Introduction to Pharmacology

Pharmacology
Etymologically, pharmacology is the science of drugs (Greek pharmakos: medicine
or drug; and logos: study)

What is pharmacology?
Pharmacology ‫ علم االدوية‬is the science of studying substances – drugs- that interact
with living organs, or systems through chemical processes especially by binding to
regulatory molecules activating or inhibiting normal body function.
Example: reduce blood glucose levels, dilate bronchioles, and constrict blood
vessels.

Pharmacy ‫الصيدلة‬
Is the profession concerned with manufacturing, preparing and dispensing drugs.

What is a drug?
A drug is any substance that has an effect on living systems. It is a chemical molecule
that interacts chemically with body molecules (i.e. attraction forces, ionic bonds,
covalent bonds,…)
Examples: coffee, nicotine, alcohol, morphine (non medical use),
Apirin, penicillin, diazepam,… (medical use)
Fenugreek ‫ الحلبة‬pepper mint ‫( … النعناع‬herbs, home remidies)

Uses of drugs
Drugs are used in the treatment, prevention, or diagnosis of disease or condition.

Sources of drugs
• Plant source: e.g. atropine
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 • Animal source: heparin, insulin and thyroxin
• Semisynthetic: human insulin (recombinant DNA technology)
• Synthetic: aspirin

Advantage s of synthetic drugs:

• Can be manufactured in large amounts
• Cheap than natural drugs
• The drug could be subjected to modifications that increase efficacy or decrease
toxicity.

Pharmacology is broadly divided into to sections:

Pharmacodynamics and, Pharmacokinetics.

Pharmacodynamics:
Is the study of the molecular interaction between the drug and body molecules
through which subsequent series of events result in pharmacological or therapeutic
effect i.e. how the drug affects the body.
We study things like mechanism of action, responses produced, uses, adverse effects
and toxicity.

Pharmacokinetics:
Is the study of the time course of drug absorption, distribution, elimination and the
corresponding pharmacological or therapeutic effect i.e. how the body affects the drug.
We study routes of administering the drug, drug metabolism and excretion

Other sciences related to pharmacology

Pharmacotherapy:
Deals with the proper selection and use of drugs in the prevention and treatment of
disease.
Here we are concerned with guide lines, proper combination of drugs, clinical out comes
of treatment, …

Pharmaco-epidemiology
Study of beneficial and adverse effect of drugs on populations
Example: the influence of aspirin use on heart attack.

Pharmco-economics
The study of financial cost of a disease under treatment, and the true cost of drugs.
Example: aspirin costs 10SDG for a cardiovascular patient for a month. But is requires
monitoring and treating GI and renal effects making the real cost above 2000SDG
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Pharmacogetics
Is the use of genetic information to guide the choice of drug therapy on an individual
basis.

Pharmacovigillance
Is the study of drug related events and adverse drug reactions.
It depends on reporting drug events by the medical staff for example by the yellow
pages on the BNF

Drug nomenclature
Drugs are named according to:
• Exact or abbreviated chemical name
• Generic name
• Brand or commercial name.

A drug may have many names

e.g. para-amino benzoic acid (chemical name), paracetamol (generic), panadol (brand)

Drug effects
• Therapeutic effect (intended)
• Unwanted effects:
o Side effect (annoying but not harmful e.g. dry mouth)
o Adverse effect (harmful e.g. diarrhea)
• Toxic effect:
o Acute e.g. renal failure, death.
o Delayed; teratogenicity, cancer.
Types of drug action/ effect:
A/ Local or topical action: drug acts at its site of application e.g. skin and eye drops.

B/ Systemic action: drug acts after being introduced to the general circulation (after
absorption and distribution).

* Drugs applied locally can have systemic effects if they are absorbed.
* Ingested drugs could act locally if they are not absorbed from the GIT.

