1

PHARMACODYNAMICS

Receptor theory: A receptor is a component of a cell or oganism that interacts with drugs which results in a sequence of events which lead
to an observed change in function. Receptors determine the quantitative relationship between dose or concentration of the drug and the
pharmacological effects. Receptors are responsible for the selectivity of the drug function. Receptors mediate the actions of pharmacological agonists and antagonists. Katzung pg 15, Miller pg 215
Evidence for the presence of receptors is inferred from the biological response of tissues to drugs, from genome sequencing and from
molecular biology
Classic receptor theory describes interaction between ligand and receptor based on the laws of mass action. In simplest form this can be
represented by a the following formula;
[D][R]
K dissociation
K dissociation
This is the dissociation constant!
=
= KD It is the concentration when 50%
[Drug] + [Receptor]
[Drug-Receptor]
rearranged:
K
association
K association
of receptors are occupied
[D-R]
(@ steady state)
A low Kd value indicates that less drug is required to occupy 50% of the receptors, implying that each molecule of drug is tightly associated with the receptor. A high Kd value indicates that more drug is required to occupy 50% of receptors, implying a weak binding to the
receptor. Kd has been determined for many of the drugs administered during anesthesia. The reciprocal of Kd is Ka - the association
constant. Ka is a measure of the affinity of the drug for the receptor. A drug with a low Kd value has a high Ka value and therefore high
affinity for the receptor.
Kd may also be represented graphically as shown here . Again it represents 50% occupancy of the
maximum number of receptors (Bmax)
EC50 represents the concentration of the drug which results in 50% of the maximal effect (Emax)

GRADED, QUANTAL DOSES AND

THERAPEUTIC INDEX

Responses to drugs can be either graded or quantal. In a graded response there is an increasing
magnitude of response with increasing dose. In a quantal response once a certain number of
receptors are occupied there is an all-or-nothing response (examples include mortality or loss of
consciousness).
The frequency of response in the population is the important variable in quantal effects. This can
be plotted as a gaussian distribution curve or more commonly as a sigmoid plot against concentration (either standard or log). The 50% of population with a quantal response represents the
ED50. (effective dose). Animal studies are used to determine the 50% lethal dose LD50 (or 50% toxic
dose TD50).
The therapeutic index represents the ratio of LD50 to ED50. The higher the therapeutic index the
greater the range of safety. Hemmings pg 98-99 Katzung pg 30-31

AGONISTS and ANTAGONISTS

Receptors exist in activated and inactivated states, and the intrinsic efficacy of a drug is determined by
the extent to which it stabilizes the active form of the receptor (i.e., agonists such as midazolm), the
inactive form (i.e., inverse agonists such as metoprolol and bisoprolol), or displaces agonists from the
binding site without favoring either form (i.e., neutral antagonists such as flumanezil). Agents that are
only partly as effective as agonists no matter the dose employed are termed partial agonists (such as
buprenorphine).
Competitive antagonism, more agonist is required to get to Emax. With an irreversible
anatagonist even with very high doses of agonist the system is unable to get to Emax.
A chemical anatagonism works by directly binding to another drug which renders it
inactive. An example of this is protamine which forms an ionic bond with heparin.
Physiologic antagonism works by producing a countering effect by other pathways to
reduce the effect of a drug. It is less specific and sometime difficult to control.
QUANTIFYING AGONISM
Relative potency implies that in two agonists with equal efficacy, a
smaller dose of one agonist is required to achieve maximal effect
Relative efficacy that the maximal effect of one agonist is greater
that the other
Christopher Andersen 2012

DRUG

Monomers

5 G-Protien Coupled

IONS

Dimers

Receptors

a
A

Intracellular

Ligand and
voltage-gated
Channels

b
g

SIMPLIFIED MODEL OF SIGNALLING MECHANISMS

AND DRUG ACTION

A
B
Intracellular receptors Lipid soluble signalling molecules difuse across the cell membrane and interact with these receptors. The most
studied of this class are the Steroid Receptor Superfamily which include; steroids, sterols, thyroxine, retinoic acid and vitamin D. The
hormone-receptor complex then modulates gene transciption leading to a biological effect. This explains the lag with drugs such as
prednisolone which has an effect lag of ~30mins whilst the transcription takes place and can continue to have effect for days.
The remainder of the receptors above are transmembrane, and interact with hydrophillic ligands or ions on the cell surface.
Enzyme linked cell surface receptors are a very diverse group that contain intracellular catalytic domains or are closely associated with
intracellular enzymes. They may be present either as monomers (for example guanylyl cyclase which binds to atrial natriuretic factor) or
dimers such as the tyrosine kinase-associated receptors (which bind to erythropoietin or the interferons) and dimerise on contact with
the associated ligand.
Ligand-gated ion channels are involved primarily in fast synaptic transmission between excitable cells. An example is the nicotinic
acetylcholine receptor at the neuromuscular junctions.
The last class of recptors are the G-Protien Coupled Receptors. These activate or inhibit adenylyl cyclase, activate phosphilapse C or
modulate ion channels. A variety of signals, which include hormones, neurotransmitters, cytokines, pheremones, oderants and photons
produce their intracellular actions through GPCR. They are discussed below in greater detail along with second messengers.
The Adenylyl Cyclase/Protien Kinase A Pathway as an example of G-Protien function Hemmings pg 40
Adenylyl Cyclase is an effector

GPCP

G-Protien is a
heterotimeric GTP
binding protien

g B

g B

The beta and gamma

subunits also act
on targets

ATP

++

cAMP is one of several second messengers

which also include IP3, Ca and NO.

