The absolute bioavailability of a drug, when administered by an extravascular route, is the fraction of the dose that reaches the systemic circulation as intact drug, which is usually less than 1. It depends on both how well the drug is absorbed and how much drug is removed by the liver before reaching the systemic circulation. There are many factors affecting the bioavailability of drugs. Physical properties of the drug (e.g. hydrophobicity and lipid solubility) and drug formulation (e.g. manufacturing methods, modified release and sustained release) will have significant impact on the bioavailability of a drug. Whether a drug is taken with or without food will also affect absorption. Other drugs taken concurrently may alter absorption and first-pass metabolism, and intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora.
In pharmacology, relative bioavailability measures the bioavailability (estimated as the area under the curve, AUC) of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard, or compared with administration via a different route. Therefore, relative bioavailability is one of the measures used to assess bioequivalence between two drug products. Relative bioavailability is sensitive to drug formulation.
2. Answer C
Drug–protein binding is the reversible interaction of drugs with proteins in plasma. The major drug-binding proteins in plasma are albumin, alpha1-acid glycoprotein and lipoproteins.
Phenytoin binds primarily to albumin in plasma, the bound fraction being 0.9 (0.69–0.95) under normal conditions. Protein binding may be greatly reduced in the presence of the following factors:
Albumin binds drugs and ligands, and therefore reduces the serum concentration of these compounds. An example is serum calcium, the free (ionised) concentration of which needs to be corrected for albumin. Competitive binding of drugs may occur at the same site or at different sites (conformational changes, e.g. warfarin and diazepam). The drugs that are important for albumin binding are warfarin, digoxin, non-steroidal anti-inflammatory drugs and benzodiazepines.
Drug–protein binding is the reversible interaction of drugs with proteins in plasma. The major drug-binding proteins in plasma are albumin, alpha1-acid glycoprotein and lipoproteins.
Phenytoin binds primarily to albumin in plasma, the bound fraction being 0.9 (0.69–0.95) under normal conditions. Protein binding may be greatly reduced in the presence of the following factors:
- Hypoalbuminaemia, e.g. due to severe hepatic or renal disease
- The last trimester of pregnancy, perhaps because of dilutional hypoalbuminaemia
- Renal failure because of a reduced affinity of albumin for phenytoin
- Displacement from protein-binding sites by salicylates, sodium valproate and sulphonylureas.
Albumin binds drugs and ligands, and therefore reduces the serum concentration of these compounds. An example is serum calcium, the free (ionised) concentration of which needs to be corrected for albumin. Competitive binding of drugs may occur at the same site or at different sites (conformational changes, e.g. warfarin and diazepam). The drugs that are important for albumin binding are warfarin, digoxin, non-steroidal anti-inflammatory drugs and benzodiazepines.
3. Answer D
Ligand-gated ion channels (LGICs) are a group of transmembrane ion channels that open or close in response to the binding of a chemical messenger (a ligand), such as a neurotransmitter (Mathie, 2010). The direct link between ligand binding and opening or closing of the ion channel, which is characteristic of LGICs, is contrasted with the indirect function of metabotropic receptors, which interact with G proteins and use second messengers and activating protein kinases. LGICs are also different from voltage-gated ion channels (which open and close depending on membrane potential), and stretch-activated ion channels (which open and close depending on mechanical deformation of the cell membrane).
Neurotransmitters activate LGIC receptors, such as glutamate, gamma-aminobutyric acid (GABA)A, purinergic P2X, nicotinic acetylcholine (ACh) and 5-hydroxytryptamine (5-HT3) receptors, and represent important therapeutic targets. Diazepam, varenicline, memantine and odansetron interact with GABA, nicotinic ACh, glutamate N-methyl-d-aspartic acid (NMDA) and 5-HT3 receptors, respectively. Insulin binds to the extracellular portion of the alpha subunits of the insulin receptor. This, in turn, causes a conformational change in the insulin receptor that activates the kinase domain residing on the intracellular portion of the beta subunits. The activated kinase domain autophosphorylates tyrosine residues on the C-terminus of the receptor as well as tyrosine residues in the insulin receptor substrate 1 (IRS-1) protein.