The effect of dose on response

For drugs to produce a therapeutic effect they must reach an effective concentration.
High concentrations produce toxic effects. Therefore drug doses should be given
within a therapeutic level.
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Drug development
1. Molecule selection (lead compound)
a. Screening natural products for pharmacological activity.
b. Target selection;
Example: isolate the receptor, determine its chemical structure and find substances
that react with it (lead finding→ optimization → drug candidate).
2. Preclinical development
➢ Pharmacological testing
➢ Toxicity testing; acute (single dose) and chronic (28 days)
➢ Pharmacokinetics (in animals)
➢ Chemical and pharmaceutical development
If succeeds obtains permission to clinical trials; and experiments continue on
long term toxicity (2 years), and effect on fertility, and fetus.
3. Clinical trials
Are bioassay conducted on human subjects.They require lenience from authorities
and written consents from volunteer subjects.They include four phases, approval and
permission from authorities is required to proceed to the next phase.
They could be single or double blind or cross over experiments.

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Phase I
Conducted on 20-80 normal healthy volunteers. The aim of the trail is to assess:
➢ Safety; exclude any dangerous effects (on CVS. CNS...)
➢ Tolerance: whether the drug produces untolerated effects like nausea.
➢ Pharmacodynamics
➢ Pharmacokinetics

Phase II
Conducted on 100-300 patients. It is a single blind design. The trials aims at testing
the clinical efficacy of the drug (on patients).The trial is conducted on distinct types
of patients’ groups to determine indication
Example: a new antihypertensive is developed; different groups of hypertensive
patients, and other vascular and cardiovascular disorders are included in the trial

Phase III
Is a double blind trail. Conducted on 1000-3000 patients. Takes a long time to
complete and probably conducted over many hospitals/ centers. The aim of the trail is
to compare the efficacy of the new drug to the standard therapy.
If successful the drug is approved and gets to the market.

Phase IV (Post marketing surveillance)

Aims to detect long term and/or rare side effects. This is also termed
pharmacovigilance.
If a drug is found to be harmful:
➢ Could be withdrawn from the market
➢ Restricted to certain categories of patients

Examples:
Astemazol and terfenadin (non sedating antihistamine) caused arrhythmia and
withdrawn from market.
Thalidomide (anxiolytic and antiemetic) was used in the 60s for morning sickness
caused limb deformity in fetus. Withdrawn from market but now is used in selected
patients for autoimmune disorders.

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 Dosage of drugs:

Here are some important terms:

Therapeutic dose: the average dose for an adult required to produce a therapeutic
effect ED50.
Maximal tolerated dose: The largest dose of a drug that can be taken safely.
Lethal dose or fatal dose: the dose that produces death LD50.
Therapeutic index (window): Is a measure of drug safety, mathematically equals
lethal dose/therapeutic dose (LD50/ED50). If the index is more than 2 the drug is
safe, if 2 or less the drug has narrow therapeutic window and should be used with
caution.

• Examples of safe drugs (wide therapeutic window)

Penicillin.Paracetamol.Folic acid.
• Examples for drugs with narrow therapeutic window
o Phenytoin (antiarrthmic-anticonvulsant).
o Lithium carbonate (bipolar depression).
o Aminophyllin (asthma).
o Warfarin (anticoagulant)
o Digoxin (heart failure, antiarrythmic)

These drugs require monitoring plasma drug levels.

Initial dose: the dose used to start the treatment.

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 Loading dose: a large initial dose, is given to achieve a rapid high plasma therapeutic
level e.g. chloroquine 4 tabs firstly

Maintenance dose: the dose required to maintain the therapeutic effects attained by
the initial dose.

Factors modifying the dosage and action of drug:

- Age.
- Weight.
- body surface area.
- Sex
- Route of administration
- Time of administration
- Hypersensitivity, tolerance
- Genetic factors

Children doses:

In children there is:

- Underdevelopment of many microsomal enzyme (drug metabolism)
- Reduced renal excretion of drug due to lower glomerular filtration, tubular
reabsorption and secretion in neonates.
- Lower total plasma protein and albumin in newborn
- Immaturity of the BBB leads to increased sensitivity of newborn to drugs e.g.
morphine

Calculating Children doses:

A/ Young’s formula
Child dose = adult dose X age in year/age + 12

B/ Clark’s formula
Child dose = adult dose X weight in pounds / 150

Doses in elderly

Elderly people (over 60) require lower doses.