It is degraded by phosphodiesterases
to 5AMP which stops rxns

GTP
GDP

Activation of the G-Protien

causes the alpha subunit to
drop the GDP for GTP, seperate
and travel to adenylyl cyclase

GTP
The catalytics subunits then travel
to different sites such the nucleus
where they phosphorylate
transciption factors to cause a
biological effect. Other sites of action
include ion channels.

cAMP binds to Protien Kinase A and

the catalytic subunits detach.

PKA

Receptors are regulated in number, location and sensitivity. Frequent or continuos exposure leads to short term diminution of the
receptor response sometimes called tachyphylaxis (literally fast-guarding). There are three main mechanisms for this, intracellular
protiens may block access to a G-protien to the activated molecule. An example is Beta-arrestin which blocks continuos activation of the
Beta-adrenoceptor. Second, agonist bound receptors may be internalised by endocytosis (eg morphine receptors). Third, continuos
activation may lead to depletion of a substrate needed for downstream effects. Long term changes lead to down regulation or up
regulation of receptors.
An adverse reaction to a drug is a harmful or unintended response. Overdose, excessive effects and drug interactions may occur in any
patient. Adverse reactions occuring only in susceptible patients include intolerance, idiosyncrasy (often genetic in origin) and allergy
(usually immunological mediated). See following Pharmacological Basis of Poisoning for further information.
Christopher Andersen 2012

PHARMACOKINETICS
Volume and clearance are fundamental concepts in pharmacokinetics: volume represents the dilution of drug into fluids and tissues,
and clearance is the flow of blood or plasma that is completely cleared of the drug.
Volume of distribution (apparent) The ratio of the amount of drug in the body divided by
the drug concentration in the plasma or blood. This is shown graphically in the fig
Clearance The ratio of the rate of elimination of a drug divided by the concentration of the
drug in the plasma or blood
Concentration =

amount
volume

Volume =

amount (dose)
concenration

Clearance = rate of elimination

concentration

Metabolizing enzymes and transporters usually are not saturated, and thus the absolute rate of elimination of the drug is essentially a
linear function (first-order kinetics) of its concentration in plasma, where a constant fraction of drug in the body is eliminated per unit of
time. Most drugs obey first order kinetics. If mechanisms for elimination of a given drug become saturated, the kinetics approach zero
order, in which a constant amount of drug is eliminated per unit of time. Three important drugs which use zero order kinetics are
phenytoin, ethanol and aspirin.
The area under the blood concentration-time curve (area under the curve, or AUC, shaded in blue) can be used
to calculate the clearance for first-order elimination.
Clearance =

