Chapter 3b – Pharmacology Answers


Pharmacology Answers

Chapter 3b Pharmacology Answers

Question 1: TTFTF

Racemic mixtures are mixtures of different enantiomers in equal proportions. While the mixture may contain equal amounts of the two isomers, the contribution to activity (pharmacodynamic and pharmacokinetic) may be very different. One isomer may be completely inactive or, at worst, be responsible for toxicity and undesirable side effects.

All of the volatile agents, with the exception of sevoflurane, are racemic mixtures. Other examples include racemic bupivacaine, ketamine, atropine and racemic epinephrine. Levobupivacaine, by virtue of the fact that it is one of the optical isomers of bupivacaine, is enantiopure (i.e. not a mix of two isomers). This selection of the more desirable moiety from the racemic mixture improves the safety profile of the drug, by using the isomer with fewer side effects and less chance of toxicity.

Question 2: TFTFF

S(+)-ketamine has several advantages over racemic ketamine. It produces less intense (although no less frequent) emergence phenomena. It also has greater affinity for the NMDA receptor than R(–)-ketamine, meaning that it is three times as potent an analgesic. S(+)-ketamine is thought to produce less direct cardiac depression; therefore the risk of cardiac ischaemia is lower. Recovery is more rapid with S(+)-ketamine.

The single advantage of levobupivacaine (the S-enantiomer) over bupivacaine and other local anaesthetics is its potential for reduced toxicity. It has two useful properties: firstly, the dose required to produce myocardial depression is higher for levobupivacaine and, secondly, excitatory CNS effects or convulsions occur at lower doses with bupivacaine than levobupivacaine.

Ropivacaine is prepared as the pure S-enantiomer (the R-enantiomer is less potent and more toxic). The main differences between it and bupivacaine lie in its pure formula, improved side effect profile and lower lipid solubility. This lower lipid solubility may result in reduced penetration of the large myelinated Aβ motor fibres, so that these are initially spared.

Question 3: FFFTF

Since only the unbound fraction of a drug in the plasma is free to cross the cell membrane, it is in fact the degree of protein binding that determines the duration of drug action (the higher the degree of protein binding, the greater the duration of action). The lipophilic cell membrane will only allow the passage of the uncharged fraction of a drug. The degree of drug ionization depends on the molecular structure of the drug and the pH of the solution in which it is dissolved. Ionization therefore determines the speed of onset of the drug action.

Although lipid solubility reflects the ability of a drug to cross the cell membrane, it does not necessarily equal rapid onset of action. Alfentanil is almost seven times less lipid-soluble than fentanyl yet its onset is much more rapid. This is due to various factors, including the fact that it has a smaller volume of distribution and a lower pKa than fentanyl (meaning that at physiological pH a greater fraction of alfentanil is unionized). Aspirin is almost wholly ionized at physiological pH as it is an acid. However, in the acidic environment of the stomach, pH is closer to the pKa of aspirin and the drug becomes essentially unionized, thus increasing its rate of absorption. Applying the same principles to the addition of sodium bicarbonate to lidocaine, by raising the pH of the solution, this increases the proportion of unionized local anaesthetic, enabling it to penetrate nerve membranes more readily. Thus, speed of onset is increased. The degree of protein binding will affect placental transfer. Bupivacaine is more highly bound than lidocaine, so less crosses the placenta. If the fetus becomes acidotic there will be an increase in the ionized fraction and local anaesthetic will accumulate in the fetus (ion trapping).

Question 4: FTTTF

Dose is plotted on the x-axis and the response on the y-axis. The log10 dose–response curve can be used to determine the potency of a drug. In general, the more potent a drug, the further to the left it will lie on a dose–response curve and indeed the steeper the curve will be. The ED50 can be determined from the log10 dose–response curve and used to define potency. This is the dose of the drug that produces 50% of the maximal response. Lower efficacy of a drug is exhibited when the curve does not reach the same plateau as another drug in comparison.

The effect of an antagonist on the dose–response curve of an agonist is to shift it to the right. There are two types of antagonist, competitive and non-competitive. The action of a competitive antagonist can be overcome by increasing the dose of the agonist. However, in the case of non-competitive antagonism this is not possible due to the fact that the binding sites are different.

Question 5: FFFFF

Phenylephrine is a direct-acting sympathomimetic α1 receptor agonist. It causes an increase in blood pressure due to an increase in the systemic vascular resistance with an associated reflex bradycardia.

Doxazosin is an α-adrenergic blocking agent that is used in the treatment of essential hypertension.

The antiemetic drug ondansetron is highly selective as an antagonist at the 5HT3 receptor. It has actions centrally and peripherally.

Ketamine is a non-competitive antagonist at the NMDA-type glutamate receptor. It causes a dose-dependent depression of the CNS, resulting in a dissociative state characterized by analgesia and amnesia.

Dexmedetomidine is a specific α2-adrenergic receptor agonist that may be used for the short-term sedation of ventilated patients on an intensive care unit. As a single agent it may provide effective sedation, analgesia and anxiolysis with a stable respiratory rate.

Question 6: FFFTF

The therapeutic window is the range of doses of a drug that leads to a therapeutic response in the absence of toxic effects. This can be quantified by the use of the therapeutic index, which is a ratio of LD50:ED50, hence it has no units. For greater safety the drug should have a high therapeutic index.

Warfarin, vancomycin and digoxin are examples of drugs with a low therapeutic index. Penicillin and ibuprofen have a high therapeutic index.

Question 7: FTFTF

The efficacy of a partial agonist is greater than zero but less than the full agonist, despite full receptor occupancy. Antagonists require the presence of an agonist or partial agonist to exert their effect. The fact that an agent may have affinity does not mean that it will have efficacy. Once binding has occurred then the ability to bind and the size of response are associated, but this is not a linear relationship. Partial agonists and full agonists bind to the same site on the receptor and thus can reduce the effect of the full agonist. This means that partial agonists can act as competitive antagonists. Buprenorphine is a partial agonist at the μ-opioid receptor and as such is used in opioid addiction programmes.

