Absorption and distribution Flashcards
Bioavailability
Definition
= fraction of drug dose reaching the systemic circulation, compared with the same dose given intravenously
Determined by the ratio of area under the concentration time curves for an identical bolus dose given both orally and intravenously.
NB in general, oral route has lowest bioavailability
What factors influence oral bioavailability
4 factors, formula to calculate
- Pharmaceutical preparation: small particle size, liquid -> disperse rapidly. Large particle size, or binding agents preventing drug dissolution in the stomach (enteric coated preparations) -> delayed absorption
- Physiochemical interactions with other drugs or food: e.g. absorption of tetracyclines is reduced by concurrent Ca2+ (e.g. in milk)
- Patient factors: malabsorption syndromes (Coeliac disease, tropical sprue) or gastric stasis (trauma, drugs) will affect absorption or slow transit time
- Pharmacokinetics, first-pass metabolism: metabolism at either gut wall (e.g. GTN) or liver. Hepatic enzyme inducers/inhibitors will therefore reduce/increase oral bioavailability.
Therefore, for an orally administered drug:
Bioavailable fraction = fraction absorbed * fraction remaining after metabolism in gut mucosa * fraction remaining after hepatic metabolism
Absorption through the gut mucosa
Examples of acids, bases, permanently charged
For drugs without specific transport mechanisms, only the unionised fraction passes readily through the lipid membranes of the gut
* In stomach: low pH, therefore acidic drugs (e.g. aspirin) are more unionised than basic drugs and absorbed more rapidly
* In duodenum (pH ~6): weak bases (e.g. propranolol) are more unionised and absorbed
* Permanently charged drugs e.g. vecuronium, glycopyrrolate, remain ionised and are not absorbed from the GI tract
NB even acidic drugs are mostly absorbed from the small bowel due to much larger surface area due to presence of mucosal villi. However advantage of acidic drugs= initially rapid absorption, which will continue even in GI stasis
Extraction ratio
What depends on, 3 relevant groups of drugs
= fraction of drug removed from blood by the liver
Depends on
* Hepatic blood flow
* Uptake into hepatocyte
* Enzyme metabolic capacity within the hepatocyte
Importance of each varies between drugs. 3 distinct groups
* Drugs for which hepatocyte has rapid uptake and high metabolic capacity –> extraction is highly dependent on liver blood flow, independent of protein binding
* Drugs with low metabolic capacity and high level of proten binding —> extraction is more influenced by protein binding ** than changes in hepatic blood flow
* Drugs with low metabolic capacity **and low level of protein binding –> extraction is unaffected by hepatic blood flow or changes in protein binding
Michaelis constant
Describes the activity of an enzyme
= the concentration of substrate at which it is working at 50% of its maximum rate
Enzymes with high metabolic capacity will have Michaelis constants»_space; substance concentrations likely to be found clinically.
Enzymes with low metabolic capacity: Michaelis constants close to clinically relevant concentrations
Drugs with rapid uptake by hepatocytes and high metabolic capacity: what determines ER
Examples (2)
ER = fraction of drug removed from blood by liver
Examples = propofol, lidocaine
- Free drug is rapidly removed from plasma
- Bound drug is released to maintain equilibrium. NB protein binding has rapid equilibrium
- Metabolism is rapid, maintaining concentration gradient between plasma and hepatocyte
Therefore amount of drug metabolised is
* independent of protein binding (because protein binding has rapid equilibrium)
* highly dependent on liver blood flow
Drugs with low metabolic capacity and high levels of protein binding: what determines ER
Examples (2)
ER = fraction of drug removed from blood by liver
Examples = phenytoin, diazepam
ER is limited by metabolic capacity of the hepatocyte and not by hepatic blood flow. ER is more influenced by changes in protein binding than changes in hepatic blood flow
Mechanism:
* If protein binding is altered (e.g. by competition) -> free concentration of drug increases significantly
* Initially increases uptake into hepatocyte and increases rate of metabolism: plasma levels of free drug do not change significantly
* However if intracellular concentration > maximum metabolic capacity (enzyme saturated) -> drug levels iwthin the cell remain high -> reduced concentration gradient -> reduced uptake -> reduced extraction ratio
If drug has narrow therapeutic index, toxicity may develop
Sublingual, nasal and buccal routes of drug admistration
Advantages (2), with examples
- Rapid onset
- Higher bioavailability (avoid portal tract)
- Useful when rapid effect is essential e.g. GTN spray for angina, sublingual nifedipine for rapid control of hypertension
Rectal route of drug administration
Comparison with oral route
- Avoids first-pass metabolism
- Drugs may be given for local (e.g. steroids for IBD) or systemic effects
- Little evidence that more effective than oral route: relatively small surface area, absorption may be slow or incomplete
IM and subcutaneous route of drug administration
Advantages, comparison to oral and IV, contraindications
IM
* Avoids first-pass metabolism, bioavailable fraction approaches 1
* Speed of onset generally more rapid than oral route, for some drugs approaches that of IV
Rate of absorption depends on local perfusion at site of IM injection
* Deltoid, quadreiceps, gluteus are well-perfused
* Systemic hypotension or local vasoconstrictoin -> IM injection will not be absorbed until muscle perfusion is restored.