Dose
Area under Curve

The AUC is also used as a measure of bioavailability. It is defined as the fraction of unchanged drug reaching
the systemic circulation by any route. By definition is is 100% for IV drugs.
For drug administration orally, the bioavailability is less than 100% for two main reasons:
1. Incomplete extent of absorption this is usually due to drugs being two hydrophilic (eg atenolol) or lipophilic (aciclovir).
Drugs may also be actively transported back to the gut lumen by transporters such as P-glycoprotien (which is inhibited by
grapefruit juice which leads to increased bioavailability)
2. First pass elimination following absortion from the gut wall the venous blood returns via the portal system via the liver
which may metabolise a large portion of the drug (some metabolism also happens in tissues such as the gut wall). Morphine is well
absorbed at the gut but metabolised extensively in the liver (Extraction ratio is 67%), therefore the bioavailability is only 33%.
Sublingual - Venous drainage from the mouth is to the superior vena cava, which protects highly soluble drugs like nitroglycerin from
rapid hepatic first-pass metabolism.
Transdermal - Absorption of drugs able to penetrate the intact skin is dependent on the surface area over which they are applied and
their lipid solubility
Rectally - Approx 50% of the drug that is absorbed from the rectum will bypass the liver, thus reducing the hepatic first-pass effect.
Pulmonary - Gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium and mucous membranes of the
respiratory tract. Access to the circulation is rapid by this route because the lungs surface area is large (~140 m2) and first-pass metabolism is avoided.
Subcutaneous The rate of absorption following subcutaneous injection of a drug often is sufficiently constant and slow to provide a
prolonged effect. Variations in particle size, protien complexation and pH can also vary absorption (eg insulin types)
Intramuscular Drugs in aqueous solution are absorbed rapidly after intramuscular injection depending on the rate of blood flow to the
injection site and the fat versus muscular composition of the site. Gluteus maximus injections in women often lead to slower rates.
Intrathecal The bloodbrain barrier and the bloodcerebrospinal fluid (CSF) barrier often preclude or slow the entrance of drugs into the
CNS. Therefore, when local and rapid effects on the meninges or cerebrospinal axis are desired, drugs sometimes are injected directly into
the spinal subarachnoid space. Some of the common local anesthetics (e.g., tetracaine) are esters; they are hydrolyzed and inactivated
primarily by a plasma esterase, probably plasma cholinesterase. Hepatic enzymes also hydrolyze local anesthetic esters. Since spinal fluid
contains little or no esterase, anesthesia produced persists until clearance by the systemic circulation.
Biotransformation of drugs typically reduces the lipophilicity, resulting in metabolites that are more likely to be excreted by the kidney, or
discharged into the intestine. Biotransformation occurs in nearly all tissues, but the main site is the liver. Hepatic metabolism is responsible for systemic clearance of almost all IV drugs in anaesthesia. There are two types of biotransformation reactions:
Phase I Reactions: which expose a linking group (usually oxygen or nitrogen). This can be achieved by cleaving a a molecule
(Odealklation or N-dealkylation), altering an existing oxygen to increase reactivity (deamination) or by adding an OH group (hydroxylation)
or double bonded O (s-oxidation). Phase 1 rxns are often catalysed by cytochrome P450 enzymes present in the smooth endoplasmic
reticulum (others catalysers include Flavin-containing monooxygenases (FMO) and Epoxide hydrolases (mEH, sEH)). The most important is
CYP3A4 which is responsible for metabolism of more than 50% of drugs including many anaesthetics such as (fentanyl, alfentanil, methadone, midazolam, diazepam, lignocaine, bupivacaine & ondansetron). CYP3A4 may be induced by rifampicin, glucocorticoids, barbituates,
phenytoin and carbemazepine. It is inhibited by St Johns Wort, macrolide antibiotics (which are metabolised then bind tightly to P450
rendering it inactive) and the -azole antifungals. Grapefruit juice inhibits CYP3A4 at the intestinal lumen.
Phase II Reactions: the drug undergoes conjugation, typically by glucuronic acid (via UDP-glucuronosyltransferases (UGT)), acetate
(N-acetyltransferases (NAT)), glutathione (Glutathione-S-transferases (GST)), sulfate (Sulfotransferases (SULT)) or an amino group. This may
mask an exisiting functional group. The main purpose of this rxn is to transform hydrophobic molecules into hydrophilic molecules by
addition of a polar group. Phase II rxns are relatively faster than P450 catalysed rxns, thus effectively accelerating drug biotransformation.
Biotransformation may result in toxic metabolites. This is often exaberated when substrates are exhaused as occurs in paracetamol which
is 95% conjugated by UGT or SULT and 5% by P450 dependent glutathione (GSH). When UGT & SULT are saturated GSH becomes dominant. As GSH is depleted a toxic metabolite accumulates causing liver death. This is neutralised by N-acetylcysteine.
Christopher Andersen 2012

Extraction ratio is the fraction of drug flowing into the liver which is removed. Clearance can therefore also be
expressed as blood flow times extraction ratio. In drugs with a high extraction ratio such as propofol, clearance is
flow dependent, in drugs with a low ER such as alfentanil the capacity of the liver is the rate limiting factor. This is
shown graphically in the image adjacent. As previously noted systemic clearance of anesthetic drugs generally
occurs by means of hepatic metabolism. Other mechanisms include plasma and tissue ester hydrolysis (e.g.,
remifentanil, succinylcholine,esmolol), renal elimination (e.g., pancuronium), and nonspecific, "extrahepatic"
metabolism for drugs whose clearance exceeds hepatic blood flow (e.g., propofol).

Renal excretion of drugs and metabolites in the urine involves three distinct processes: glomerular filtration, active tubular secretion, and
passive tubular reabsorption. Changes in overall renal function generally affect all three processes to a similar extent. Almost all drugs are
filtered at the glomerulus. Filtration is directly related to the rate and unlike the liver it is possible to estimate filtration rate using the
cockroff-gault formula or eGFR. If a drug is in a lipid soluble form during its passage down the tubules a significant portion will be
reabsorbed by simple passive diffusion. It may be therefore advantageous to have a drug in its ionised form which will increase removal of a
drug in an overdose situation by alkanising or acidifying the urine. Pancuronium is the only anaethetic extensively execreted renally.
log

(protonated) = pKa - pH
(unprotonated)

recall that log 1 equals 0 therefore when the protonanted and

unprotonated forms are equal pKa and pH are the same

Most drugs are weak acids or bases that are present in solution as both the lipid-soluble and
diffusible nonionized form, and the relatively lipid-insoluble nondiffusible ionized species.
Therefore, the transmembrane distribution of a weak electrolyte is determined by its pKa (pH at
which 50% is ionized) and the pH gradient across the membrane.. The ratio of nonionized to
ionized drug at each pH is readily calculated from the HendersonHasselbalch equation:

