Drugs act in four ways:
- Physico-chemical properties
- Activity at receptors
- Inhibition of enzyme systems
- Influence on synthesis of nucleic acid
Sodium citrate neutralises acid to aid prevention of aspiration pneumonitis.
Receptors
Receptors bind with endogenous substances to transduce the chemical signal into initiation of a change in the cell.
Agonist: a compound which binds to a receptor and changes intracellular function
Partial agonist: Cmax is a lower % of the maximum effect
Maximum effect: (Cmax) is reached when the receptor become saturated
Efficacy: maximum effect is the same but occurs at a different dose
Antagonists: bind to the receptor but produce no effect. Can be reversible or irreversible.
In the reversible case, the dose-response curve is shifted to the right but Cmax remains the same (e.g.
displacement of acetylcholine by non-depolarising muscle relaxants).
An irreversible, or non-competitive, antagonist shifts the dose-response curve to the right and also reduces Cmax
(e.g. the alpha 1-blocker phenoxybenzamine, used in preoperative preparation of patients with
phaeochromocytoma).
Drugs acting on enzymes
Either inhibit enzyme or compete for its substrate, e.g.:
- allopurinol (xanthine oxidase)
- aminophylline (phosphodiesterase)
- captopril (angiotensin-converting enzyme [ACE])
- omeprazole- irreversible (H+/K+ ATPase)
Drugs influencing nucleic acid synthesis
Affect synthesis of protein by production of messenger RNA via steroid receptors, e.g. corticosteroids.
Plasma proteins
- Only the unbound portion of a drug is active
- Albumin is important (binds acidic and neutral drugs)
- There is decreased albumin in the elderly, neonates, malnutrition, liver and in renal and cardiac failure
Basic pharmacokinetic parameters
The pharmacokinetic behaviour of most drugs can be summarised by the parameters listed below. The parameters
are constants, although their values may differ from patient to patient, and in the same patient under different
conditions.
Bioavailability expresses the extent of drug absorption into the systemic circulation. The absorption rate
constant expresses the speed of absorption. These parameters influence the maximum (peak) concentration, the
time at which the maximum concentration occurs (peak time) and the area under the concentration-time curve
(AUC) after a single oral dose. During long-term drug therapy, the extent of absorption is the more important
measurement because average concentration depends on it; the degree of fluctuation is related to the absorption
rate constant.
The apparent volume of distribution is the amount of fluid that would be required to contain the drug in the
body at the same concentration as in the blood or plasma. It can be used to estimate the dose required to produce
a given concentration and the concentration expected for a given dose. The unbound concentration is closely
associated with drug effects, so unbound fraction is a useful measure, particularly when plasma protein binding
is altered --e.g. by hypoalbuminaemia, renal or hepatic disease or displacement interactions. The apparent volume
of distribution and the unbound fraction in plasma are the most widely used parameters for drug distribution.
The rate of elimination of a drug from the body varies with the plasma concentration. The parameter relating
elimination rate to plasma concentration is total clearance, which equals renal clearance plus extrarenal
(metabolic) clearance.
The fraction excreted unchanged helps to assess the potential effect of renal and hepatic diseases on drug
elimination. A low fraction indicates that hepatic metabolism is the likely mechanism of elimination and that hepatic
disease may therefore affect drug elimination. Renal diseases produce greater effects on the kinetics of drugs with
a high fraction excreted unchanged.
The extraction rate of a drug from the blood by an eliminating organ, such as the liver, cannot exceed the rate of
drug delivery to the organ. Thus, clearance has an upper limit, based on drug delivery and hence on blood flow to
the organ. Furthermore, when the eliminating organ is the liver or gut wall, and a drug is given orally, part of the
dose may be metabolised as it passes through the tissues to the systemic circulation; this process is called first-
pass metabolism. Thus, if extraction (clearance) of a drug is high in the liver or gut wall, oral bioavailability is
low, sometimes precluding oral administration or requiring an oral dose much larger than an equivalent parenteral
dose. Drugs with extensive first-pass metabolism include alprenolol, hydralazine, isoproterenol, lidocaine,
meperidine, morphine, nifedipine, nitroglycerin, propranolol, testosterone and verapamil.