They have increased sensitivity to most drug because of:

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 impaired ability to metabolize and excrete drugs (decreased organ function), thus
drugs stay longer in the body and have longer/greater effects compared to young
adults
response may alter with age e.g. decrease number of B-receptor

* In the elderly body weight is more reliable index of the dosage than age.
* Surface area is the most accurate guide for dosage than age or body weight.

PHARMACODYNAMICS
Pharmacodynamics:
Is the study of the molecular interaction between the drug and body molecules
through which subsequent series of events result in pharmacological or therapeutic
effect
i.e. how the drug affects the body.

There are four levels of drug action:

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 Molecular mechanisms of drug action:
A/ Interaction with body regulatory proteins. (main)
Bind to receptors
Bind to ion channels and carriers
Bind to enzymes (Affect metabolic processes in the cell)
Bind to DNA/RNA (Affect gene transcription and protein synthesis)

B/ Without interaction with regulatory proteins:

Physically: e.g. by adsorption (kaolin in diarrhoea), osmosis (osmotic diuretics), etc..
Chemically: e.g. neutralization (Na bicarbonate in hyperacidity), chelating
(dimercaprol in mercury poisoning)…

Targets for drug action:

Mainly drugs target are regulatory proteins in the body like: Receptors.
Enzymes. Ion channels and gates. Carrier molecules.DNA, RNA and Structural
proteins.

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 Binding: for drugs to act they must bind to receptors, this bond could be reversible or
irreversible
Reversible: ionic bonds (weak), attraction forces (very weak).
Irreversible: covalent bonds (strong)

Affinity is the likeliness of a molecule to a target (receptor), for drugs to bind they
must have affinity to the receptor.

Occupancy theory:
There are many theories that explain the binding relationship between drugs and
receptors.
Occupancy theory states that the response produced is proportional to the
number/fraction of receptors occupied.
The maximal response (100%) is achieved when all the receptors are occupied.

Ligand: is any substance that is capable of producing a physiological response when

combined to a receptor.
Effectors: are molecules that translate drug receptor interaction into cellular activity.
Efficacy: is the ability of a molecule to activate the receptor and produce a
physiological response

Agonist: is a ligand that when bound to the receptor activates the cell (produce a
response) e.g. noradrenalin, acetylcholine.

Agonists are either full agonist: which fully activate the effector system when in
sufficiently high concentration. They have full efficacy or partial agonist; the
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 maximum response produces is much less than the maximum the tissue is capable of
producing. They have partial efficacy.

Antagonist: is a ligand that produces no cellular response when bound to the

receptor. They block or diminish the effect of agonist. They have affinity but zero
efficacy.

Inverse agonist
Usually receptors are “off” until they bind to an agonist to become activated “on”.
Some receptors develop constitutive activity and become active “on” without
stimulation of an agonist (pathology).
Inverse agonist when bound to this type of receptor, blocks the activation and return
the receptor to the resting sate

Agonist : +ve efficacy >0

Antagonist zero efficacy =0
Inverse agonist: -ve efficacy <0

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 Types of responses to drugs:

There are two types of responses:

1. Graded response; the response increases with increase in concentration. E.g.
glucose levels fall more with increased doses of antidiabetic, the concentration in
intestinal smooth muscles increases with increase in acetylcholine.
2. Quantal responses: are all or none, i.e. the drug either produces a response or not.
E.g. pain killers either stop pain or not (feel the pin prick or not), antiepileptic either
prevent seizure or not.

Dose-response curve
Is the graphical representation of the relationship between drug concentration and the
corresponding response.
Responses increase with increase in dose whether this response in graded or quantal.

* Dose response curves cab be made for both agonist and antagonist

Potency: is the amount of drug used to produce a specific response. Comparing

between A and B at the same response, if a smaller conc. of A is used then it is potent.
Potency has no clinical value.