Question 8: FTTFT

G-protein-coupled receptors (GPCRs) are intracellular trimeric proteins associated with a transmembrane receptor. The trimer consists of α, β and γ subunits. Extracellular receptor binding causes activation of the GPCR. The α subunit of the trimer is activated and substitutes GDP for GTP. This causes splitting of the trimer and activation of downstream cell signalling cascades. The physiological effects depend on the ligand binding the receptor and the receptor type. Receptor variation arises via variances in the α subtype. Gi GPCR activation results in the deactivation of adenylyl cyclase and a reduction in cAMP levels. Opiates are agonists at the Gi GPCR. α1-Adrenoreceptors are of the Gq subtype and binding of an agonist results in the activation of protein kinase C. α2-Adrenoreceptors are of the Gi subtype.

Question 9: TFFFT

The differences between tachyphylaxis, desensitization and tolerance are subtle but important to recognize. Ephedrine is an example of a drug that, with repeated doses, displays tachyphylaxis. The rapid loss of response to repeated doses of ephedrine is attributed to depletion of noradrenaline stores at sympathetic nerve terminals, which ephedrine indirectly stimulates. Tolerance is the phenomenon associated with progressively larger doses of drug being needed to produce the same biological effect. Theoretically, the maximal biological response is still possible. Opiate abuse is an example of this. In contrast, desensitization and tachyphylaxis cause a reduction in maximal biological effect. With tachyphylaxis the mechanism is due to the depletion of a messenger intermediate. Desensitization results in qualitative or quantitative deficiency in receptors.

Question 10: TFFTF

Acetylcholinesterase inhibitors have direct everyday relevance to the anaesthetist, therefore detailed pharmacological knowledge is expected. Edrophonium reversibly binds to the anionic and esteratic sites of acetylcholinesterase, rendering the enzyme incapable of catalyzing the breakdown of acetylcholine. The relative instability of the complex accounts for the short duration of action. It therefore has a diagnostic rather than a treatment role in the management of myasthenia gravis. Neostigmine binds to the anionic site of acetylcholinesterase and results in the formation of a carbamylated enzyme complex. It is an analogue of the naturally occurring compound physostigmine. Both of these agents are known as ‘carbamates’, and are related to carbamic acid. The carbamylated complex has greater stability than the acetylcholinesterase–edrophonium complex. Therefore the duration of action of carbamates is longer. Neostigmine is used to reverse non-depolarizing neuromuscular blockade. Paradoxically, it can prolong the duration of action of suxamethonium due to its additional inhibition of plasma cholinesterase. Neostigmine is also used in the treatment of myasthenia gravis.

One of several hypotheses for the aetiology of Alzheimer’s disease is depletion of acetylcholine as a central neurotransmitter. Rivastigmine and galantamine are other carbamates used in the treatment of this disease. Organophosphates irreversibly phosphorylate acetylcholinesterase, and victims of organophosphate poisoning may die from the subsequent cholinergic effects. Treatment includes administration of pralidoxime, which hydrolyzes the phosphorylated enzyme and promotes recovery. Dicobalt edetate is the treatment for cyanide poisoning.

Question 11: FTTTF

Lidocaine is a Class 1b antiarrhythmic agent. By blocking fast sodium channels it reduces the rate of rise of membrane depolarization and increases the membrane depolarization threshold (prolongation of phase 0). The refractory period is reduced owing to faster repolarization (phase 3). Flecainide (Class 1c) similarly blocks sodium channels resulting in a prolonged phase 0. However, it has no effect on the refractory period. Verapamil is a calcium channel blocker with a predilection for the pacemaker ion channels. It has less effect on vascular smooth muscle, although it does cause a degree of coronary artery vasodilatation. By blocking slow L calcium channels in the SA and AV nodes, the degree of spontaneous membrane depolarization is reduced, therefore leading to reduced automacity. Amiodarone is primarily a Class 3 agent and a potassium channel blocker. The result is a slower repolarization rate (phase 3) and consequently a longer refractory period and action potential.

Question 12: TFTFF

G-proteins are cell membrane proteins that mediate the intracellular response to coupled membrane receptors. They consist of three subunits: α, β and γ. The GABAA receptor is a member of the pentameric family of receptors and has five subunits, which span the cell membrane. Another example from this family is the nicotinic acetylcholine receptor at the neuromuscular junction. There are at least four different types of receptors that co-ordinate biochemical events within the cell:

  • Type 1: Ligand gated ion channel. Examples: nicotinic acetylcholine receptor and GABAA.

  • Type 2: G-protein coupled receptor. Examples: muscarinic acetylcholine receptor and opioid receptors.

  • Type 3: Enzymes e.g. tyrosine kinase. Example: insulin receptor.

  • Type 4: Intracellular receptors (which act via gene transcription). Examples: steroid and thyroid hormones.

Question 13: FTFFT

An adverse drug reaction may be defined as ‘the occurrence of any drug effect that is not of therapeutic, diagnostic or prophylactic benefit to the patient’. They may be subdivided into type A and B reactions. Type A reactions are predictable and dose dependent, e.g. hypotension following propofol administration. Type B reactions are also known as idiosyncratic drug reactions. These are less common than Type A reactions. They are unpredictable, dose independent and unrelated to the known pharmacological properties of a drug. These reactions usually involve the immune system. Anaphylaxis (IgE mediated) and anaphylactoid (non-IgE mediated) reactions are examples of Type B drug reactions. All unexpected or life-threatening adverse drug reactions should be reported to the MHRA.

Question 14: TTTFF

Cytochrome P450 is found in the smooth endoplasmic reticulum of hepatocytes. Inhibitors and inducers of this enzyme system cause drug interactions; inhibition will result in reduced/delayed metabolism of other cytochrome-metabolized drugs, whereas inducers will shorten the effect of other cytochrome-metabolized drugs. Cytochrome P450 inducers in common use include phenytoin, carbamazepine, rifampicin, chronic alcohol, barbiturates and cigarette smoking. Cytochrome P450 inhibitors in common use include erythromycin, metronidazole, omeprazole, amiodarone, grapefruit juice and cyclosporin.