The elimination rate constant is a function of how a drug is cleared from the blood by the eliminating organs
and how the drug distributes throughout the body.
Half-life (elimination) is the time required for the plasma drug concentration or the amount of drug in the body
to decrease by 50%. For most drugs, half-life remains the same, regardless of how much drug is in the body.
Exceptions include phenytoin, theophylline and heparin.
Mean residence time (MRT), another measure of drug elimination, is the average time a drug molecule remains
in the body after rapid IV injection. Like clearance, its value is independent of dose. After an IV bolus,
MRT=AUMC
-----
AUC
AUMC is the area under the first moment of the plasma concentration-time curve. For a drug with one-
compartment distribution characteristics, MRT equals the reciprocal of the elimination rate constant.
Drug excretion
Ionised compounds
Excreted mainly by renal mechanisms
Ionisation is a barrier to reabsorption
Basic drugs excreted more in acid urine
Acid drugs excreted more in alkaline urine
Active secretion
Penicillins
Aspirin
Diuretics
Morphine
Lidocaine
Glucuronides
Secretion in bile
Generally larger molecules (MW >400)
Glycopyrronium
Vecuronium
Pancuronium
Morphine-6-glucuronide
Enzyme inducers and inhibitors
Enzyme inducers
Barbiturates
Carbamazepine
Ethanol (chronic)
nhalational anaesthetics
Griseofulvin
Phenytoin
Primidone
Rifampicin
Enzyme inhibitors
Amiodarone
Cimetidine
Ciprofloxacin
Dextropropoxyphene (co-proxamol)
Ethanol (acute)
Etomidate
Erythromycin
Fluconazole
Ketoconazole
Metronidazole
Hypersensitivity reactions
There are two types:
Type A: dose-dependent/ predictable/ mechanism-based reactions
There may be random variability and individual variation
i.e. physiological (extremes of age, pregnancy), pathological (renal failure, hepatic impairment)
Morphine is an example of a type A drug
Histamine release (anaphylactoid reaction):
This can be caused by:
- basic drugs
- solubilising agents, e.g. cremophor EL
- radiocontrast media
- colloidal plasma expanders
- polypepetides, e.g. polymixins, vancomycin (red man syndrome)
Most deaths are due to TYPE A reactions!!
Type B: dose-independent/ unpredictable/ idiosyncratic reactions
(i) reactions due to genetic factors:
Malignant hyperthermia
- triggered by suxamethomium and volatiles (halothane)
- abnormality in the RYR gene, causng an abnormal Ryanodine receptor
- massive Ca release from sarcoplasmic reticulum
- high RR/tachycardia/acidosis
- treatment: dantrolene, which uncouples electrical processes
Prolonged apnoea
- susceptibility to acetylcholinesterase and also mivacurium
- allelomorphic genes E1u, E1a, E1f, E1s
Acute hepatic porphyria
- overproduction of haem
- wide range of drugs including barbiturates, some antibiotics and drugs metabolised by p450
(ii) reactions due to drug hypersensitivity
- type I: immediate, anaphylactic shock, release of IgE causing release of mediators from mast cells
- type II: drug combines with cell components, i.e. antibiotics
- type III: serum sickness (not important)
- type IV: exposure to silver
Isomerism
The property of isomerism occurs when two or more compounds have the same atomic formulae, but a
different structural arrangement which often results in different properties.
There are two broad categories of isomerism:
Structural isomerism
Stereoisomerism
Structural isomerism
Structural isomers are molecules that have identical chemical formulae, but a different order of atomic
bonds. This may result in the compounds having similar actions like the anaesthetic volatile agents
isoflurane and enflurane or different actions such as dihydrocodeine and dobutamine.
Tautomerism
Tautomerism is a special case of structural isomerism. Tautomers are organic compounds that are
interchangable by a chemical reaction precipitated by a change in the physical environment. This
reaction often results in the formal migration of a hydrogen atom or proton, accompanied by a switch
of a single bond and adjacent double bond. A common example of this is keto-enol tautomerism, as
seen with barbiturates. Their solubility depends on the transformation from the keto to the enol form,
which occurs readily in alkaline solutions.
