Many anaesthetic complications can be attributed to improper use of drugs. So it is important to understand the various concepts of pharmacology before reading about anaesthetic drugs. Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion while pharmacodynamics deals with mechanism of action and clinical effects of drug.
Most drugs used by us are given via intravenous route. This gives the immediate and predictable effect most of the times. The few terms which are used to describe drug–patient interaction, are:
- Bioavailability
- Volume of distribution
- Clearance
- Chirality and isomerism (levo-, dextro-)
- Half-life
- Efficacy and potency
- Drug receptor interaction
- Adverse drug reaction
- Patient physiology
BIOAVAILABILITY
It means percentage/fraction of the drug which reaches systemic circulation in unchanged form. When given via 2IV route, bioavailability is 100% because drug is injected into the blood. After giving drug by oral/subcutaneous or intramuscular (IM) route, bioavailability is less due to metabolism (in liver or intestines) or incomplete absorption. During oral ingestion of drug, some may dissolve in gastrointestinal (GIT), some is metabolized in liver, and the remaining drug reaches systemic circulation. Bioavailability is an important concern for drugs with low safety profile or where precise dose control is required (oral anticoagulants, digoxin, etc.). As most of the times, we give drugs via IV route, reduced bioavailability is not much of a problem in anaesthesia practice.
Bioavailability depends on route of administration (oral drug absorption is affected by GIT diseases, size of drug particles), drug interaction with other drugs in GIT, liver metabolism of drugs (first-pass metabolism depends on liver blood flow, condition of liver).
VOLUME OF DISTRIBUTION
Initially, the drug enters blood and then distributes to other tissues. The factors which affect distribution of drug inside body are drug related (lipid solubility, pKa, plasma-protein binding) and patient related (fat percentage, diseases affecting circulatory volume such as CHF, renal diseases).
The volume of distribution is a proportionality factor that integrates the amount of drug in the body to the concentration of drug measured in plasma or any other fluid compartment. This parameter has the dimensions of volume (e.g. litres):
For example, if we give 500 mg of drug and the plasma concentration of the drug is 20 mg/litre, then VD is 25 litres. Knowledge about the volume of distribution (VD) 3is useful in determining the loading dose to achieve a specific concentration (see below).
VD is an indicator of the extent of distribution of a drug. As the drug gets distributed in the body tissues, plasma concentration falls and VD increases.
If the drug remains in blood only, VD will be equal to blood volume. As the drug moves out of blood, VD increases. So, VD indicates distribution of the drug in the body (high VD means more distribution into body tissues and less drug in blood).
Water-soluble drugs do not enter the cells, so their VD equal, extracellular fluids (ECF) volume (most drug remains in plasma). Also, if the drug is highly protein bound, it will remain in plasma.
Non-depolarizer muscle relaxants remain in plasma as these are lipid-insoluble drugs.
Drugs given IV first go to high blood flow organs and then redistribute to fat and muscles.
Most induction agents follow the above model. This is due to the fact that these are lipid-soluble drugs. They reach highly perfused organs first and create clinical effect. After some time, less vascular tissues (fat, muscle) take up the drug leading to fall in plasma concentration. The half-life of lipid-soluble drug may be of long duration but peak clinical action terminates due to redistribution (Table 1.1).4
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Volume of distribution at steady state (VDSS) is used when the drug has been given for a long period (e.g. via infusion). This implies that drug has distributed throughout the body (central and peripheral compartments). High blood flow organs are taken as central compartments, while fat/muscles are peripheral compartments.
Drugs that have a volume of distribution 7 L or less are thought to be confined to the plasma, or liquid part of the blood. If the volume is between 7 L and 15 L, the drug is thought to be distributed throughout the blood (plasma and red blood cells). If the volume of distribution is larger than 42 L, the drug is thought to be distributed to all tissues in the body, especially the fatty tissue. Some drugs have volume of distribution values greater than 1000 L. This means that most of the drug is in the tissue, and very little is in the plasma. Larger the volume of distribution, the more likely the drug is found in the tissues of the body. Smaller the volume of the distribution, the more likely the drug is confined to the circulatory system. Lipid-soluble drugs can move across all cell membranes so their VD is more. In patients with drug toxicity, drug with large VD may not be easily removed by dialysis.
Capillaries in brain have tight endothelial junctions so drug molecules (non-lipid soluble) cannot move into brain. At some anatomical sites, this blood-brain barrier is absent so drug molecules can move freely.
CLEARANCE
It means volume cleared of drug per unit of time (in litre/min). Clearance (CL) is determined by blood flow to organ 5that metabolizes or eliminates the drug and efficiency of organ at extracting drug from blood stream.