Question 15: TTFTT

Moclobemide is a reversible monoamine oxide (MAO) inhibitor used to treat depression. It selectively inhibits MAO-A, resulting in a reduced breakdown of serotonin, noradrenaline and dopamine. Selective MAO-A inhibitors are thought to be safer than the older, non-selective MAO inhibitors. These were associated with potential hypertensive crises when taken in conjunction with tyramine-containing foods (the ‘cheese reaction’). Tyramine is also metabolized by MAO, and tyramine accumulation can cause hypertension via potential displacement of noradrenaline at nerve terminals. Selective MAO-A inhibitors allow MAO-B to continue to function and clear dietary tyramine. However, a potential hypertensive crisis may still be precipitated by co-administration of indirectly acting sympathomimetic agents, e.g. ephedrine and metaraminol. ACE inhibitors and non-steroidal drugs may cause acute kidney injury, especially in the elderly and during the perioperative period. Warfarin and grapefruit juice may increase the risk of bleeding via cytochrome P450 inhibition. β-Blockers and the non-dihydropyridine calcium channel blockers (verapamil and diltiazem) can cause profound bradycardia, conduction defects and depression of myocardial contractility. Metoclopramide is a dopamine antagonist and as such may cause extrapyramidal side effects and worsen the symptoms of Parkinson’s disease.

Question 16: FTTTF

Drug interactions are a common cause of morbidity and mortality. In the same way as classification of the properties of an individual drug, interactions may be classified into physicochemical, pharmacokinetic and pharmacodynamic interactions. Physicochemical interactions result from chemical or physical incompatibility, e.g. the activity of the acidic heparin is terminated by the strongly basic protamine. Pharmacokinetic interactions occur due to the effects of co-administered drugs on absorption, distribution, metabolism and elimination. For example, β-blockers reduce cardiac output, which may reduce the distribution of other drugs to their site of action. Pharmacodynamic interactions occur as a result of competition for the binding site of an enzyme or receptor. Competition may be direct – substance A and B compete for the same site on a receptor (e.g. flumazenil and benzodiazepines) – or indirect – in the presence of substance A on one site of a receptor, substance B is unable to bind to another site on a receptor (e.g. neostigmine and acetylcholine). Synergism occurs where the net effect of two or more drugs is more than the sum of the individual actions. For example, in the Oxford league table of analgesic efficiency, the NNT to cause a 50% reduction in pain is 16.7 with 60 mg of codeine, 3.8 with 1 g of paracetamol, but only 2.2 with a combination of 60 mg codeine and 1 g paracetamol. The isobolograms seen with remifentanil and propofol, when given as total intravenous anaesthesia, are another example of synergism.

Question 17: TTTFT

Most processes involving drugs within the body can be described by first-order kinetics. This means that plasma levels of the drug are proportional to the amount of drug present (i.e. an exponential function – the rate of change of drug A is proportional to the concentration of A). The majority of metabolic processes are first-order as there is a relative excess of enzyme compared to substrate, so enzyme activity is not rate-limiting. In zero-order kinetics, the rate of change of plasma drug concentration is constant rather than being dependent on the concentration of drug present. It is otherwise known as saturation kinetics, indicating that enzyme activity cannot be increased by increasing substrate concentration. A good example is the metabolism of ethanol. Humans metabolize ethanol at a constant rate, regardless of how much we have ingested. This is because the enzyme alcohol dehydrogenase requires a co-factor for its reaction, which is only present in small amounts. There is no steady state in zero-order kinetics. If rate of drug delivery exceeds excretion, plasma levels will continue to rise to toxic levels. Drugs that undergo zero-order kinetics may therefore have a narrow therapeutic window; a small increase in dose may cause a large increase in plasma levels, making toxicity more likely. Phenytoin obeys first-order kinetics at low dose, but zero-order at higher therapeutic doses.

Question 18: TFFTF

The blood–brain barrier (BBB) is an anatomical and functional barrier of tight junctions between the circulation and the central nervous system. In health, this barrier is tightly controlled, and the predominant method of molecular transfer is by active transport and facilitated diffusion. Only lipid-soluble, low molecular weight drugs can cross by simple diffusion, whilst large, polar molecules cannot.

Whilst atropine readily crosses the BBB (it is an uncharged, tertiary amine), glycopyrronium does not, due to its quaternary, charged nitrogen. This means it is far less likely to produce the centrally mediated confusion or sedation seen with atropine use. In health, penicillin poorly penetrates the BBB. However, in conditions such as meningitis, the BBB becomes inflamed and compromised. This allows greater permeability for drugs such as benzylpenicillin and hence allows them to have a more therapeutic action. Thiopentone is highly lipid-soluble, therefore crosses the BBB easily. Vecuronium is a large, polar muscle relaxant, which explains why it cannot penetrate the BBB.

Question 19: FFFTT

A number of pharmacokinetic differences are seen in the elderly population. Older people have a relative reduction in muscle mass with a resulting increase in the proportion of adipose tissue; this increases VD.

Hepatic impairment alters many aspects of drug handling. Protein synthesis is decreased, resulting in reduced protein binding and increased free drug. Phase I and II reactions are affected, which reduces the metabolism of drugs. Ascites increases VD and portocaval shunts increase bioavailability by reducing hepatic clearance of drugs. Although it would be expected that it is necessary to reduce the dose of renally excreted drugs in those with renal impairment, this may not always be the case. In renal failure, patients may have significant fluid retention and hence the VD is often increased. The implication of this is that patients may require a higher loading dose of the drug to achieve desired plasma concentrations initially.

In the neonate, the pH of blood tends to be lower than in the adult. Therefore, the acid–base value will affect the relative proportions of ionized and unionized drug available. Since lidocaine has a pKa of 7.7, a slightly higher proportion will be ionized in the more acidic neonatal blood, hence the amount of free unionized drug will be lower.