Another example is midazolam, which is ionized in solution at pH4, but changes structure at
physiological pH 7.4 to form a seven-membered unionized ring which is lipid-soluble and able to cross
the blood brain barrier.
Sterioisomerism
Stereoisomerism describes those compounds which have the same molecular formula and chemical
structure, but a different 3-dimensional configuration.
Sterioisomers may be:
Geometric
Optical
Geometric isomers
Geometric isomerism or cis-trans isomerism describes the orientation of functional groups within the
molecule. Such isomers typically contain double bonds which cannot rotate, but they can also arise
from ring structures where the rotation of bonds is greatly restricted. If the groups are on the same side
the conformation is called cis- and if on opposite sides trans-. Cis isomers and trans isomers often have
different physical properties. Differences between isomers generally arise from the differences in the
shape of the molecule or the overall dipole moment. The benzylisoquinolinium muscle relaxants, such
as atracurium, have two identical heterocyclic groups linked through an ester-containing carbon chain.
Each of the heterocyclic groups contains a planar ring with groups that may be arranged in either the
trans- or cis- conformation. Atracurium is formulated as a mixture of 10 stereoisomers, resulting from
the presence of 4 chiral centres. Cis-atracurium is one of the 1o Sterioisomers present in atracurium.
Mivacurium contains three such geometric isomers, trans-trans (58%), cis-trans (36%) and cis-cis
(6%).
Optical isomers
Optical isomers are the same in every way except being non-superposable mirror images of each other.
This is brought about by one or more chiral centres such a quaternary nitrogen or carbon atom
surrounded by four different chemical groups. Imagine a three dimensional tetrahedron in front of a
mirror.
The chiral centre
The four different groups around the carbon or quaternary nitrogen can now be used to distinguish
isomers.
They are also called optical isomers because they rotate the plane of polarised light either to the right
referred to as +, dextro, d or D isomer, or to the left referred to as -, laevo (levo), l or L isomer. More
recently 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 the Latin for right, and S for sinister, left).
The atom of the lowest atomic number is imagined to lie behind the plane of the page. The other three
atoms now lie in the plane of the page and if their atomic numbers descend in a clockwise manner then
this is the R enantiomer, if anticlockwise it is the S form. As with other isomers, they can have
different properties. The R and S structures are mirror images of each other and are referred to as
enantiomers. The R and S structures may be laevo or dextro-rotary to polarized light, demonstrating
that there is no relationship between these classifications.
Clinical examples of different isomers.
A racemic mixture is in which the different enantiomers are present in equal proportions.
Examples:
Bupivacaine
Atropine
Inhalational anaesthetic agents (except sevoflurane)
In sheep experiments in which racemic bupivacaine was administered in toxic quantities, it was found
that the concentration of the dextro isomer was higher in the myocardium and brain than the
concentration of the levo isomer. The levo isomer was used in rats and its effect was compared with
the dextro isomer. It was found that with doses of 2mg/kg, all the animals of the dextro group
developed apnoea, bradycardia, hypotension and finally died. In contrast, no animal in the
levobupivacaine group had apnoea and only 30% had a slight bradycardia.
The pharmaceutical industry have now developed single enantiomers with the most desirable
characteristics.
Examples of such enantiopure preparations include:
S(-)ropivacaine
S(-)bupivacaine (Levobupivacaine)
S(+)ketamine
Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine,
despite being in higher concentrations. electrophysiological studies have been made which demonstrate
that blockade of the inactive sodium channels is stereoselective, with the D isomer being more potent
and faster than the L isomer. As this includes the cardiac fibres, it explains the higher cardiotoxicity
associated with the D isomer.
The single S(+) enantiomer of ketamine is 2-3 times as potent as the R(-) enantiomer and produces
less cardiac depression. The S(+) enantiomer does not block myocardial ischaemic preconditioning and
causes less intense hallucinations
Metabolism of drugs
Metabolism in the liver into inactive compounds which are inactive and more ionised and therefore excreted by the kidney.