To put it in a simple formula,
Clearance = Metabolism (in liver) + Elimination (in kidney)
For numerical calculation,
So, clearance of most drugs is reduced in liver and renal diseases. This means that the drug amount has to be reduced or dosing interval is to be increased.
Drugs such as remifentanil, succinylcholine, esmolol, mivacurium and ester LA undergo ester hydrolysis in plasma so they are cleared in plasma.
As can be seen in Table 1.2, clearance of propofol and remifentanil is rapid.
Protein Binding of Drugs
Most drugs have an affinity for plasma proteins. Drugs are usually lipid soluble but poorly soluble in water so drug molecules do not dissolve in plasma water. Plasma-protein attachment provides a way to transport of drug in blood. When drug molecules reach systemic circulation, they attach to albumin or α-acid glycoprotein. Following are the important considerations for drug-protein binding:
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6Only free form of drug can take part in pharmacokinetics. Free drug and drug-protein complex are in dynamic equilibrium and drug lost by metabolism and elimination gets replaced by drug- protein complex dissociation. Protein-bound drug is not metabolized/eliminated.
Acidic drugs bind to albumin while basic drugs bind to α-acid glycoprotein. This is true for most drugs. High protein binding usually means long duration of action for the drug as bound drug is not available for metabolism.
Protein-bound drug stays in intravascular compartment usually. So VD of highly plasma protein-bound drug is less. In conditions of hypoalbuminemia, the amount of unbound drug increases so the same dose will have an increased effect.
Lipid solubility affects the rate of absorption from the site of administration and movement of drug across the plasma membrane. Thus, transdermal application of lipid-soluble drugs (fentanyl, buprenorphine) can be clinically useful.
CHIRALITY AND ISOMERISM
A drug molecule is chiral, if its mirror image cannot be superimposed on itself (like a right hand cannot be superimposed on left hand). Molecules that are mirror images of one another are termed enantiomers. When equal amounts of enantiomeric molecules are present together, the product is termed as ‘racemic’. Such a 50:50 mixture of enantiomers is optically inactive. Enantiomers differ only in their ability to rotate a polarized light, rest everything (chemical formula and preparation) is same.
Levo/left/- isomers rotate polarized light to left direction, while dextro/right/+ isomers rotate polarized light to right side.
Now, this classification has been replaced by the R or S notation, which describes the arrangement of the molecules around the chiral centre (R is for rectus, right; 7and S for sinister, left). The R and S structures may be levo- or dextrorotatory to polarised light, meaning that there is no relationship between these classifications.
Examples of racemic mixtures:
- Bupivacaine
- Atropine
- Inhalational anaesthetic agents (except sevoflurane)
- Examples of enantiopure (single enantiomer) preparations include (clinically, it is seen that one isomer has a better profile than the other):
- S(–) ropivacaine
- S(–) bupivacaine (Levobupivacaine)
- S(+) ketamine
HALF-LIFE
The half-life is defined as the time taken for the blood- or plasma-drug concentration to fall by one-half (50%), e.g if a drug serum level falls to 5 mg/mL from an initial value of 10 mg/mL in 20 min, its half-life will be 20 min. After another 20 min, the level will fall to 2.5 mg/mL till after approx. 5 half-lives minimal drug is present in the body.
The pharmacokinetic parameters that determine half-life are clearance and volume of distribution. Any change in these parameters will affect the half-life. Decrease in clearance will increase half-life as the drug will stay in the body for longer duration.
For a drug with one compartment distribution (given IV, first-order elimination), two half-lives are applied.
First is distribution/α half-life; and second is elimination/β half-life (t1/2α, t1/2β). As we can see induction agents have these two half-lives. Elimination half-life (t1/2β) is taken as the actual half-life in clinical practice.
Dose-response Curve (Fig. 1.1)
When a drug is given, dose and the measured clinical response can be plotted on a dose-response curve (DRC) with the log of drug dose on the x-axis and the measured effect (response) on the y-axis. A dose-response shows following features—potency (location of the curve along the dose axis), maximal efficacy or ceiling effect (maximal response), change in response per unit dose (slope), estimation of starting dose of the drug.
EFFICACY AND POTENCY
Potency of a drug refers to the amount of drug needed to produce a particular response. It can be observed on dose axis. If we compare the usual analgesic dose of diclofenac and paracetamol (75 mg vs 1000 mg), diclofenac is more potent as lesser dose is required to provide analgesia. Similarly, higher dose of atracurium is required for intubation than vecuronium, so atracurium is less potent than vecuronium. Potency does not have much importance in clinical practice.