Ligand-gated ion channels (LGICs) are a group of transmembrane ion channels that open or close in response to the binding of a chemical messenger (a ligand), such as a neurotransmitter (Mathie, 2010). The direct link between ligand binding and opening or closing of the ion channel, which is characteristic of LGICs, is contrasted with the indirect function of metabotropic receptors, which interact with G proteins and use second messengers and activating protein kinases. LGICs are also different from voltage-gated ion channels (which open and close depending on membrane potential), and stretch-activated ion channels (which open and close depending on mechanical deformation of the cell membrane).
Neurotransmitters activate LGIC receptors, such as glutamate, gamma-aminobutyric acid (GABA)A, purinergic P2X, nicotinic acetylcholine (ACh) and 5-hydroxytryptamine (5-HT3) receptors, and represent important therapeutic targets. Diazepam, varenicline, memantine and odansetron interact with GABA, nicotinic ACh, glutamate N-methyl-d-aspartic acid (NMDA) and 5-HT3 receptors, respectively. Insulin binds to the extracellular portion of the alpha subunits of the insulin receptor. This, in turn, causes a conformational change in the insulin receptor that activates the kinase domain residing on the intracellular portion of the beta subunits. The activated kinase domain autophosphorylates tyrosine residues on the C-terminus of the receptor as well as tyrosine residues in the insulin receptor substrate 1 (IRS-1) protein.
Mathie, A. (2010). Ion channels as novel therapeutic targets in the treatment of pain. J Pharm Pharmacol 62, 1089–1095.
4. Answer D
Lithium is 100% renally cleared and has a narrow therapeutic index. Therefore, an estimate of renal function helps to select a starting dose for treatment. Subsequent dosing should be guided by measured drug concentrations and clinical response. Oxypurinol is the metabolite of allopurinol and it is 100% renally cleared, but has an intermediate therapeutic index. An estimate of renal function as an estimate of drug clearance provides useful guidance to dosing and can be used together with clinical and biochemical (e.g. serum urate concentration) measures of effect. Amoxicillin is 100% renally cleared, but has a wide therapeutic index. Most dosing guidelines for amoxicillin do not discriminate on the basis of renal clearance, except for patients with end-stage renal disease. A small change in the concentration of drugs with narrow therapeutic indices can cause toxicity or loss of efficacy (Doogue and Polasek, 2011).
Lithium is 100% renally cleared and has a narrow therapeutic index. Therefore, an estimate of renal function helps to select a starting dose for treatment. Subsequent dosing should be guided by measured drug concentrations and clinical response. Oxypurinol is the metabolite of allopurinol and it is 100% renally cleared, but has an intermediate therapeutic index. An estimate of renal function as an estimate of drug clearance provides useful guidance to dosing and can be used together with clinical and biochemical (e.g. serum urate concentration) measures of effect. Amoxicillin is 100% renally cleared, but has a wide therapeutic index. Most dosing guidelines for amoxicillin do not discriminate on the basis of renal clearance, except for patients with end-stage renal disease. A small change in the concentration of drugs with narrow therapeutic indices can cause toxicity or loss of efficacy (Doogue and Polasek, 2011).
Doogue, M.P. and Polasek, T.M. (2011). Drug dosing in renal disease. Clin Biochem Rev 32, 69–73.
5. Answer E
The optimal route and dose of antibiotic administration will depend on the pharmacological properties of the drug, which can be separated into three categories: concentration-dependent killing, total exposure and time-dependent killing.
The lincosamide antibiotics include clindamycin and lincomycin. This lipophilic class of antibiotics achieves wide distribution throughout the body and therapeutic concentrations in most body compartments. The time the concentration is above the minimum inhibitory concentration (T > MIC) has been determined to be the pharmacodynamic factor correlated with efficacy. Free drug levels of lincosamides should exceed the MIC of the infective pathogen for at least 40–50% of the dosing interval. Beta-lactams (penicillins, cephalosporins and carbapenems) also display this property.