Question 20: TTFFT

The rapid onset of thiopentone is due to the high blood flow to the brain (hence increased drug delivery to the desired site of action), the high degree of lipophilicity (therefore making it able to cross the blood–brain barrier with ease) and finally its low degree of ionization at physiological pH. Only the unionized fraction of thiopentone crosses the blood–brain barrier; it has a pKa of 7.6, meaning that 61% is unionized at p. 7.4. The relatively brief duration of anaesthesia following a bolus of thiopentone is due to redistribution to muscle and fat; this has no impact on the onset of action. Likewise, hepatic metabolism will affect the duration of action and the plasma concentration rather than the speed of onset.

Question 21: FTTFT

Bioavailability can be defined as the proportion of a dose of a specified drug preparation entering the systemic circulation after administration by a specified route and may be calculated by the area under a plasma concentration–time curve. By virtue of this definition, if a drug is given intravenously, 100% of it will reach the systemic circulation. The sublingual, nasal and buccal routes all have rapid onset and, by avoiding the portal tract, have higher bioavailability than the enteral route. The presence of congenital or acquired malabsorption syndromes, such as coeliac disease, will affect absorption. Drugs absorbed from the gut pass via the portal tract to the liver, where they may be subjected to first pass metabolism, thus reducing the amount reaching the systemic circulation. Therefore, if a drug undergoes minimal first pass metabolism, more drug reaches the circulation and bioavailability is higher. First pass metabolism may be increased or decreased through the induction or inhibition of hepatic enzymes.

Question 22: TTTTT

When considering drug transfer from mother to fetus across the placental barrier, the usual factors affecting drug transfer across lipid layers still apply. Low molecular weight, lipophilic, uncharged drugs are transferred with greater ease than larger, charged molecules. Anaesthetists should consider placental transfer whenever giving anaesthetic or non-anaesthetic drugs to pregnant women. This may be in the immediate antenatal/labour/operative delivery setting, or when looking after women in earlier stages of pregnancy who may require anaesthetic intervention. All volatile agents and induction agents cross the placenta, and caesarean section under general anaesthesia is associated with poorer neonatal condition. Often, it is difficult to determine whether poor Apgar scores are a consequence of fetal exposure to anaesthetic agents, or due to whatever process necessitated emergency delivery. However, it is desirable to avoid fetal exposure to sedating anaesthetic agents. Morphine crosses the placenta and should be avoided antenatally. Babies born to women with opioid dependence may display features of neonatal abstinence syndrome and require specialist care for the management of opioid withdrawal. Diclofenac should be avoided if possible in pregnancy, and especially in the third trimester, where it is associated with closure of the fetal ductus arteriosus or neonatal pulmonary hypertension. NICE recommend that all women undergoing caesarean section are offered prophylactic antibiotics prior to knife-to-skin. Although the British National Formulary states that co-amoxiclav is not known to be harmful in pregnancy, the 2011 NICE guidelines for caesarean section suggest it is avoided due to an association with neonatal necrotizing enterocolitis.

Question 23: TFFFF

Propofol, like other IV induction agents, is predominantly metabolized via conjugation by the cytochrome P450 system in the liver. However, the rate of clearance of propofol exceeds the rate of hepatic blood flow, suggesting that propofol undergoes some degree of extrahepatic metabolism. Various enzymes from the cytochrome system have been identified in other tissues, including the central nervous system.

Cisatracurium, like its parent compound atracurium, does undergo hepatic metabolism, however the majority of the drug undergoes Hofmann elimination, a pH- and temperature-dependent degradation of the drug.

Esmolol is marketed as Breviblock®, and has a very short duration of action. This is due to rapid metabolism via ester hydrolysis by cholinesterase enzymes found in red blood cells. Mivacurium, like suxamethonium, is metabolized by butyrylcholinesterase (also known as plasma cholinesterase and pseudocholinesterase, to differentiate it from acetylcholinesterase). Therefore, patients with a history of any form of suxamethonium apnoea should not be given mivacurium. Several ACE inhibitors are prodrugs and metabolized to the active compound in vivo. For example, ramipril is converted to ramprilat by liver estaerases. Lisinopril, however, is not a prodrug, does not undergo hepatic metabolism, and is excreted unchanged in the urine. Mechanisms of metabolism are important to know, particularly for patients with significant organ dysfunction. Drugs that display organ-independent metabolism may be used with a greater safety margin in patients with failing livers or kidneys. Bear in mind, however, that many drugs are hepatically metabolized and renally excreted; those drugs that are metabolized by extrahepatic systems may still have pharmacologically active metabolites which can accumulate in renal disease.

Question 24: TFTFT

Many drugs are required to cross a variety of cell membranes during their distribution from site of administration to site of action. This process may be passive or active. In general, small, unionized, lipid-soluble drugs cross membranes via passive diffusion, which requires no energy, and occurs as a consequence of concentration gradients on either side of the membrane. Conversely, large, polar drugs are less able to cross lipid bilayers, and require specific transport proteins and energy in the form of ATP to facilitate transport. The majority of drugs of relevance to anaesthesia, including most intravenous induction agents and opioids, are transported by passive diffusion.

Larger drugs may require a transmembrane carrier protein to take them into cells in a non-energy-dependent manner. This process, known as facilitated diffusion, is also dependent on concentration gradients and is subject to saturation and inhibition. Examples: glucose (via the GLUT4 receptor), cephalexin, azoles. Active transport involves the movement of compounds, via transmembrane channels, against their concentration gradients. This is an energy-dependent process, driven by ATP. Examples include the movement of sodium and potassium via Na+/K+ ATPase, and the chemotherapeutic agent 5-fluorouracil. The predominant mechanism by which penicillin is cleared from the plasma is active transport into the nephron, a process that can be inhibited by probenecid. Very large or toxic molecules can enter cells via an invagination of the cell membrane. The molecule may also be bound to a transport protein. An example is iron. This process is called pinocytosis (for liquids) or phagocytosis (for solids).