Virtually all anaesthetic drugs are reversibly bound to plasma protiens. Acidic drugs (salicylates and barbituates) bind to albumin, basic
drugs (fentanyl, diazepam and propanolol) also bind mainly to alpha1-acid glycoprotien. Only free unbound drugs may diffuse accross the
membrane. The extent of plasma protein binding may be affected by disease-related factors (e.g., hypoalbuminemia). Conditions resulting
in the acute-phase reaction response (e.g.,cancer, arthritis, myocardial infarction, and Crohns disease) lead to elevated levels of alpha1-acid
glycoprotein and enhanced binding of basic drugs. Decreases in protien binding can increase the clearance of drugs with low extraction
rations by driving gradient into the liver (high extraction ratio drugs are not affected as all of the drug is metabolised whether it is bound or
not). Decreases in protien binding may also increase the apparent potency of a drug by increasing free drug at the site of action.
Half life is the time required to change the amount of drug in the body by one half. Using a single
t1/2 = 0.693 x Vd
CL
compartment model the half life depends on the volume of distribution and the clearance. It may
be represented by the following formula (0.693 is the log of 2). It can be used to describe change
to steady state or rate of elimination. Note that after one half life the amount is 0.5, then 0.5+0.25,
then 0.75+0.125, then 0.875+0.0612. This means steady state basically occurs after 4-5 half lives
(greater than 94%).
Many drugs in anaesthesia are not easily described as single compartments. Whilst it is possible to create
BOLUS
models with ten or more compartments they are cumbersome mathematically. Frequently a three
compartment model is used with the central compartment (plasma), fast tissues (roughly correlating to
Fast
Slow
Central
muscles and splancic) and slow tissues (fat). Although this is gross simplification of what is actually
Tissue
Tissue
Compartment
happening, polyexponential pharmacokinetic models are useful because
the models describe the data.
OUT
This adjacent picture shows the plasma concentration following a bolus injection into a three compartment
model. This is described as the algerbraic sum of three exponential functions. The solid lines are the exponential
fns and the dotted line is their sum (and the measured amount). An example of a drug that follows this behaviour
is fentanyl.
When an infusion is given at an input rate of I, the plasma concentration rises as long as the rate of drug going into the body, I, exceeds
the rate at which drug leaves the body, C Cl, in which C is the drug concentration. When I = C Cl, drug is going in and coming out at
the same rate, and drug concentration in the body is at steady state. Clearance is the most important pharmacokinetic term to be
considered when defining a rational steady state drug dosing regime. Because the maintenance rate of drug administration is equal to
the rate of elimination at steady state (this is the definition of steady state), the maintenance dosage is a function of clearance
Dosing rate =

CL x Desired Plasma Concentration

Bioavailability

If the therapeutic concentration must be achieved rapidly and the Vd is large, a large loading dose may be needed at the onset of
therapy. This can be calculated from the following equation noting that unlike maintenence dose it is the volume of distribution which is
most important. It is often prudent to give doses as a slow infusion to avoid toxic plasma concetrations as the drug distributes.
Loading dose =

Vd x Desired Plasma Concentration

Bioavailability

The therapeutic window is the safe range between the minimum therapeutic concentration and the minimum toxic
concentration of a drug. The concept is used to determine the acceptable range of plasma levels when designing a
dosing regimen. Thus, the minimum effective concentration usually determines the desired trough levels of a drug
given intermittently, whereas the minimum toxic concentration determines the permissible peak plasma concentration
When drugs are administered there is a delay from peak plasma concentrations to drug effect. This represents the time taken to transit to
the effect site (or biophase). Ke0 is a constant which determines elimination from the effect site, and in combination with plasma pharmacokinetics determine the time to plasma-effect site equilibrium. Drugs with a high Ke0 such as thiopental, propofol, and alfentanil reach
rapid plasma effect site equilibrium. Intermediate medications include midazolam, fentanyl, vec and pancuronium and slow for morphine.
Christopher Andersen 2012

VARIABILITY IN DRUG RESPONSE

Four general mechanisms contribute to variability in responsiveness to drugs.
1.
Absorption
Effect site equilibrium
Volume of Distribution
Clearance

2. Other endogenous and exogenous ligands

3. Receptor number and function

4. Downstream effects and

response to receptor activation

1. Alteration in the amount of drug that reached the receptor. This is usually due to changes in the total absorption of
the drug and the rate that this occurs, the volume of distribution and the clearance of the drug (PHARMACOKINETIC FACTORS). This
may sometimes be predicted in terms of age, race, weight, physiological or pathological state (especially lung function, renal and
hepatic funtion) and specific genetic factors which may be predicted with a careful history and genetic testing if indicated (find
example).
2. Differences in the presence of endogenous and exogenous ligands This mechanism contributes significantly to
antagonist response. In patients with phaeochromocytoma (high endogenous ligand) propanolol will have a large effect, in
marathon runners the response will be negligble (low catecholamines)
3. Variation in the number or function of receptors This may be due to both genetic and environmental factors,
hormone responses (eg thyroid hormone up regulates beta adrenoceptors in the heart and response to catecholamines), or as a
specific response to drug therapy. In particular agonists may reduce the number of receptors (down regulation) or coupling
efficiency (desensitisation). Antagonists may prevent endogenous down regulation of recpetors leading to a relative increase in
receptors (PHARMACODYNAMIC FACTORS). These mechanisms contribute to the concept of tolerance, tachphylaxis, dependence
and importantly withdrawal (discussed below).
4. Changes in components of the response distal to the receptor Although a drug initiates a response by binding to
receptors, the response is dependent on the functional integrity of the biological system and associated cellular and physiological
responses. Physiological and pathological states may lead to variability of response.