Efficacy is the maximal response, which can be elicited by the drug. It is not necessary that increasing the dose will increase the measured response (on y-axis).
9There comes a point on y-axis after which increasing the dose doesn't improve the maximal response. So, there is no need to give drug beyond maximal response.
Some drugs can have dramatic change in response even with slight change of dose. Observing the slope of DRC, we can have an idea about the magnitude of response with change in dose. A steep slope means slight increase in dose will show a higher degree of response when compared with a flat slope.
Estimation of starting dose/minimal dose required to produce a measurable response can be made from DRC. On x-axis, the starting of slope is the starting dose of that particular drug.
Basic Receptor Features (Table 1.3)
DRUG-RECEPTOR INTERACTION
Receptor (R) is a part of a cell to which a drug molecule attaches and this complex starts a biochemical change leading to an effect. It can be present in membrane/cytoplasm/nucleus. The drug molecule binds to receptor and this causes the desired effect.
Many theories exist to explain the drug receptor interaction. Here we will consider only the simple concept of active and inactive receptors.
In normal conditions (absence of any drug), equilibrium is maintained between two types of receptors.
Concept of Agonist, Partial Agonist and Antagonist
An agonist is a drug, which binds to receptor and causes it to convert to an active confirmation. Agonists can be full, partial or inverse depending on the effect observed (Fig. 1.2).
Partial agonist is a drug, which binds to receptor and converts it to an active confirmation but effect produced is less than that of an agonist. Dose-response curve of a partial agonist shows a ceiling effect, thus reflecting lower maximal response.11
12Partial agonist can precipitate withdrawal of an agonist in dependent subjects. A partial agonist exhibits less than 100% response even with maximum effective concentration.
When both agonist and partial agonist are given, the partial agonist acts as competitive antagonist and competes with agonist to occupy the receptor. This produces a less than maximal response. So, in practice, there is no need to combine a partial agonist and an agonist for a clinical effect. For example, a hypothetical patient given buprenorphine (partial μ-agonist) would require higher doses of morphine to produce the same degree of analgesia as morphine alone (i.e. buprenorphine will antagonise the effects of morphine at the μ-receptor).
An antagonist is a drug which binds to receptor to inhibit the action of agonist or an inverse agonist. Antagonist has no action in absence of agonist/inverse agonist. This means clinical action of antagonist will be seen only when agonist has been given to the patient and agonist will not produce the expected effect. When agonist and antagonist are present together, percentage of receptor occupied follows the law of mass action (the rate of a chemical reaction is directly proportional to the molecular concentrations of the reacting substances). So higher concentration means more receptors occupied.
An inverse agonist binds to the same receptor as an agonist but response is opposite to that of an agonist. β anatgonists, H1, H2 antagonists show inverse agonist activity.
When agonist is given, it stabilises the R-active form and clinical effect is seen.
Partial agonist stabilises both the forms but has greater affinity for R-active, so a lesser response in relation to agonist, is seen.
Antagonist stabilises both the forms and no effect is seen.
13Antagonists can be competitive (reversible, surmountable) or non-competitive (irreversible, insurmountable). In competitive antagonism, antagonist is chemically similar to agonist and binds to receptor at the same site as of agonist. As antagonist stabilises both forms, no effect is seen. Increasing the concentration of agonist can overcome this antagonism. A linear relationship exists between agonist dose and competitive antagonist concentration. This is seen when we give ‘reversal’ to overcome the effect of non-depolariser muscle relaxants. Also, naloxone is a competitive antagonist at all opioid receptors.
Non-competitive antagonists bind to different sites on receptor. This implies that agonist is not able to combine with receptor and no effect is produced. Increasing the concentration of agonist will not overcome this antagonism. Ketamine is a non-competitive antagonist at the N-methyl-D-aspartate (NMDA)-glutamate receptor.
Irreversible antagonists may bind to the same site as the agonist or at a different site. Increasing agonist concentration will not overcome the blockade. Phenoxybenzamine antagonises the effects of catecholamines at α-adrenoceptors. Aspirin blocks all platelet COX-1 and so return of normal function requires new platelet formation. This irreversible antagonism cannot be overcome by increasing agonist concentration.
Loading Dose
If no drug is present in the body, then
Loading dose (mg) = Target concentration (mg/L) × Volume of distribution (L)
This means that loading dose is affected only by VD and desired concentration in plasma. Once the drug is eliminated and concentration falls, maintenance dose is given. This depends on clearance of the drug. So, if any factor reduces the clearance or increases the half-life, maintenance dose is reduced.14
ADVERSE DRUG REACTIONS
Side effects: Clinical effect which is not desirable but occurs at the therapeutic dose, e.g. anticholinergics, cause drying of airway, pain on injection of propofol.