Question 25: TTFFF

There are several factors to consider when administering drugs to patients receiving renal replacement therapy. Firstly, patients with renal failure and a reduced glomerular filtration rate will accumulate drugs that are normally metabolized by the kidney. Active metabolites that are normally renally excreted will also accumulate in these patients. Consequently, doses of drugs and/or intervals between doses should be altered. The situation becomes more complex when renal replacement therapy is commenced, as some drugs will be cleared from the plasma by this process, particularly water-soluble substances. Specialist guidance should be sought in such patients. Another important topic is the removal of toxins, or toxic levels of drugs, via haemofiltration. Aspirin is a lipid-soluble drug that is usually rapidly absorbed from the small intestine, metabolized by the liver and excreted by the kidneys. When ingested in excess, it can cause severe metabolic, acid–base and neurological disturbances. Overdose may be managed by administration of activated charcoal (shortly after ingestion), administration of sodium bicarbonate (to alkalinize the urine and enhance excretion) or via haemodialysis (in severe cases). Although aspirin is lipid soluble in the acidic environment of the stomach, it becomes more ionized and therefore more water soluble in the less acidic environment of the plasma. Water solubility favours removal via haemofiltration. Although charcoal haemoperfusion is a more efficient system for removing aspirin from plasma, haemofiltration is preferred in clinical practice. The increasing water solubility in plasma permits some removal of the drug, but the system also permits manipulation of volume and acid–base status. Low molecular weight heparins (LMWH), e.g. enoxaparin are often used in patients receiving continuous renal replacement therapy on the intensive care unit. This may be for thromboprophylaxis, as well as reducing the risk of clots forming within the filter. LMWHs are not removed by haemofiltration and have the potential to accumulate with an increased risk of bleeding. Dose reduction should be considered and the effect may be monitored by measurement of anti-Xa levels. Atenolol is water soluble and renally excreted. The dose should be reduced in patients with renal impairment. Atenolol is cleared by haemofiltration. Therefore, patients on atenolol should receive their dose after a dialysis session. Massive β-blocker overdose is rare. It may be managed with glucagon, but haemodialysis can be used to remove renally cleared β-blocker overdoses that are refractory to pharmacological therapy. Factors that impair drugs being cleared by haemofiltration are: large size, large volume of distribution (e.g. digoxin) and high protein binding (e.g. warfarin).

Question 26: FFTTT

Most drugs are eliminated from the body by the kidneys. Consequently, impaired renal function leads to decreased clearance of most drugs. This is not always the case, however, as some drugs are metabolized and eliminated by other organ systems, or display entirely organ-dependent metabolism. For most drugs, elimination usually follows first-order kinetics; the rate of elimination is directly proportional to the serum drug concentration. However, the proportion of drug eliminated per unit time remains constant, e.g. there is 1000 mg of drug X in the plasma, after 10 minutes, 500 mg remain, after 20 minutes, 250 mg remain. Although the absolute amount of drug X eliminated in the second 10 minutes is half that of the first 10 minutes, there is a consistently a 50% reduction in the amount of drug X eliminated. This consistent proportion is known as the elimination rate constant (Kel). Clearance (Cl) of a drug refers to the rate at which the drug is removed from the plasma. It is a theoretical value, defined as the volume of plasma from which the drug is entirely removed per unit time and expressed in ml.min–1. Therefore, as clearance of a drug increases, the half-life will fall. Most drugs are cleared only from the plasma. Therefore, those drugs with a small volume of distribution (VD), with the majority of drug remaining in the plasma, will be cleared at a faster rate than those with a higher VD. Those with a higher Kel will also be cleared at a faster rate: Cl = Kel × VD

The half-life (t½) of a drug refers to the time taken for the amount of drug in the plasma to fall by 50%. The time constant (tau or τ) is 1/Kel and represents the time taken for the amount of drug in the plasma to fall to 36.7% of its starting value. Therefore, the time constant is longer than the half life, and τ = t1/2 /0.693.

Question 27: TFFTT

Multicompartmental pharmacokinetic models attempt to represent more physiological drug distribution and elimination. Mammillary models depict a well-perfused central compartment (for instance plasma) to which a drug is introduced and eliminated. Terminal elimination can only take place from this compartment. Peripheral compartments are connected to the central compartment. They are not anatomically distinct, but represent less-vascular structures in the body. Distribution of a drug from central to peripheral compartments will vary depending on the degree of perfusion. A three-compartment model represents a central compartment linked to two peripheral compartments of intermediate and poor perfusion. Therefore rates of equilibration will vary. Catenary models, in contrast, depict compartments linked adjacently rather than peripherally and centrally. The sum of y intercepts of a tri-exponential decay curve (representing three-compartment model drug elimination) is equal to the concentration 0 value.

Question 28: FTFFT

Context sensitivity is defined as the time taken for the plasma concentration of a drug to fall by 50% subsequent to the cessation of an infusion. This is after steady state plasma concentration has been achieved. Remifentanil is unique among infusion drugs by displaying context insensitivity. Regardless of the duration of infusion, when a remifentanil infusion is terminated it will be eliminated within 3–5 minutes. This is because it is metabolized by non-specific plasma esterases that are in abundant supply. Context-sensitive half-life has no bearing on predicting waking time. The decrement time to waking may be greater than 50% when waking occurs. Interestingly, context insensitivity is displayed with alfentanil infusions of greater than 2 hours. Fentanyl displays a long context-sensitive half-life, rendering it unsuitable for use in infusions.

Question 29: TTTTF

Total intravenous anaesthesia (TIVA) is a viable alternative to the use of volatile agents. It is certainly indicated in patients with a history of malignant hyperpyrexia, where volatile agents are contraindicated. In the interests of avoiding awareness under anaesthesia, a dedicated cannula should be used and regularly inspected for patency. Plasma concentrations of agent cannot be measured during TIVA, unlike end tidal volatile agent. Therefore complex algorithms are required to calculate desired plasma or effect-site concentration of agent. They require parameters such as age, weight, height and gender. Special infusion pumps programmed with three-compartment pharmacokinetic models control infusion rates to maintain steady state concentrations associated with anaesthesia. The Schnider pharmacokinetic model, unlike the Marsh model, calculates the lean body mass of patients. This in turn restricts the estimated volume of the central compartment, preventing the overdosing of patients. It may therefore be more suitable for use in elderly patients. It is important to use a long-acting opiate towards the end of TIVA for satisfactory postoperative analgesia. Indeed, stopping remifentanil after prolonged periods of infusion in the absence of adjunctive analgesia may result in rebound hyperalgesia.