Tolerance to the effect of opioids or other drugs simply means that the drug loses its effectiveness over time and an increased dose is
required to produce the same physiological response. When a drug rapidly loses it responsiveness it is termed tachyphylaxis (fast
guarding).
Dependence refers to a complex and poorly understood set of changes in the homeostasis of an organism that causes a disturbance of
the homeostatic set point of the organism if the drug is stopped. This disturbance often is revealed when administration of an opioid is
stopped abruptly, resulting in withdrawal.
Withdrawal is the pathological repsonse to the removal of a drug. An example is the agonist clonidine used to lower blood pressure by
potentiating alpha-2 adrenoceptors. Administration of this medication leads to down regulation of these receptors and acute
withdrawal may lead to a hypertensive crisis.
Addiction is a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and
use. Tolerance and dependence are physiological responses seen in all patients and are not predictors of addiction.
Pharmacogenetics is the study of the molecular mechanisms that underlie the individual differences in drug metabolism, efficacy and
side effects. Important genes with respect to anaesthetics are RYR1 mutations which are associated with malignant hyperthermia
syndrome and the gene that codes for butyrylcholinesterase, a precursor to pseudocholinesterase which hydrolyses suxmethonium.
Neonates: An important generality is that pharmacokinetic variability is likely to be greatest at times of physiological change (e.g., the
newborn or premature baby or at puberty) such that dosing adjustment, often aided by drug monitoring for drugs with narrow
therapeutic indices, becomes critical for safe, effective therapeutics. Most drug-metabolizing enzymes are expressed at low levels at
birth, followed by an isozymespecific postnatal induction. CYP2E1 and CYP2D6 appear in the first day, followed within 1 week by
CYP3A4 and the CYP2C subfamily. CYP2A1 s not expressed until 13 months after birth. Some glucuronidation pathways are
decreased in the newborn, and an inability of newborns to glucuronidate chloramphenicol was responsible for the gray baby
syndrome. Renal elimination of drugs also is reduced in the neonatal period. Neonates at term have markedly reduced GFR (24
mL/min/1.73 m2), and prematurity reduces renal function even further. As a result, neonatal dosing regimens for a number of drugs
(e.g., aminoglycosides) must be reduced to avoid toxic drug accumulation. GFR (corrected for body surface area) increases progressively to adult levels by 812 months of age.
Elderly: As adults age, gradual changes in pharmacokinetics and pharmacodynamics increase the interindividual variability of doses
required for a given effect. Pharmacokinetic changes result from changes in body composition and the function of drug-eliminating
organs. The reduction in lean body mass, serum albumin, and total-body water, coupled with the increase in percentage of body fat,
alters drug distribution in a manner dependent on lipid solubility and protein binding. The clearance of many drugs is reduced in the
elderly. Renal function variably declines to ~50% of that in young adults. Hepatic blood flow and drug metabolism also are reduced
in the elderly but vary considerably. In general, the activities of hepatic CYPs are reduced, but conjugation mechanisms are relatively
preserved. Frequently, the elimination half-lives of drugs are increased as a consequence of larger apparent volumes of distribution
of lipid-soluble drugs and/or reductions in the renal or metabolic clearance.
Alterations in renal function may lead to impairment of renally exceted drugs. Drug dosage should be adjusted according to the
estimation of GFR. Patients with cirrhosis, hepatitis and other hepatic disease also have impairment of drug metabolising enzymes
particularly microsomal oxidases, but unlike the kidneys there is no quantative basis for dose adjustment beyond plasma levels and
clinical response. Cardiac disease may result in an reduction of blood flow to the liver, modifying clearance of flow dependent drugs.
In patients with circulatory shock neuroendocrine response may drastically reduce renal and hepatic blood flow reducing the
clearance of many drugs. Pulmonary disease may also affect drug metabolism as indicated by impaired hydrolysis or procanamide
and procaine in patients with COPD. Finally disease states may lead to reductions in circulating protiens and in drugs with high
protien binding this may lead to an increase in free drug and therefore potency. In this case measurement of free drug is more
accurate that total drug.
Christopher Andersen 2012

When drugs are given together the pharmacological response may be additive (1+1=2), synergistic
(1+1>2) or antagonistic (1+1<2). It is possible to represent this quantitative relationship using an
isobole shown adjacent. In this case midazolam (y axis) is added to morphine (x axis). Using the
isobole we can see that the result is supra-additive (synergistic), both drugs have a reduction in
their ED50 therefore they have increased potency. Isoboles do not describe qualitative interactions.

Line of additivity

There are three main mechanisms of drug interaction.