Contraindications/ cautions:
* Concerns about inadequate perfusion e.g. hypotension
* Abnormal clotting -> may cause haematoma or local abscess
* NB risk of inadvertent IV injection
Subcutaneous
* Useful if patient compliance problematic e.g. depot injections for contraception, antipsychotics
* Kinetics of absorption are dependent on local and regional blood flow
Transdermal route of drug administration
Factors favouring transdermal absorption, examples
- Avoids first-pass metabolism: improves bioavailability
- High lipid solubility and good regional blood supply improve absorption (therefore thorax, abdomen preffered to limbs)
- Patches can ensure slow constant release of drug: only small amounts of drug are released, so potent drugs better suited
Examples
* Fentanyl patches
* Nitrate patches
* Topical EMLA
* Topical amethocaine
EMLA and amethocaine
Drugs involved, effects
EMLA = eutectic mixture of local anaesthetic. A eutetic mixture (each agent lowers boiling point of other forming a gel-phase) of lidocaine and prilocaine
* Causes vasoconstriction
Amethocaine = ester-linked local anaesthetic.
* May cause mild histamine release -> local vasodilation
Inhaled route of drug administration
Systemic vs local effects
Determinants of whether drug reaches alveolus and therefore systemic circulation:
* Particle size: droplets of <1 micron diameter can reach alveolus
* Method of administration
Some drugs are intended for local site of action but can be systemically absorbed -> systemic side effects
* Inhaled or nebulised bronchodilators: bronchial airways
* Nebulised adrenaline: upper airway oedema
* Topical lidocaine for fibreoptic intubation
Some drugs are intended for systemic action
* Volatile anaesthetic agents
* Note large surface area of lung (70m sq in adult) -> rapid increase in systemic concentration -> rapid onset of action
Does inhaled nitric oxide cause systemic effects?
Usually no
Inhaled nitric oxide reaches the alveolus and dilates the pulmonary vasculature i.e. is systemically absorbed
However does not produce unwanted systemic effects as has short half-life, as a result of binding to haemoglobin
Epidural route of drug administration
Deteminants of speed of onset and duration of block
Given epidurally:
* For acute pain: local anaesthetics, opiods, ketamine, clonidine
* Diagnostic and therapeutic purposes in chronic pain: steroids
Speed of onset of block: determined by proportion of unionised drug available to penetrate the cell membrane:
* Local anaesthetics are weak bases with pKa > 7.4 i.e. are predominantly ionised at physiological pH. Those with lower pKas e.g. lidocaine, will be less ionised, with faster onset than e.g. bupivacaine
* Addition of sodium bicarbonate to local anaesthetic solution increases pH and unionised fraction -> faster onset
Duration of block: depends on tissue binding of agent and loss of local anaesthetic from epidural space
* Addition of vasoconstrictor e.g. adrenaline, felypressin, increases duration of block by reducing loss of local anaesthetic from epidural space
Systemic absorption of drugs from epidural and intrathecal spaces
Significant amounts of drug may be absorbed from epidural space, particularly during infusions
Compared with epidural route, amount of drug required given intrathecally is very small, and little reaches systemic circulation.
