapril and morphine.
Drugs that induce hepatic enzymes will increase first-pass metabolism, and vice versa.
It is avoided by using one of the below routes:
Nasal
Sublingual
Intravenous
Intramuscular
Inhalational
Rectal
Transdermal
Intrathecal
Epidural
Topical
Subcutaneous
What is bioavailability?
IMAGE
The percentage of an orally adminstered drug that reaches the systemic circulation, compared to an IV dose.
It is the area under the oral concentration/time curve, divided by the area under the IV curve, multiplied by 100%.
Most of the time, maximal bioavailability is desirable - but zero bioavailability may also be useful - such as PO vancomycin for C. diff, or antacids/laxatives.
What factors affect bioavailability?
Route of administration & compliance (is the drug actually being taken?)
Molecule size (smaller = faster absorption)
Ionisation (Ionised drugs have lower bioavailability)
**Presence of active transport mechanisms **(levodopa is an analogue of amino acids)
Metabolism in the stomach (Benzylpenicillin inactivated by acid)
GI disease (Acquired & congenital malabsorption syndromes)
First pass metabolism (Lidocaine, morhine, midazolam have high first pass metabolism, and induction of enzymes increases first pass metabolism)
What factors specifically affect transdermal absorption of a drug?
Patient factors:
Age - Older skin absorbs less well, with structural differences such as reduced hypodermal & dermal layer thickness
Gender - Men have thicker & more acidic skin
Ethnicity - Darker skin has more melanocytes & thicker lipid matrix in the stratum corneum, reducing drug absorption
Skin status - Stratum corneum is the outermost layer of human skin, designed to act as a barrier - almost completely prevention absorption of polar molecules.
Absorption is affected by blood supply, surface area, moisture & temperature.
Disease - Inflamed or hyperkeratotic skin reduces absorption
Application site - lidocaine plasters must be directly over the rib # or affected nerve in the case of shingles.
Device factors:
Drug - Smaller molecule (< 500 daltons) will transfer more easily, partition coefficient, and potency
Adhesion - Patches need adequate glue, ointments/gels need to be well rubbed in
Skin penetration - some devices use microneedles to physically inject the drug under the stratum corneum.
What are the advantages & disadvantages of IM drug administration?
Advantages
Almost 100% bioavailability
Faster onset than oral
Disadvantages
Painful
Risk of accidental IV delivery
Haematoma & Abscess
Risk of overdose if poorly perfused area injected, then a second dose given, especially if perfusion then improves suddenly (such as IM adrenaline in shock)
What factors impact the amount of drug absorbed by the inhalational route?
Particle size
Determines where the drug will settle
Above 1μm deposits in the airway - causing local effect
Below 1μm reaches the alveolus, allowing systemic effects (such as the side effects of asthma inhalers)
Alveolar ventilation
Depending on the target site of action, dead space ventilation can reduce the amount of drug absorbed systemically.
The lungs provide a surface area of >70m² in an adult
Drug factors
Inhaled NO causes pulmonary vasodilation and is systemically absorbed, but due to binding to haemoglobin, it doesn’t persist long enough to cause systemic symptoms
What factors influence how long it takes for PO drugs to reach the blood?
Drug specific characteristics
Vomiting & compliance
Gut motility
Digestive enzymes
Interactions with other drugs
GI disease
Interactions with GI microbiome
What determines where in the gut a drug is absorbed?
Surface area - The enourmous surgace area of the small intestine means most drugs absorbed here
Gut transit time
pH and pKa
Weak acids (aspirin) are more unionised in the stomach - absorbed more rapidly - this is helpful in gastric stasis (such as in migraine), as gastric absorption is relatively unhindered
Weak bases (propranolol) are more unionised in the duodenum
Permanently charged ions (glycopyrrolate) are not absorbed from the gut
What drugs can be given by the epidural route?
Local anaesthetics (and Bicarbonate to speed up their onset)
Opioids
Ketamine
Clonidine
Steroids
Adrenaline to induce vasoconstriction & prevent systemic spread (reducing toxicity & increasing block duration)