Pharmaceutical interactions often occur before a drug is given to the patient. Chemical interactions can occur because of
acid base rxns, oxidation-reduction, salt formation, hydrolysis, or epimerization (change in the conformation of a compound). An
example is thiopental and rocuronium forming a precipitate due to change in pH.
Pharmocokinetic interactions may infulence the absorption, distribution and the elimination. Aborption may be
influenced by changing the gastrointestinal pH and motility (opiates), intraluminal binding or chelation, changing regional blood
flow (peripheral vasoconstrictors), inhibition or stimulation of first pass metabolism (ketoconazole inhibits CYP3A4 which leads to
16-fold increase in oral midazolam). Likewise, drug metabolism may be induced or inhibited due to drug interaction greatly
influencing elimination. The CYP450 enzymes are again very important in this process. St John Wort is a potent inhibitor of CYP3A4
leading to potentially hazardous interactions with the substrates of this enzyme.
Pharmacodynamic interations although pharmacokinetic interactions are very well studied and significant in specific
circumstances, it is the pharmacodynamic that have greater significance in anaesthesia. The concurrent use of drugs acting at the
same site or on the same physiological system can have increased or decreased effect. The most common example is drugs acting on
the CNS. Inhalational anaesthetics have an additive effect. Interactions between benzodiazepienes and opiates is synergistic (as
shown above). Volatile anaesthetics potentiate the effects of neuromuscular blockade.
Classification of Adverse Drug Reactions
An adverse drug reaction (ADR) can be considered as any potentially harmful untoward outcome of therapeutic drug
Administration errors
administration. The unwanted outcome may be a side effect of the drug, an exageration of the therapeutic effect, failure of
Intolerance
therapeutic effect or a totally unexpected effect. ADR may be classified into the adjacent categories; Administration errors
Idiosyncrasy
may result for accidental under or over dosing or from the use of inaccurate or outdated guidelines. When a patient gets the
Anaphylaxis/anaphylactoid
the correct intended dose and has a ADR but is within a unimodal population variation or response, the phenomenon is
Direct organ toxicity
usually terms a drug intolerance. Although the therapeutic index (ED50/LD50) is often referred to it is not always clinically
Secondary effects
useful in describing drug intolerance. For this reason the certain safety factor may be more useful. This also a quantal
Drug effects
response curve that relates the % of population with a unwanted effect (TD% toxic dose) to the effective dose % (ED%).
Usually this will be 1%, therefore the certain safety factor (and therefore therapeutic window) is the range from TD01/ED99.
Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual. The idiosyncratic is usually related to
pharmacogenetic disorders. These have been identified in drug metabolism (acetylation, cytochrome P450 variants, plasma cholinesteras variants), inability to
compensate for drug effects (G6PD deficiency, acute porphyrias), and in the drug effects themselves(Malignant Hyperthermia). Allergy is an immune mediated ADR
discussed in greater detail below. Specific secondary effects and organ toxicity are discussed in the system specific overviews. Drug interactions are discussed above.

Idiosyncrasy
Drug metabolism

Acetylator status - one of the phase II metaboliseds N-acetyltransferase exists in fast or slow forms (60% slow in caucasians, only 20% in asians) leading to increased
side effects in the slow metabolisers. Drugs implicated include isoniazid, hydralazine, nitrazepam.
CYP450 variants - CYP2D6 - involved in metabolism of 25% of drugs. 6% of caucasians and 1% of asians have reduced activity. Drugs implicated include; Beta-blockers
(metoprolol, propanolol), antiarythmics (flecanide, amiodarone), antidepressants (most TCAs and SSRIs), and neuroleptics CYP3A4-5 - 6% caucasians have reduced
activity (drugs - midazolam, fentanyl), CYP2C9 - warfarin, CYP2C19 - diazepams and Omeprazole.
Plasma Cholinesterase- responsible for the breakdown of sux in plasma, an autosomal recessive trait, leading to prolonged duration of action.

Inability to compensate for drug effects

Glucose-6-Phosphate Dehydrogenase required in the pentose phosphate pathway which leads to restoring glutathione levels required to combat H2O2 relased by the
cell in the presence of oxidants. Therefore highly oxidant drugs like chloramphenicol, primaquine, may lead to haemolytic anaemia
The Porphyrias - A group of disorders characterised by excessive build up of the precursors of heme. These precursors porphyrinogens are execreted in the urine
where they are exposed to light and air to convert to purple coloured porphyrins. Usually this is regulated by inhibition of ALA synthetase. Some drugs such as
propofol may upregulate this enzyme.

The drug effects themeselves

Malignant Hyperthermia is an autosomal dominant condition which susceptible individuals have a defect in skeletal muscle intracellular regulation. Under most
circumstances homeostatic mechanisms compensate for increased calcium turnover, but the potent inhalational anaesthetics and sux cause a massive acceleration
of calcium release which overwhelms the compensatory mechanisms. The massive Ca release leads to increased muscle activity and metabolism. Oxygen supply
can not match the demand and CO2, lactate and heat builds up. The other feature of MH is rhabdomyolysis. Mutations of the skeletal muscle ryanodine receptor
gene (RYR1) lead to the susceptibility to the condition.