Other sites
suxamethonium and mivacurium: plasma cholinesterases
esmolol: erythrocyte esterases
dopamine: kidney
prilocaine: lungs
Active Metabolites
Morphine
Pethidine
Diazepam
Atracurium
Pancuronium
Prodrugs: inactive form administered which is
converted into an active metabolite
Methyl-dopa
Prednisone
Midazolam
Phase I and Phase II Reactions
Phase I: reduction, hydrolysis and oxidation
oxidation: occurs at the smooth endoplasmic reticulum by cytochrome p450
oxidation: can also perform reduction reactions
hydrolysis: important in metabolism of ester and amide drugs
Phase II: conjugation of the drug or metabolite with an endogeous substrate
conjugation with glucuronic acid, sulphate and glycine
acetylation
methylation
Induction and inhibition
Some drugs can induce the activity of enzyme systems, particularly cytochrome p450 and glucuronyl transferase.
Some drugs can inhibit the action of enzymes e.g. etomidate; inhibits the synthesis of cortisol and aldosterone
(increased mortality seen with infusions)
pH and local anaesthetics
Membrane permeability is related to ionisation, and many drug molecules exist as weak acids or bases and
therefore in an ionised and un-ionised form. The ratio of the two forms varies with pH.
Weak base: BH+ = B + H+
Dissociation constant pKa is given by the Henderson-Hasselbach equation
pKa = pH + log [BH+]/[B]
In an ACID ENVIRONMENT, the above equation will shift towards the left, i.e. the ionised form
In an ALKALINE ENVIRONMENT, the above equation will tend towards the right, i.e. un-ionised
form
A base in an alkaline solution will be non-ionised and have a greater ability to cross lipid membranes.
However, in an acid environment it will be trapped, as it is ionised. The result is that an alkaline drug
will be concentrated in a compartment with a low pH.
Weak acid: AH = A- + H+
pKa = pH + log [AH]/[A-]
In and ACID ENVIRONMENT, the equation will tend to the left, i.e. the un-ionised form
In and ALKALINE ENVIRONMENT, the equation will tend towards the right, i.e. the ionised form
A weak acid in an acid solution will be mainly in its un-ionised form. However, in an alkaline solution
it will be trapped, as it is ionised. The result is that an acid drug will be concentrated in a compartment
with a high pH.
Important consequences
a weak acid is more likely to be absorbed from the stomach
urinary acidification will accelerate the excretion of weak bases and retard that of weak acids
increasing the plasma pH will cause weakly acidic drugs to be extracted from the CNS to the plasma.
LOCAL ANAESTHETICS AS AN EXAMPLE OF THE ABOVE SITUATION
Local anaesthetics block action potential generated by blocking Na+ channels
Most local anaesthetics are weak bases with pKa between 8-9, so that they are mainly but not completely
ionised at physiological pH. The uncharged species (B) penetrates the nerve sheath and axonal membrane
and is then converted to the BH+ active form, which then blocks the Na+ channels. Increasing the acidity
of the external solution would favour ionisation and render local anaesthetics ineffective.
LOCAL ANAESTHETICS ARE INEFFECTIVE IN INFECTED TISSUE (ACIDIC).
Quaternary derivatives of local anaesthetics (Q+) do not work when applied outside but can block channels
Extra information on local anaesthetics
Many local anaesthetics are use-dependent (depth of block increases with action potential frequency)
because the molecule gains access more readily when the channel is open
Local anaesthetics block conduction in the following order: small myelinated > non-myelinated > large
myelinated. Therefore, nociceptive and sympathetic transmission is blocked first.
if introduced directly into cytoplasm.
N.B. Partition coeffcient is between oil:gas and measures the lipid solubility. It is the main
determinant of potency.
Most of the ester linked local anaesthetics (prilocaine) are rapidly hydrolysed by plasma cholinesterase, so
plasma half-life is short.
The amine-linked drugs (lidocaine and prilocaine) are metabolised by the liver (via N-dealkylation) and
metabolites are often active.