Question 30: TFFFT

Plasma cholinesterase activity may be reduced by genetic variants or acquired conditions, leading to prolonged neuromuscular block. Four alleles – usual (normal), atypical (dibucaine-resistant), silent (absent) and fluoride-resistant – have been identified at a single locus of chromosome 3 and make up the 10 genotypes.

Most (96%) of the population is homozygous for the normal Eu gene and rapidly metabolize suxamethonium. Up to 4% may be heterozygotes, resulting in a mildly prolonged block of up to 10 minutes. A very small percentage (Ea:Ea, Es:Ea and Es:Es) have little or no cholinesterase activity, meaning blocks could last for many hours, requiring a period of sedation and ventilation until it wears off. Alternatively, administration of fresh frozen plasma provides a source of plasma cholinesterase that reverses the block.

Dibucaine is an amide local anaesthetic that inhibits normal plasma cholinesterase, but inhibits variant forms less effectively. At a standard concentration (10−5 mol.l–1), dibucaine inhibits the Eu:Eu form by 80% and the Ea:Ea form by only 20%. The dibucaine number refers to the percentage inhibition of plasma cholinesterase and indicates the genotype of an individual, but gives no information regarding the quantity of enzyme in the plasma.

Question 31: FTFTT

Malignant hyperpyrexia (MH) is a rare (1:200 000) autosomal dominant condition associated with a defect in the ryanodine (RYR1) receptor on chromosome 19. Trigger agents (which are the volatile anaesthetic agents and suxamethonium) cause excessive calcium release from the sarcoplasmic reticulum, which activates muscle contraction. Etomidate is not associated with this reaction. Although ephedrine causes catecholamine release and an increase in intracellular calcium causing vasoconstriction, it is not related to the calcium release involved in MH.

The UK MH investigation unit is in Leeds, and a diagnosis is based on the response of biopsied muscle to 2% halothane and caffeine. Patients are labelled as ‘susceptible’ (positive to both), ‘equivocal’ (positive to either halothane or caffeine) or ‘non-susceptible’ (negative to both).

Acetylation is a phase 2 metabolic pathway in the liver. Drugs metabolized by this route include hydralazine and isoniazid. There are variants in isoenzymes that are genetically determined that acetylate at either a fast or a slow rate. The acetylator status of the individual causes variation in the pharmacokinetic and pharmacodynamic profiles of certain drugs. There does appear to be racial variation, with 50% of Europeans/North Americans being ‘slow’ acetylators – this means a deficiency in N-acetyltransferase, which is likely to result in accumulation of drugs that undergo acetylation. Of the oriental population, 90% are ‘fast’ acetylators, meaning that drugs requiring acetylation will be rapidly metabolized and are unlikely to have an effect.

Other examples of relevant pharmacogenetics include the metabolism of codeine. 5–15% of codeine undergoes O-demethylation to morphine, which is dependent on the CYP2D6 isoenzyme. This exhibits genetic polymorphism, meaning that poor metabolizers get little pain relief (9% of the UK population and 30% in the Hong Kong Chinese).

Question 32: FTTFT

Thiopentone is a thiobarbiturate and is the sulfur analogue of pentobarbitone, unlike methohexitone, which is a methylated oxybarbiturate. It is approximately 80% bound to plasma proteins, with high lipid solubility and is completely metabolized within the liver. Pentobarbitone is only 40% protein bound and is excreted unchanged in the urine.

Thiopentone is formulated as a sodium salt and is stored under nitrogen to prevent formation of the insoluble undissociated acid. Sodium thiopentone is a weak acid and forms an alkaline solution when dissolved in water, with a pH of 10.5. The 2.5% solution is stable for many days and the high pH, in theory, should ensure that it is bacteriostatic.

Barbiturates increase the duration of GABA-dependent Cl channels opening in the central nervous system. Increased Cl conductance leads to hyperpolarization and neuronal inhibition. Thiopentone appears to potentiate only the β-subunit of the GABAA receptor and also affects central Na+ and K+ channels.

It may be used in the treatment of status epilepticus and causes significant reduction in cerebral oxygen requirement. At high plasma concentrations, an isoelectric EEG is to be expected.

Question 33: FFFTT

Propofol (2,6 diisopropylphenol) is highly lipid soluble and is presented as a 1% or 2% lipid–water emulsion containing soya bean oil and purified egg phosphatide. Due to its lipid content, propofol has a calorie load of 1–1. This should be borne in mind when administered as a prolonged infusion, as fat overload syndrome, with hyperlipidaemia and fatty infiltration of the liver, heart, kidney and lungs, has occurred. This also explains the caution required when considering paediatric patients.

Metabolism is mostly hepatic, with approximately 40% undergoing conjugation to a glucuronide and 60% metabolized to a quinol; all metabolites are inactive and excreted in the urine.

Propofol causes a fall in systemic vascular resistance and a subsequent fall in blood pressure. A reflex tachycardia is rare and propofol is usually associated with a bradycardia, particularly with co-administration of fentanyl or alfentanil. Sympathetic activity is reduced.

The terminal elimination half-life is thought to be between 5 and 12 hours, however this may change when infused for long periods, when the context-sensitive half-life increases. This may reflect the slow release of propofol from fat.

Propofol may turn urine and hair green as a result of the phenol content.

Question 34: TFFTT

Ketamine is a phencyclidine derivative that forms an acidic solution (pH 3.5–5.5) in water. Although generally given intravenously, it has been used via the oral and rectal routes for sedation and also intrathecally or via the epidural route for prolonged analgesia. However, its use here has been limited by undesirable side effects.

Ketamine antagonizes glutamate at the NMDA receptors within the central nervous system and, in contrast with most other anaesthetic agents, it has no activity at the GABA receptors. Interaction with opioid receptors is thought to be complex, but ketamine seems to be antanalgesic, i.e. antagonistic at the OP3 (mu) receptors, while displaying agonist activity at OP1 and OP2 receptors.