What factors influence drug distribution
Physiochemical (4)
Drug distribution depends on factors that influence passage of drug across cell membrane, and regional blood flow
Physiochemical factors:
* Molecular size
* Lipid solubility
* Degree of ionisation
* Protein binding
What general groups of drugs exist with regards to distribution (3)
Examples
Confined to plasma
* Too large to cross vascular endothelium e.g. dextran 70
* Intensely protein bound so unbound fraction (available to leave the circulation) is immeasurably small e.g. warfarin
Limited distribution
* E.g. non-depolarising muscle relaxants: polar, poorly lipid soluble and bulky. Distribution limited to tissues with fenestrated capillaries (e.g. muscle) that allow movement out of plasma. Cannot cross cell membranes, work extracellularly
Extensive distribution
* Often highly lipid soluble. If molecular size is relatively small, plasma protein binding does not affect distribution due to weak nature of these interactions
* OR sequestered by tissues, essentially removing them from the circulation
Examples of drugs which are sequestered by tissues
Amiodarone by fat
Iodine by the thyroid
Tetracyclines by bone
Which tissues are drugs distributed to after administration
If not confined to plasma:
* Initially distributed to those with highest blood flow: brain, lung, kidney, thyroid, adrenal
* Then to those with moderate blood flow: muscle
* Then very low blood flow: fat
Blood brain barrier: which types of drugs can cross
Examples by mechanism, examples of drugs which cannot
Note: active transport and facilitated diffusion are the predominant methods of molecular transfer
- Simple diffusion: only lipid soluble, low molecular weight drugs: intravenous and inhaled anaesthetics
- Active transport: glucose, hormones e.g. insulin
Cannot cross BBB:
* Large, polar muscle relaxants: therefore have no central effect
* Glycopyrolate (has a quarternary, charged nitrogen)
* Substrates for ABC transport proteins which protect the brain from toxins, certain antibiotics and cytotoxics
Why does atropine, not glycopyrolate, cause confusion etc
Glycopyrolate has a quarternary, charged nitrogen, and does not cross the BBB readily
However atropine is a tertiary amine, can cross BBB and may cause centrally mediated effects e.g. confusion, paradoxical bradycardia
Monoamine oxidase in the BBB
Clinical implications
As well as anatomical barrier, BBB contains enzymes e.g. monoamine oxidase: converts monoamines to non-active metabolites by passing through the BBB.
Physical disruption of BBB -> may lead to central neurotransmitters being released into the systemic circulation -> may explain marked circulatory disturbance with head injury and subarachnoid haemorrhage.
Does penicillin cross the BBB?
In healthy subject, penicillin has poor penetration of BBB
However in meningitis, BBB becomes inflamed, and permeability to penicillin (and other drugs) increases
Placental membrane that separates fetal and maternal blood
Structure, origin, selectivity compared to BBB
- Initialy derived from adjacent placental synctiotrophoblast and eetal capillary membranes, which then fuse to form single membrane
- Phospholipid: more readily crossed by lipid soluble than polar molecules
- However much less selective than BBB, even molecules with only moderate lipid solubility appear to cross easily.
What factors promote transfer of drugs across the placenta
Drugs with low molecular weight that are lipid soluble pass more easily than large polar molecules
Rate of drug equilibration between mother and fetus depends on:
* Placental blood flow
* Free drug concentration gradient between maternal and fetal blood
May affect concentration gradient
* Protein binding: pH of fetal blood is lower than the mother - therefore fetal plasma protein binding may differ. High protein binding in fetus increases drug transfer across placenta as fetal free drug levels are low. However high protein binding in mother reduces rate of drug transfer
* Rates of metabolism: fetus may metabolise some drugs: rate of metabolism increases as fetus matures.
Transfer of bupivacaine given during labour to fetus
Ion trapping
Bupivacaine crosses placenta less readily than lidocaine as pKa is higher - so more ionised than lidocaine at physiological pH
Risk of ion trapping:
* Fetus is relatively acidotic with respect the mother. If becomes even more acidotic due to placental insufficiency: ion trapping may become significant
* Fraction of ionised bupivacaine within the fetus increases as the fetal pH falls (charged so cannot leave fetal circulation) - levels may rise towards toxicity at birth
Transfer of pethidine to fetus
Pethidine is commonly given during labour for analgesia
Highly lipid soluble: significant amounts cross placenta.
Metabolised to norpethidine, which can accumulate in fetus:
* Less lipid soluble
* Levels peak about 4 hours after initial maternal dose
* Due to reduced fetal clearance, half-lives of both pethidine and norpethidine are prolonged up to 3x
Transfer of thiopentone to fetus
- Crosses placenta rapidly: has been detected in umbilical vein within 30 seconds of administration to mother. Peak fetal levels occur within 3 minutes of maternal injection
- No evidence that fetal outcome is affected
Transfer of nondepolarising muscle relaxants to fetus
Nondepolarising muscle relaxants are large, polar molecules: do not cross the placenta - fetal NMJ is not affected.
Very small amounts of suxamethonium cross the placenta
* Usually has little effect
* If mother has inherited enzyme deficiency and cannot metabolise suxamethonium: maternal levels remain high, significant transfer may occur
* If fetus has also inherited enzyme defect, may be element of depolarising blockade at fetal NMJ