Drugs such as aminoglycosides and quinolones are dependent on the maximum plasma drug concentration at the binding site that eradicates the bacteria. These drugs are concentration-dependent in their eradication of bacteria. Vancomycin is an example of a drug that is dependent on the total exposure of the body to the antibiotic [as indicated by the ratio of the area under the concentration–time curve during a 24-h time period (AUC0–24)] to MIC.
The optimal route and dose of antibiotic administration will depend on the pharmacological properties of the drug, which can be separated into three categories: concentration-dependent killing, total exposure and time-dependent killing.
The lincosamide antibiotics include clindamycin and lincomycin. This lipophilic class of antibiotics achieves wide distribution throughout the body and therapeutic concentrations in most body compartments. The time the concentration is above the minimum inhibitory concentration (T > MIC) has been determined to be the pharmacodynamic factor correlated with efficacy. Free drug levels of lincosamides should exceed the MIC of the infective pathogen for at least 40–50% of the dosing interval. Beta-lactams (penicillins, cephalosporins and carbapenems) also display this property.
Drugs such as aminoglycosides and quinolones are dependent on the maximum plasma drug concentration at the binding site that eradicates the bacteria. These drugs are concentration-dependent in their eradication of bacteria. Vancomycin is an example of a drug that is dependent on the total exposure of the body to the antibiotic [as indicated by the ratio of the area under the concentration–time curve during a 24-h time period (AUC0–24)] to MIC.
6. Answer B
Warfarin has a complex metabolic pathway and can be metabolised by a number of cytochrome P450 enzymes, but notably CYP2C9 (Tadros and Shakib, 2010). The anti-coagulant effects of warfarin may be exacerbated through the inhibition of its metabolism by cytochrome P450. Omeprazole, metronidazole, cimetidine and amiodarone may all do this, so the international normalised ratio (INR) should be carefully monitored in people taking these drugs. Rifampicin induces cytochrome P450 and thus reduces the anti-coagulant effects of warfarin (as may other inducers of cytochrome P450, such as some anti-convulsants). Oestrogen may reduce the anti-coagulant effect independently of cytochrome P450.
Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C and protein S. Other proteins not involved in blood clotting, e.g. matrix Gla protein, may also be affected and this may contribute to the rare association of warfarin with calciphylaxis.
Warfarin activity is determined partially by genetic factors. Polymorphisms in two genes (VKORC1 and CYP2C9) are important. VKORC1 polymorphisms explain 30% of the dose variation between patients as well as why African–Americans are on average relatively resistant to warfarin while Asians are generally more sensitive. CYP2C9 polymorphisms explain 10% of the dose variation between patients.
Warfarin has a complex metabolic pathway and can be metabolised by a number of cytochrome P450 enzymes, but notably CYP2C9 (Tadros and Shakib, 2010). The anti-coagulant effects of warfarin may be exacerbated through the inhibition of its metabolism by cytochrome P450. Omeprazole, metronidazole, cimetidine and amiodarone may all do this, so the international normalised ratio (INR) should be carefully monitored in people taking these drugs. Rifampicin induces cytochrome P450 and thus reduces the anti-coagulant effects of warfarin (as may other inducers of cytochrome P450, such as some anti-convulsants). Oestrogen may reduce the anti-coagulant effect independently of cytochrome P450.
Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C and protein S. Other proteins not involved in blood clotting, e.g. matrix Gla protein, may also be affected and this may contribute to the rare association of warfarin with calciphylaxis.
Warfarin activity is determined partially by genetic factors. Polymorphisms in two genes (VKORC1 and CYP2C9) are important. VKORC1 polymorphisms explain 30% of the dose variation between patients as well as why African–Americans are on average relatively resistant to warfarin while Asians are generally more sensitive. CYP2C9 polymorphisms explain 10% of the dose variation between patients.
Tadros, R. and Shakib, S. (2010). Warfarin – indications, risks and drug interactions. Aust Fam Physician 39, 476–479.