It produces a state of dissociated anaesthesia with intense analgesia and amnesia. Vivid dreams, delirium and hallucinations may follow its use. Cerebral blood flow, oxygen consumption and intracranial pressure (ICP) are all increased and this should be considered when dealing with patients with head injuries or raised ICP.

Following administration, ketamine (which is only 25% protein bound) is demethylated to the active metabolite norketamine by P450 enzymes in the liver. Norketamine (which is 30% as potent) is further metabolized to inactive glucuronides, which are then excreted in the urine.

Question 35: FFFTT

Etomidate is a carboxylated imidazole derivative and an ester. It is prepared as a 0.2% solution at a pH of 4.1 and traditionally contains 35% v/v propylene glycol to improve stability and reduce pain on injection. However, a lipid emulsion of equivalent strength is now available.

Despite some unpleasant side effects, such as excitatory movements, nausea, vomiting and the aforementioned pain on injections, etomidate is one of the least likely agents to cause histamine release. Hypersensitivity reactions are also much less common. Thiopentone is most likely to cause anaphylaxis, with an incidence of approximately 1:15 000. In contrast, etomidate is well known to be a trigger for an acute porphyric crisis.

Etomidate suppresses adrenocortical function by inhibition of the enzymes 11β-hydroxylase and 17α-hydroxylase, resulting in inhibition of cortisol and aldosterone synthesis. It was associated with an increased mortality when used for sedation in critically ill patients. Although single doses can affect adrenocortical function, this is not thought to be significant in otherwise healthy subjects.

Question 36: FTFTT

Thiopentone is a barbiturate and these compounds are not readily soluble in water at neutral pH. Their solubility depends on transformation from the keto to the enol form (tautomerism). Tautomerism refers to the dynamic interchange between two forms of a molecular structure, which is often precipitated by a change in the physical environment.

Thiopentone is a highly lipid-soluble, highly protein-bound drug that is completely metabolized within the liver. It tends to produce anaesthesia at induction doses in one arm–brain circulation time. Its high lipid solubility means that rapid emergence is due to rapid initial distribution into tissues, not metabolism.

Although thiopentone causes a reduction in systemic vascular resistance and stroke volume, and hence a decrease in cardiac output, it does not reduce urine output by this method alone (i.e. reduced renal blood flow). The resultant central nervous system depression leads to an increase in ADH production, which in turn conserves water and reduces urine output.

Thiopentone is one of the more likely drugs to cause a severe anaphylactic reaction; these are seen in approximately 1:15 000 administrations. Although this is by no means common, it is the highest incidence amongst all of the intravenous induction agents.

Question 37: TFFTT

Propofol is 98% protein-bound to albumin and yet has the largest volume of distribution of all the induction agents at 4–1. Following a bolus dose, its duration of action is short due to the rapid decrease in plasma levels as distribution to vessel-rich tissues occurs. Although metabolism is mostly hepatic, clearance of propofol (30–60–1.min–1) exceeds hepatic blood flow, suggesting some extrahepatic metabolism. As a result of this high clearance, plasma levels fall more rapidly than those of thiopentone (clearance 3.5–1min–1).

Excitatory effects have been seen with propofol in up to 10% of patients; these are not thought to be epileptiform and do not represent true cortical seizure activity. Movements are typically dystonic with choreiform elements and opisthotonus. In fact, propofol can be used to control status epilepticus.

Despite the change in preparation to a lipid emulsion, patients still report pain on injection of propofol. Lidocaine 1% is regularly added to propofol in paediatric practice and does seem to reduce the discomfort. There are some studies that have looked at pretreatment with lidocaine rather than an admixture and this may be superior.

Question 38: TTTTT

There are two primary pathways of benzodiazepine biotransformation, involving hepatic microsomal oxidation (N-dealkylation or aliphatic hydroxylation) and glucuronide conjugation. The hydroxylated metabolites are pharmacologically active, and many of them have long half-lives, some longer than the parent compound. Metabolites of diazepam include nordiazepam, temazepam and oxazepam. Subsequent conjugation of the microsomal metabolites by glucuronyl transferases results in glucuronides that are excreted in the urine.

Question 39: FTTFF

Benzodiazepines have a high oral bioavailability and high protein binding (70–95%). Diazepam and subsequent metabolites have half-lives of between 40 and over 100 hours. This may be prolonged up to 200 hours in those who have a genetically slower metabolism. The volume of distribution is large, ranging from around 0.8 to 2.5–1 across the class. Midazolam has a relatively high clearance of around 6–10–1.min–1 compared to diazepam, which has a clearance of around 0.8–1.8–1min–1 and lorazepam, with a clearance of 0.2–0.5–1.min–1.

Question 40: FFTTT

Urinary excretion for all benzodiazepines ranges from around 20% to 80%. They are not readily removed by dialysis and therefore this option is not considered effective in isolated benzodiazepine overdose.

Chlordiazepoxide does have active metabolites, including oxazepam, desmethyl chlordiazepoxide and desmethyl diazepam. Lorazepam, oxazepam and temazepam do not have active metabolites and therefore may be considered as a better choice for elderly patients. The elimination half-life of diazepam is long and considered to be greater than 24 hours.

Question 41: FFFTF

Isoflurane is a halogenated ether with a molecular weight of 184.5, boiling point of 49 °C and saturated vapour pressure of 33 kPa at 20 °C. It has a blood:gas partition coefficient of 1.4 and an oil:gas partition coefficient of 97. Halothane and enflurane cause a greater degree of myocardial depression than isoflurane, though all three cause hypotension. Dose-dependent uterine relaxation may exacerbate uterine atony, thus worsening obstetric haemorrhage. Isoflurane is less than 0.2% metabolized.

Question 42: FFFTT

Desflurane has a blood:gas partition coefficient of 0.45. It is less soluble in blood than nitrous oxide, which has a blood:gas partition coefficient of 0.47. One could therefore assume that desflurane would reach FA/Fi equilibration more rapidly. However, nitrous oxide is typically administered in far higher inspired concentrations of around 50–60%. This has a concentrating effect on alveolar nitrous oxide. When nitrous oxide is absorbed into the blood, alveolar volume diminishes thus concentrating it and any other inhalational agents in the gas mixture. These phenomena are referred to as the concentration and second gas effects respectively. Nitrous oxide is produced by the heating of ammonium nitrate to 240 °C. It has no effect on uterine muscle tone. With prolonged use it inhibits the enzyme methionine synthetase, leading to a megaloblastic anaemia. Nitrous oxide occupies and expands air-filled spaces. This could lead to large increases in the size of pneumothoraces. Its use is therefore contraindicated in these patients.