Allergic reactions to drugs administered IV are acute hypersensitivity reactions. By definition these occur on the second or subsequent exposure to an allergen. It is recognised that more than 50% of patients who have anaphylactic-like (anaphylactoid) responses
are during their first exposure. The anaphylaxis results from IgE mediated mast cell degranulation and release of mainly histamine
and vasoactive amines but also proteases (tryptase) and lipid derived mediators (such as leukotrienes and prostaglandins). Anaphylactoid reactions occur through complement pathways or direct drug action on mast cells and result in similar outcomes although
anaphylactoid reactions may be more dose dependent. Latex sensitivity is increasingly becoming a problem in anaethesia with
20-50% or reactions due to this precipitant. The reactions tend to occur after 30-60 minutes whereas drug reactions typically occur
within minutes. Chlorhexidine is also increasingly associated with severe systemic rxns.
Therapeutic drug monitoring. Given the multiple factors that alter drug disposition, measurement of the concentration in body fluids can
assist in individualizing therapy with selected drugs. Determination of the concentration of a drug is particularly useful when well-defined
criteria are met:
1. A demonstrated relationship exists between the concentration of drug in plasma and the desired therapeutic effect or the toxic effect to
be avoided.
2. There is sufficient variability in plasma level that the level cannot be predicted from the dose alone.
3. The drug produces effects, intended or unwanted, that are difficult to monitor.
4. The concentration required to produce the therapeutic effect is close to the level that causes toxicity (narrow therapeutic window)
Christopher Andersen 2012

PHARMACOLOGICAL BASIS OF POISONING

Decontamination

Activated Charcoal (AC) is the preferred means of gastric decontamination for ingested poisoning. It
is inert, insoluble and has a very extensive network of pores created when organic matter is treated
with pyrolysis then acid and steam The resultant binding surface of area 950-2000m2 per gram. The
amount of drug absorbed is dependent on the time since the poison was ingested, the dose of
charcoal (usually 1g/kg) and the type of charcoal. It is not particularly effective with small ionised
molecules (metals, electrolytes, highly ionised acids and alkali, and alcohol). The main contraindications are similar for all the ingested decominators; perforation or obstuction, decreased GCS without
definitive airway, uncooperative concious patient and significant risk of GI bleed. Specific contraindications (relative) are likelyhood of gastroscopy (makes the procedure redundant).
Gastric Lavage (GL) May be useful for drugs that are not effectively absorbed by activated charcoal. Typically it is given via a wide bore OG or NG tube. The lavage fluid is
usually around five litres of warmed saline. Of note it is associated with an increased risk of ICU admission and aspiration.
Ipecac very limited indications for this emetic agent, it may be useful in witnessed out of hospital ingestion of poison.
Whole Bowel Irrigation enteral administration of polyethylene glycol balanced electrolyte solution (PEG-ELS). Despite volumes of 5 to 50 litres typically being used it
does not normally result in electrolyte disturbances. Like GL it may be useful when AC is not effective, particularly with enteric coated and slow release medications.
Cathartics Cathartics are intended to decrease poison absorption by osmotically enhancing rectal evacuation of the poison-activated charcoalcomplex. The most
common of these is sorbitol. They are only used as an adjunct therapy.

Cyanide
Fires - most common cause, the combustion
of carbon and nitrogen in domestic fires
liberate cyanide which is then inhaled

Mitochondria - Cyanide binds to the

Industrial byproduct in mining and engineering

ferric (3+) ion of the Cytochrome Oxidase

a3 enzyme which is required for the final
step in oxidative phophorylation OP in
the mitochondrial. The result is the body must use anaerobic
metabolism, resulting in increased lactatic acidosis with the
associated HCO3 decrease. Despite ample O2 the body
cannot utilise it due to the blocked OP which results in
functional or histotoxic hypoxia. The high O2 demand organs
(CNS and Heart) are usually the worse affected.

Management

Cyanide

Medical sodium nitroprusside contains five units

of cyanide per molecule and may develop into toxic
levels folloing prolonged admission. (this is why it
is stored and delivered in a covered bag and silver
foil covered tubing.

Brain A number of other mechanisms may exacerbate brain injury.

Cyanide's nonspecific inhibition of antioxidants results in the accumulation of toxic oxygen free-radicals. Cyanide causes the release of
glutamate, and also inhibits glutamic aciddecarboxylase (GAD), the
enzyme responsible for the formation of the inhibitory neurotransmitter
gammaaminobutyric acid (GABA) from glutamic acid. Consequently,
cyanide reduces the seizure threshold as GABA levels fall.

Treat symptoms ABCs, reduce seizure risk, continue high flow O2

Reduce absorption if the cyanide has been ingested. AC binds cyanide poorly but is nevertheless recommended
Bind cyanide directly hydroxycoalbumin binds cyanide to form cyanocoalbumin which is excreted in urine
Produce Fe3+ to compete with mitocondrial binding sites by inducing methemoglobulin which oxidises Fe2+ in the blood
Provide sulphur donors to assist rhodanese - a ubiquitous enzyme that detoxifies cyanide by transforming it to thiocyanate

Carbon Monoxide Poisoning usually due to inhalation but may be due to ingestion of methyl-

ene chloride which is metabolised in the liver to CO. CO binds to heme with an affinity 240 times that
of O2. It causes an allosteric change in which greatly inhibits the three other heme binding sites from
offloading O2. The result is a shift of the O2 dissociation curve to the left. CO also inhibits OP like
cyanide but to a less extent which exacerbates the hypoxia. The mechanism of the delayed
neurological sequelae is not well understood but may be related to toxic oxygen species generated
by xanthine oxidase. Treatment is via high flow O2 and HBOT may be indicated.