Toxic effects: Extreme pharmacological action due to overdose/multiple doses, e.g. cardiac effects of ketamine, respiratory depression due to opioids, liver damage from paracetamol. To minimise overdose, the patient age, weight and organ dysfunction should be taken into account before giving the drug.
Idiosyncrasy: Due to genetic makeup of the patient, there is an abnormal reaction to the drug. Only a particular patient who has some genetic variation is affected and the response is not always predictable. There is severe response to the usual dose of a drug. Unlike drug allergy, desensitisation is not possible in the patient having idiosyncrasy to a particular drug.
Drug allergy: It means a specific immune response to the drug or its component. The response can be in combination with a body protein acting as allergen. Allergy can be immediate or delayed/ localized or systemic. Immune-mediated allergic reactions are classified in the following (Gell and Coombs classification) Table 1.4.
Management of anaphylaxis: This is a medical emergency. As mentioned in Table 1.4, CVS and cutaneous and respiratory signs are most commonly observed. Diagnosis requires a high degree of clinical suspicion. Epinephrine is the drug of choice in the treatment of anaphylaxis. Epinephrine is used at 5–10 mg IV bolus (0.2 mg/kg) doses for severe hypotension.
100% oxygen should be given. Respiratory support could be invasive or noninvasive. Extubation should be delayed and the patient should be observed even if acute symptoms have resolved. Antihistaminic drugs (diphenhydramine, ranitidine), hydrocortisone (1–3 mg/kg) are given IV.
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Anaphylactoid reactions are due to release of histamine and other compounds from mast cells and basophils. These are not immunologically mediated but clinical presentation may be same as anaphylaxis. Management is same as of anaphylaxis.
Anaesthetic drugs with minimal allergic reactions:
- Opioids–synthetic opioids (e.g.fentanyl)
- Preservative-free amide local anaesthetics
Table 1.5 Pharmacological considerations in paediatric and geriatric patients Organ systemPaediatricClinical effectGeriatricClinical effectBody water, lean body mass- More total body water content (large volume of distribution), decreased protein binding (decreased albumin, α-acid glycoprotein
- Normal levels by 6 months of age
- High dose of IV induction drugs needed
- TBW reduced, increased body fat.
- Loss of skeletal muscle (lean body mass)
- Decreased protein binding
- Decreased vol. of distribution means increased peak concn. of drug
- Lipophilic drugs accumulate means more duration of action
Central nervous system- Immature blood brain barrier, less response to hypoxia, hypercarbia
- Sympathetic system not fully developed till 6–8 years
- Decrease in neurons, neurotransmitters, decreased cerebral metabolism
- Decrease in conduction velocity, myelination of neurons
- Less dose of opioid, barbiturates, propofol, BZDs needed
Cerebrospinal fluid- More CSF in spinal cord region. High CSF to body weight ratio
- Greater blood flow to the spinal cord as compared with adults so rapid removal of LA from CSF
- Less duration of spinal anaesthesia for the same LA dose as adult
- Reduction in CSF volume, closure of intervertebral foramina, increased epidural compliance
Renal- Unable to concentrate urine, GFR up to 90% of adult value by 1 year of age
- Decreased GFR, concentrating ability
- Loss of glomeruli.
- Tubular excretion declines, therefore renal clearance of drugs and metabolites prolonged
- Increased duration of drugs dependent on renal excretion
Autonomic system- Immature sympathetic autonomic system, and compensatory reduction in vagal efferent activity
- Minimal hemodynamic changes after central neuraxial block
- Decreased sensitivity of baroreceptors
- Endogenous β-blockade
- Adrenergic drugs have less effects on myocardial contractility, conduction velocity
- Ketamine/etomidate
- Midazolam.
So, it would mean that we can prefer the above drugs and minimise the incidence of allergic reactions. Above drugs have no mention of skeletal muscle relaxants as relaxants constitute majority of allergic reactions in anaesthesia practice.
PATIENT PHYSIOLOGY
Drug effects are also influenced by the age of patient. It is, sometimes, difficult to assess whether the effects are normal, i.e. physiological or due to some underlying pathology. Most pharmacological studies are based on non-pregnant adult healthy patients. The readers should consider the age-related changes in body physiology before deciding upon the appropriate drug. A brief description of organ system physiology in paediatric, geriatric patients regarding anaesthetic drugs, is given in Table 1.5.
The proper use of any drug requires theoretical knowledge, clinical experience and a readiness to expect an unpredictable drug effect.