Effects on other physiological systems
CNS: causes stimulation, restlessness, tremor and even convlusions and CNS depression (including
respiratory depression)
CVS: myocardial depression (inhibition of Na+ current in cardiac muscle, thereby reducing intracellular
Ca2+ stores) and vasodilatation (direct effect on smooth muscle and inhibition of sympathetic nervous
system)
Inotropes
Muscle relaxants
Pharmacology of Non-Depolarising Muscle Relaxants
Non-depolarising muscle relaxants are commonly used during anaesthesia to provide relaxation for
surgery, to allow mechanical ventilation and they are also regularly used in intensive care. This article
describes the mechanisms by which the drugs work and also the differences between specific drugs.
Mechanism of action
Non-depolarising muscle relaxant drugs (NDMRD) compete with acetyl choline (ACh) molecules
released at the neuromuscular junction to bind with the ACh receptors on the post synaptic membrane
of the motor endplate. They therefore block the action of ACh and prevent depolarisation (or
activation) of the muscle contraction process. Muscle groups differ in their sensitivity to muscle
relaxants; ocular muscles responsible for opening and moving the eyes are the most sensitive followed
by the muscles of the jaw, neck, limbs, intercostals and abdomen. The diaphragm is the least sensitive
muscle, which is why patients undergoing surgery sometimes hiccup or breathe as an early sign that
the relaxants are wearing off.
Non-depolarising muscle relaxant drugs also act on presynaptic receptors interfering with the entry of
calcium which causes an inhibition in the release of ACh. Other drugs such as the aminoglycoside
antibiotics (eg gentamicin) and volatile agents may also effect this mechanism and increase sensitivity
to relaxants.
A variety of relaxant drugs are in use in different parts of the world. All produce profound muscle
paralysis but have varying effects on the autonomic nervous system. None of the drugs cross the blood
brain barrier as they are water soluble, polar molecules and therefore have no effect on the central
nervous system. All non depolarising drugs should be used with care in patients suspected to be
suffering with myasthenia gravis or myasthenic syndrome as patients with these conditions are
extremely sensitive to their effects.
Tubocurarine (Curare, d-tubocurarine) is a naturally occurring drug which takes
about 3 minutes to act when given intravenously and lasts for 30-40 minutes.
Cardiovascular effects: Curare has no direct action on the heart but there is often a slight fall in the
blood pressure secondary to a vasodilating effect via the sympathetic ganglia. In the presence of
volatile agents the blood pressure fall may be greater. Care should be taken with this combination in
hypotensive patients.
Respiratory effects: Curare has occasionally been associated with bronchospasm due to the release of
histamine. It should be used with caution in asthmatic patients.
Histamine release may occur following the administration of curare and frequently presents as a red
weal in the line of the vein which has been used for the injection. Problems associated with this
reaction are very rare.
Placental transfer is not a feature of curare and the drug may be safely used in obstetrics.
Effect of metabolic abnormalities: Curare is potentiated by the presence of respiratory acidosis and
hypokalaemia.
Distribution, metabolism and excretion: Thirty to forty percent is excreted unchanged in the urine and
most of the remainder in the bile. In renal failure the drug is excreted effectively by the biliary route
provided large or repeated doses are avoided.
Dose, administration and use: The initial dose should be 0.3-0.6mg/kg followed by supplementary
doses of 5mg when required (usually after 20-30 minutes). Neonates (less than 1 month old) are
sensitive to curare and an initial dose of 0.3mg/kg is recommended.
Storage: Curare does not need to be refrigerated.
Gallamine (Flaxedil) is a synthetic (manufactured) drug which acts 1-2 minutes after i.v.
injection and lasts 20-30 minutes.
Cardiovascular effects: Gallamine produces an increase in heart rate, usually by 20-30 beats/minute
due to an inhibitory action on the vagal supply to the heart. Blood pressure is usually unaltered unless
bradycardia was previously present.
Histamine release is very rare.
Placental transfer: Gallamine is thought to cross the placenta more than other relaxants although it has
been used successfully for Caearean section.
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