Organophosphates Acute toxicity from organophosphorous agents presents with

manifestations of cholinergic excess. Primary toxic effects involve the autonomic nervous
system, neuromuscular junction, and central nervous system. The parasympathetic nervous
system is particularly dependent on acetylcholine regulation, since both the autonomic
ganglia and end organs of the parasympathetic nervous system are regulated by nicotinic
and muscarinic cholinergic receptors. Treatment is with atropine which competes with
acetylcholine at muscarinic recpetors to reduce the deleterious affects (but not at nicotinic).
Oximes such as pralidoxime reactivates cholinesterase therefore works at both musc/nict
receptors. Benzos are useful for seizure reduction.

Methanol and Ethylene Glycol The "parent alcohols" methanol and ethylene glycol are relatively nontoxic, and cause mainly central nervous system (CNS) sedation.
However, profound toxicity can ensue when these parent alcohols are oxidized (primarily by alcohol dehydrogenase and aldehyde dehydrogenase). The methanol metabolite
formate and the ethylene glycol metabolites glycolate, glyoxylate, and oxalate accumulate following large ingestions. Formate causes retinal injury with optic disc hyperemia,
edema, and eventually permanent blindness, as well as ischemic or hemorrhagic injury to the basal ganglia. Ethylene glycol metabolites target the kidney and lead to
reversible oliguric or anuric acute kidney injury (acute renal failure), which in turn slows elimination of ethylene glycol. The renal failure is primarily due to glycolate-induced
damage to tubules, although tubule obstruction from precipitated oxalate crystals may contribute. Hypocalcemia in ethylene glycol overdose results from calcium oxalate
formation. With ingestions of either parent alcohol, a profound anion gap metabolic acidosis develops, which directly correlates with the accumulation of toxic acid metabolites. Acidemia increases the ability of the toxic metabolites to penetrate cells, further depressing CNS function and causing a rapid downward spiral of hypoxia and acidemia.
Treatment is ABCs, HCO3 for acidosis, and ADH inhibitor fomepezil or ethanol, and consider hemodyalisis if there is end organ damage.
Christopher Andersen 2012

PHARMACEUTICAL ASPECTS AND DRUG DEVELOPMENT

The four main phases of drug development

Trials of drugs in human beings in the U.S. generally are conducted in three phases, which
must be completed before an NDA can be submitted to the FDA for review. Although assessment
of risk is a major objective of such testing, this is far more difficult than is the determination of
whether a drug is efficacious for a selected clinical condition. Usually about 20003000 carefully
selected patients receive a new drug during phase 3 clinical trials. At most, only a few hundred
are treated for more than 36 months regardless of the likely duration of therapy that will be
required in practice. Thus, the most profound and overt risks thatoccur almost immediately after
the drug is given can be detected in a phase 3 study if they occur more often than once per 100
administrations. Risks that are medically important but delayed or less frequent than 1 in 1000
administrations may not be revealed prior to marketing (e.g., COX-2 inhibitors). Consequently, a
number of unanticipated adverse and beneficial effects of drugs are detectable only after the drug
is used broadly. Many countries, including the U.S., have established systematic methods for the
surveillance of the effects of drugs after they have been approved for distribution.

STEREOCHEMISTRY (Chirality)

Enantiomer
of Carvedilol

Kd for alpha
receptors

Kd for beta
receptors

(+)R
(-) L
Racemic

14
16
11

45
0.4
0.9

The R-enantiomer of carvedilol is a

potent beta blocker but the
enantiomers are roughly the same
for alpha blockade.

Stereochemistry is the study of how molecules are structured in three dimensions. Enantiomers (substances of
opposite shape) are pairs of molecules existing in two forms that are mirror images of one another (right- and
lefthand) but that cannot be superimposed. A pair of enantiomers is distinguished by the direction in which,
when dissolved in solution, they rotate in polarized light, either clockwise (dextrorotatory, d [+]) or counterclockwise (levorotatory, l [-]). When the two enantiomers are present in equal proportions (50:50), they are
referred to as a racemic mixture. The most rapidly applicable and unambiguous convention for designating
isomers is the sinister (S) and rectus (R) classification that specifies the absolute configuration in the name of
the compound. Pharmacologically, not all enantiomers are created equal. Enantiomers can exhibit differences
in absorption,distribution, clearance, potency, and toxicity (drug interactions). The administration of a racemic
drug mixture may in fact pharmacologically represent two different drugs with distinct pharmacokinetic and
pharmacodynamic properties. More than one third of all synthetic drugs are chiral (thiopental, ketamine,
inhaled anesthetics except sevoflurane, local anesthetics, neuromuscular-blocking drugs, opioids), although
most of them are utilized clinically as racemic mixtures.

Christopher Andersen 2012