7. Answer B
Renal drug clearance is the net result of filtration clearance (at the glomerulus) plus clearance by active secretion (in the proximal tubule) minus reabsorption (which occurs all along the renal tubule). Passive tubular reabsorption is determined by the magnitude of the concentration gradient (which depends on the extent of water reabsorption) and the ease with which the drug can move through the membranes of the tubular cells. Only non-ionised drugs can pass through the lipid membrane readily and the ease with which this occurs depends on the lipid solubility of the non-ionised drug. The extent to which the drug is non-ionised depends on the pH of the urine and the acid dissociation constant (pKa) of the drug. Therefore, for drugs that are lipid soluble enough to be reabsorbed, and can ionise to an anion or a cation, renal clearance varies with the urine pH.
Renal drug clearance is the net result of filtration clearance (at the glomerulus) plus clearance by active secretion (in the proximal tubule) minus reabsorption (which occurs all along the renal tubule). Passive tubular reabsorption is determined by the magnitude of the concentration gradient (which depends on the extent of water reabsorption) and the ease with which the drug can move through the membranes of the tubular cells. Only non-ionised drugs can pass through the lipid membrane readily and the ease with which this occurs depends on the lipid solubility of the non-ionised drug. The extent to which the drug is non-ionised depends on the pH of the urine and the acid dissociation constant (pKa) of the drug. Therefore, for drugs that are lipid soluble enough to be reabsorbed, and can ionise to an anion or a cation, renal clearance varies with the urine pH.
8. Answer D
Ivabradine, unlike the traditional anti-anginal medications, has an anti-anginal effect by reducing heart rate but without any negative effect on left ventricular function (Marquis-Gravel and Tardif, 2008). Its anti-anginal and anti-ischaemic effects are not inferior to those of the beta-blocker atenolol and calcium-channel blocker amlodipine, and are superior to placebo. It acts on a specific channel, the f channel (If) in the sinus node, to reduce heart rate. Myocardial oxygen demand is reduced when the heart rate is decreased and oxygen supply is improved. Current guidelines recommend beta-blockers as first-line therapy, especially in post-myocardial infarction patients. Combination with calcium-channel blockers or long-acting nitrates may be indicated if the initial therapy fails. Ivabradine is indicated in patients with chronic stable angina who are in sinus rhythm and have a contraindication or an intolerance of beta-blockers. It is also a logical addition to the treatment of such patients when symptoms are not controlled by other anti-anginal medications.
Ivabradine, unlike the traditional anti-anginal medications, has an anti-anginal effect by reducing heart rate but without any negative effect on left ventricular function (Marquis-Gravel and Tardif, 2008). Its anti-anginal and anti-ischaemic effects are not inferior to those of the beta-blocker atenolol and calcium-channel blocker amlodipine, and are superior to placebo. It acts on a specific channel, the f channel (If) in the sinus node, to reduce heart rate. Myocardial oxygen demand is reduced when the heart rate is decreased and oxygen supply is improved. Current guidelines recommend beta-blockers as first-line therapy, especially in post-myocardial infarction patients. Combination with calcium-channel blockers or long-acting nitrates may be indicated if the initial therapy fails. Ivabradine is indicated in patients with chronic stable angina who are in sinus rhythm and have a contraindication or an intolerance of beta-blockers. It is also a logical addition to the treatment of such patients when symptoms are not controlled by other anti-anginal medications.
Marquis-Gravel, G. and Tardif, J.C. (2008). Ivabradine: the evidence of its therapeutic impact in angina. Core Evid 3, 1–12.
9. Answer B
Continuous intravenous infusion is an alternative way of administering drugs such as β-lactam and glycopeptide antibiotics. Given as a continuous infusion, the drug accumulates to a steady-state concentration determined only by the dose rate and clearance. The maintenance dose rate to achieve a target concentration can be calculated if the clearance is known. The time to reach steady-state is determined by the half-life, usually three to five half-lives.
It is well established that β-lactam and glycopeptide antibiotics exhibit time-dependent killing. The degree of anti-microbial killing correlates well with the amount of free drug remaining above the minimum inhibitory concentration (MIC) for a given amount of time over the dosing interval. Continuous infusion is a method of administration that allows for consistent steady-state concentrations and maximises the time above an organism’s MIC. Studies have shown that continuous infusion of piperacillin/tazobactam or vancomycin is a safe and effective alternative to intermittent infusion for the treatment of appropriate infections. Continuous infusion of piperacillin/tazobactam should be considered for infections due to multidrug resistant organisms when sensitivities to piperacillin/tazobactam are reported as ‘intermediate’. There is insufficient evidence to support the use of meropenem or cefepime administered as a continuous infusion.