Question 43: FTTTT

MAC is defined as the concentration of inhalational agent preventing movement of 50% of subjects in response to a standard surgical stimulus. This is at normal barometric pressure, with the patient inspiring oxygen and no other inhalational agent or analgesics. It is increased in hyperthyroidism and decreased in pregnancy. The oil:gas partition coefficient is analogous to potency. Therefore the higher the oil:gas partition coefficient, the lower the fractional concentration of agent (and hence MAC) required to induce anaesthesia. Nitrous oxide is far less potent than halothane. Its MAC is consequently far higher, 105% versus 0.76%. It is defined as a percentage of 1 atmosphere.

Question 44: TFFTF

Sevoflurane is an inhalational anaesthetic agent with useful properties. These include its use in gaseous induction of anaesthesia owing to its lack of respiratory irritation. It has rapid onset and offset therefore making it an ideal agent in day case surgery and difficult airway situations. It is a clear colourless liquid with a molecular weight of 200, a boiling point of 58 °C and a saturated vapour pressure of 21 kPa at 20 °C. It owes its rapid onset and offset to a blood:gas partition coefficient of 0.69. The oil:gas partition coefficient of 53 correlates with moderate potency. It is 3–5% metabolized. The toxicity of compound A has only been demonstrated in rats at high temperatures under conditions of prolonged low-flow anaesthesia. The toxicity of compound A has not been demonstrated in humans, even with low-flow anaesthesia.

Question 45: FFTFF

The potency of inhalational anaesthetic agents is directly related to their lipid solubility and thus the oil:gas partition coefficient (which is a reflection of lipid solubility). Minimal alveolar concentration is inversely proportional to the oil:gas partition coefficient (and thus potency). Halothane has a oil:gas partition coefficient of 225 and is more potent than sevoflurane, which has an oil:gas partition coefficient of 53. The oil:gas partition coefficient of methoxyflurane is 970 versus 98 for enflurane. It is important to understand that anaesthetic potency has no relationship with speed of onset and offset. This is governed by the blood:gas partition coefficient, which is a measure of solubility. The lower the blood:gas coefficient the more rapid the onset and offset.

Question 46: TTFTF

Halothane is a potent volatile anaesthetic (oil:gas partition coefficient = 225). It has a molecular weight of 197, a boiling point of 50 °C with a saturated vapour pressure of 32 kPa at 20 °C. It is non-flammable, but is slightly unstable in light and is therefore formulated with thymol as a preservative. It was a popular inhalational induction agent due to its smooth and rapid action, along with its non-irritant respiratory properties. Its use in the UK has been discontinued for a number of reasons. It is the most extensively hepatically metabolized volatile agent at 20%. Associated with this is an increased hepatitis risk, particularly with repeated use. Furthermore, nodal rhythms and bradycardias can result. It also sensitizes the myocardium to catecholamines.

Question 47: FFTTF

The mechanism of action of general anaesthetics is still not fully understood. The Meyer–Overton rule was proposed at the turn of the twentieth century. This stated that the hydrophobicity of an agent is directly related to its potency as an anaesthetic. Thus hydrophobic anaesthetics are more potent and may act by dissolving in the lipid bilayer of cells. However, one of the several flaws in the rule is that not all hydrophobic agents have anaesthetic properties, the long-chain hydrocarbons for example. GABAA and glycine receptors (a ligand-gated ion channel) are indeed inhibitory receptors and the potentiation of these by certain anaesthetic agents is another proposed mechanism. Excitatory receptors (nicotinic acetylcholine, 5HT3, and NMDA) are inhibited by anaesthetics. Thus to induce anaesthesia there has to be enhancement of inhibition, inhibition of excitation or a combination of the two.

Question 48: TTTFT

It is the relationship between pKa and tissue pH that will relate to the ionization of the drug. The pKa is the pH at which the drug exists as a 50:50 mixture of ionized and non-ionized molecules. The lower the pKa of a drug in physiological solution, the more drug is available in the neutral form. It is this neutral form that is able to cross the cell membrane to block the sodium channels, thus preventing conduction. The pKa of lidocaine is 7.9 and for bupivacaine it is 8.1.

Lipid solubility of local anaesthetics is a significant determining factor of drug potency. The more lipid soluble an agent, the greater the potency.

There is avid binding of local anaesthetics to circulating plasma proteins, which will effectively inactivate the drug. The affinity of the agent for protein molecules has been correlated with the duration of anaesthetic effect, not speed of onset. The protein binding of lidocaine is 65% and bupivacaine 96%.

The type and location of block will both impact on the speed of onset.

Question 49: FTTFT

In theory, the maximum dose of lidocaine can be increased from 3–1 to 7–1 by the addition of a vasoconstrictor such as epinephrine. It should be noted, however, that the maximum safe dosage in the individual can vary significantly depending on clinical status, site of injection and concomitant use of other agents.

Question 50: FFFTF

Ester local anaesthetics undergo rapid metabolism by pseudocholinesterase enzymes. The rapid hydrolysis in plasma results in water-soluble metabolites, which are excreted in urine. No metabolism occurs in cerebrospinal fluid and therefore intrathecally placed ester anaesthetics must be absorbed into the vascular system prior to metabolism. The extraction ratio of lidocaine is high and therefore is reliant on sufficient hepatic blood flow. Amide local anaesthetics are primarily metabolized by microsomal P450 enzymes in the liver. Bupivacaine, as an amide, is metabolized in the liver. It is conjugated to glucuronic acid with only 5% excreted unchanged in the urine. Hepatic failure generally has to be severe before metabolism is significantly affected.

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Oct 24, 2020 | Posted by in ANESTHESIA | Comments Off on Chapter 3b – Pharmacology Answers
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