Dr, waad A.

Hayder 14\11\2023

General Principles of Pharmacology

HOW DO DRUGS ACT?
Drugs produce their effects on biological systems by several mechanisms; these
include physicochemical action, activity at receptors and inhibition of reactions
mediated by enzymes. Physicochemical Properties Sodium citrate is anlkali and
neutralizes acid; it is often administered orally to reduce the likelihood of
pneumonitis after regurgitation of gastric contents.

Chelating agents (chel Is the Greek word for a crab’s claw) combine chemically with
metal ions, reducing their toxicity and enhancing elimination, usually in the
urine.Such drugs include desferrioxamine (chelates iron and aluminium),dicobalt
edetate (cyanide toxicity), sodium calcium edetate (lead) and penicillamine (copper
And lead).

Stored blood contains a citrate-based anticoagulant which prevents clotting; this

chelates calcium ions and may cause hypocalcaemia after massive blood transfusion.

Action On Receptors
A receptor is a complex structure on the cell membrane which can bind selectively
with endogenous compounds or drugs, resulting in changes within the cell which
modify its function.

These include changes in selective ion channel permeability (e.g. acetylcholine,

glutamate, GABA receptors), cyclic adenosine monophosphate (e.g. opioid, β, α2 and
dopamine receptors),

The classic dose–response relationship of an agonist the concentration of the

agonist increases,a maximum effect is reached as the receptors in the system
become saturated

Antagonists combine selectively with the receptor but produce no effect. They
may interact with the receptor in a competitive (reversible) or non-competitive
(irreversible)
antagonist, the dose–response but the maximum effect remains unaltered .
Examples of this effect include the displacement of morphine by naloxone and
endogenous catecholamines by β-blockers

A non-competitive (irreversible) with increasing concentrations , reduces the

maximum effect For example, the α1 antagonist phenoxybenzamine, used in the
preoperative preparation of patients with phaeochromocytoma, has a long duration
of action

Action On Enzymes
Drugs May act by inhibiting the action of an enzyme or competing for its
endogenous substrate. Reversible inhibition is the mechanism of action of
edrophonium (acetylcholinesterase), aminophylline (phosphodiesterase) and captopril
(angiotensin-converting enzyme).

Irreversible enzyme inhibition occurs when a stable chemical bond is formed

between drug and enzyme, resulting in prolonged or permanent inactivity e.g.
omeprazole (gastric hydrogen-potassium ATPase), aspirin (cyclo-oxygenase) and
organophosphorus compounds (acetylcholinesterase). However, the interaction
between drug and enzyme may Be more complex than this simple classification
implies. For example, neostigmine inhibits acetylcholinesterase in a reversible
manner,

THE BLOOD–BRAIN BARRIER AND PLACENTA

Many drugs used in anaesthetic practice must cross the blood–brain barrier in
order to reach their site of action. The brain is protected from most potentially
toxic agents by tightly overlapping endothelial cells which surround the capillaries
and interfere with passive diffusion.

In addition, enzyme systems are present in the endothelium which break down
many potential toxins. Consequently, only relatively small, highly lipid-soluble
molecules (e.g. Intravenous and volatile anaesthetic agents, opioids, local
anaesthetics) have access to the central nervous system (CNS). Compared with
most opioids, morphine takes some time to reach its site of action because it
has a relatively low lipid solubility. Highly ionized drugs (e.g. muscle relaxants,
glycopyrronium) do not cross the blood–brain barrie

The transfer of drugs across the placenta is of considerable importance in

obstetric anaesthesia . In general, all drugs which affect the CNS cross the
placenta and affect the fetus. Highly ionized drugs (e.g. Muscle relaxants) pass
across less readily

PLASMA PROTEIN BINDING

Many drugs are bound to proteins in the plasma. This is important because
only the unbound portion of the drug is available for diffusion to its site of
action. Changes in protein binding may have significant effects on the active
unbound concentration of a drug, and therefore its actions.

Albumin is the most important protein in this regard and is responsible mainly
for the binding of acidic and neutral drugs. Globulins, especially α1-glycoprotein,
bind mainly basic drugs. If a drug is highly protein bound (> 80%) , any change in
plasma protein concentration or displacement of the drug by another with similar
binding properties may have clinically significant effects. For example, most
NSAIDs displace warfarin, phenytoin and lithium from plasma binding sites, leading
to potential toxicity.

METABOLISM
Most drugs are lipid-soluble and many are metabolized in the liver into more
ionized compounds which are inactive pharmacologically and excreted by the
kidneys. However, metabolites may be active .The liver is not the only site of
metabolism. For example, succinylcholine are metabolized by plasma
cholinesterase, esmolol by erythrocyte esterases, remifentanil by tissue esterases
and, in part, dopamine by the kidney .