Continuous intravenous infusion is an alternative way of administering drugs such as β-lactam and glycopeptide antibiotics. Given as a continuous infusion, the drug accumulates to a steady-state concentration determined only by the dose rate and clearance. The maintenance dose rate to achieve a target concentration can be calculated if the clearance is known. The time to reach steady-state is determined by the half-life, usually three to five half-lives.
It is well established that β-lactam and glycopeptide antibiotics exhibit time-dependent killing. The degree of anti-microbial killing correlates well with the amount of free drug remaining above the minimum inhibitory concentration (MIC) for a given amount of time over the dosing interval. Continuous infusion is a method of administration that allows for consistent steady-state concentrations and maximises the time above an organism’s MIC. Studies have shown that continuous infusion of piperacillin/tazobactam or vancomycin is a safe and effective alternative to intermittent infusion for the treatment of appropriate infections. Continuous infusion of piperacillin/tazobactam should be considered for infections due to multidrug resistant organisms when sensitivities to piperacillin/tazobactam are reported as ‘intermediate’. There is insufficient evidence to support the use of meropenem or cefepime administered as a continuous infusion.
10. Answer E
The primary pathways of paracetamol metabolism are glucuronidation and sulphation to non-toxic metabolites (>90% of a therapeutic dose), while approximately 5% is metabolised by cytochrome P450 2E1 to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is extremely toxic to the liver. Ordinarily NAPQI is rapidly detoxified by interaction with glutathione to form cysteine and mercapturic acid conjugates. If glutathione is depleted, NAPQI interacts with various macromolecules, leading to hepatocyte injury and death. Glutathione is synthesised from the amino acids cysteine, glutamate and glycine. Glutamate and glycine are present in abundance in hepatocytes, but the availability of cysteine is the rate-limiting factor in glutathione synthesis. However, cysteine is not well absorbed after oral administration. In contrast, N-acetylcysteine is readily absorbed and rapidly enters cells, where it is hydrolysed to cysteine, thus providing the limiting substrate for glutathione synthesis.
The Rumack–Matthew nomogram, first published in 1975, estimates the likelihood of hepatic injury caused by paracetamol for patients with a single ingestion at a known time. To use the nomogram, the patient’s plasma paracetamol concentration and the time since ingestion are plotted. If the resulting point is above and to the right of the sloping line, hepatic injury is likely and the use of N-acetylcysteine is indicated. Patients with repeated supratherapeutic ingestion or unknown time of ingestion cannot be evaluated with the use of this nomogram (Daly et al., 2008).
The primary pathways of paracetamol metabolism are glucuronidation and sulphation to non-toxic metabolites (>90% of a therapeutic dose), while approximately 5% is metabolised by cytochrome P450 2E1 to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is extremely toxic to the liver. Ordinarily NAPQI is rapidly detoxified by interaction with glutathione to form cysteine and mercapturic acid conjugates. If glutathione is depleted, NAPQI interacts with various macromolecules, leading to hepatocyte injury and death. Glutathione is synthesised from the amino acids cysteine, glutamate and glycine. Glutamate and glycine are present in abundance in hepatocytes, but the availability of cysteine is the rate-limiting factor in glutathione synthesis. However, cysteine is not well absorbed after oral administration. In contrast, N-acetylcysteine is readily absorbed and rapidly enters cells, where it is hydrolysed to cysteine, thus providing the limiting substrate for glutathione synthesis.
The Rumack–Matthew nomogram, first published in 1975, estimates the likelihood of hepatic injury caused by paracetamol for patients with a single ingestion at a known time. To use the nomogram, the patient’s plasma paracetamol concentration and the time since ingestion are plotted. If the resulting point is above and to the right of the sloping line, hepatic injury is likely and the use of N-acetylcysteine is indicated. Patients with repeated supratherapeutic ingestion or unknown time of ingestion cannot be evaluated with the use of this nomogram (Daly et al., 2008).
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