A substance is termed a prodrug if it is inactive in the form in which it is

administered, pharmacological effects being dependent on the formation of active
metabolites. Examples of this are codeine (morphine), diamorphine

Drugs under go two types of reactions during metabolism: phase I and phase II.
Phase I reactions include reduction, oxidation and hydrolysis . Drug oxidation
occurs in the smooth endoplasmic reticulum

Phase II reactions involve conjugation of a metabolite or the drug itself with

an endogenous substrate. Conjugation but others include acetylation, methylation
and conjugation
Enzyme Induction And Inhibition
Some drugs may enhance the activity of enzymes responsible for drug
metabolism, . Such drugs include phenytoin, carbamazepine, phenylbutazone,
barbiturates, ethanol, steroids and some inhalational anaesthetic agents
(halothane,enflurane). Cigarette smoking A lso induces cytochrome P450 enzymes.
Drugs with mechanisms of action other than on enzymes may also interfere
significantly with enzyme systems. For example, etomidate inhibits the synthesis
of cortisol and aldosterone – effect which may explain the increased mortality in
critically ill patients which occurred when it was used as a sedative in intensive
care.

Cimetidine is a potent enzyme inhibitor and may prolong the elimination of

drugs such as diazepam, propranolol, oral anticoagulants, phenytoin and
lidocaine.

DRUG EXCRETION
Ionized Compounds with a low molecular weight (MW) are excreted mainly by
the kidneys. Most drugs and metabolites diffuse passively into the proximal renal
tubules by the process of glomerular filtration, but some are secreted actively
(e.g. penicillins, aspirin, many diuretics, morphine, lidocaine and glucuronides)
Ionization is a significant barrier to reabsorption at the distal tubule. Consequently,
basic drugs or metabolites are excreted more efficiently in acid urine and acidic
compounds in alkaline urine.

Some drugs and metabolites, particularly those with larger molecules (MW > 400
D), are excreted in the bile (e.g. glycopyrronium, vecuronium, pancuronium and
the metabolites of morphine and buprenorphine). Ventilation is responsible for
excretion of volatile anaesthetic agents.

PHARMACOKINETIC PRINCIPLES
Pharmacokinetics is the study of what happens to drugs after they have been
administered . In contrast, pharmacodynamics is concerned with their effects on
biological systems. An understanding of the basic principles of pharmacokinetics is
an important aid to the safe use of drugs in anaesthesia, pain management and
intensive care medicine. Pharmacokinetics is an attempt to fit observed changes
in plasma concentration of drugs into mathematical equations which may then
be used to predict concentrations under various circumstances. Derived values
describing volume of distribution (V), clearance (Cl) and half-life (t1/2) give an
indication of the likely properties of a drug

Volume Of Distribution
Volume of distribution is a good example of pharmacokinetics; volume but
merely a concept which helps us to understand what we observe. Nevertheless,
it is a very useful notion which enables us to predict certain properties of a
drug and also calculate other pharmacokinetic values. Imagine that a patient
receiving an intravenous dose of an anaesthetic induction agent is a bucket of
water and that the drug is distributed evenly through out the water immediately
after injection. The volume of water represents the initial volume of distribution
(V). It may be calculated easily

Drugs which remain in the plasma and do not pass easily to other tissues have
a small V and therefore a large C0. Relatively ionized drugs (e.g. Muscle
relaxants) or drugs highly bound to plasma proteins (e.g. NSAIDs dehydrated, or
have lost blood, have a significantly greater plasma C0 after a normal dose of
intravenous induction agent, increasing the likelihood of severe side-effects,
especially hypotension.

Neonates have a roportionally greater volume of extracellular fluid compared

with adults,

Clearance
Clearance is defined as the volume of blood or plasma from which the drug is
removed completely in unit time. Drugs may be eliminated from the blood by
the liver, kidney or occasionally other routes The relative proportion of hepatic
and renal clearance of a drug is important. Most drugs used in anaesthetic
practice are cleared predominantly by the liver

Elimination Half-Life
Methods of administration of a drug are influenced considerably by its plasma
t1/2, as this often reflects duration of action. It is important to remember that
t1/2 is influenced not only by clearance (Cl) but also by V:
Half-life often reflects duration of action but not if the drug acts irreversibly
(e.g. some NSAIDs, omeprazole, phenoxybenzamine) or if active metabolites are
formed

Two-Compartment Models
The body is not, of course, a single homogeneous compartment; drug plasma
concentrations are the result of elimination by metabolism and redistribution to
and from tissues such as brain, heart, liver, muscles and fat . The mathematics
describing this real situation are extremely complex. However,plasma
concentrations of many drugs behave approximately as if they were distributed
in two or three compartments. Applying these mathematical models is a
reasonable compromise

METHODS OF DRUG ADMINISTRATION

1- Oral 2- Lingual And Buccal 3- Intramuscular

4- Subcutaneous 5- Intravenous 6- Rectal 7- Transdermal

8- Inhalation 9- Epidural 10- Spinal(Subarachnoid)

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