Efficacy: is the maximal response produced regardless of the amount of drug used.
Comparing drug A and B if A produces a higher response than B then it is efficous.

Therapeutic index (therapeutic window): is the ration between LD50/ED50.

Indices of 2 or more mean the drug is safe e.g. penicillin.
Drugs like digoxin, phenytoin, lithium, aminophyllin, and warfarin have narrow
therapeutic windows; a small increase in dose can produce toxic effects.

Types of receptors
Targets for drugs

Receptors
• Ion channel
• Carriers
• Enzymes
• DNA, RNA
• Structural proteins

There are four types of receptors

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 1. ligand –gated ion channels
2. G protein coupled receptors
3. kinase linked (insulin like)
4. nuclear receptors

1. Ligand- gated ion channels/ionotropic receptors

These are membrane proteins that incorporate a ligand binging site. They produce
very fast responses. Are typically involved in fast neurotransmitters actions on nerves
or muscles.
Examples: nicotinic acetylcholine receptors GABAa, and glutamate receptors.

2. G-protein coupled receptors (GPCR):

These receptors are linked with G protein that relay the signal to the effector system
that translate it into cellular responses.
It can produce rapid (minuets to hrs) or slow response taking up to weeks to appear
depending of the effecter system.

G proteins:
These are a family of membrane resident proteins whose function is to identify
activated receptors (GPCR) and pass on the message (signal) to the effecter system
that generates the cellular response. They are termed G- proteins because of their
interaction with guanine nucleotides GTP and GDP. They consist of three subunits
α,β, and γ

Guanine nucleotides binds to the α subunit, which has enzymic activity, catalysing
the conversion of GTP to GDP. The β and γ subunits remain together as a βγ
complex.

G-proteins appear to be freely diffusible in the plane of the membrane, so a single

pool of G-protein in a cell can interact with several different receptors and effectors
in an essentially promiscuous fashion.

In the 'resting' state, the G-protein exists as an unattached αβγ trimer, with GDP
occupying the site on the α subunit. When a GPCR is activated by an agonist
molecule, a onformational change occurs, involving the cytoplasmic domain of the
receptor, causing it to acquire high affinity for αβγ. Association of αβγ with the
receptor causes the bound GDP to dissociate and to be replaced with GTP (GDP-GTP
exchange), which in turn causes dissociation of the G-protein trimer, releasing α-GTP
and βγ subunits; these are the 'active' forms of the G-protein,

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 These active forms diffuse in the membrane and can associate with various enzymes
and ion channels, causing activation of the target. Association of α subunits with
target enzymes can cause either activation or inhibition, depending on which G
protein in involved.

It was originally thought that only the α subunit has a signaling function, but the βγ
complexes actually make assignations of their own. In general, higher concentrations
of βγ complex are required to produce a signal. So βγ-mediated effects occur at
higher levels of receptor occupancy than α-mediated effects.

Signaling is terminated when the hydrolysis of GTP to GDP occurs through the
GTPase activity of the α subunit. The resulting α-GDP then dissociates from the
effecter, and reunites with βγ, completing the cycle. Attachment of the α subunit to an
effecter molecule actually increases its GTPase activity, the magnitude of this
increase being different for different types of effectors.

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 Targets for G proteins: effecter systems: signal transducion

1. Adenylyl cyclase/cAMP
2. Phospholipase C/ inisitol triphosphate and diaceyglycerol
3. Ion channels
4. Rho/rhokinase

Classes of GPCR:
Gs : stimulate Adenylyl cyclase increasing cAMP
Gi: inhibits Adenylyl cyclase decreasing cAMP
Gq: activate phospholipase C
Go: limited effect of the α subunit, activity is due to βγ complex

3. Kinase linked receptors:

They mediate the action of protein molecules like hormones and growth factors .
There effects are exerted mainly at the level of gene transcription i.e. affect protein
synthesis.
Structure: have a single membrane spanning helical region associated with large
extracellular ligand binding domain and large intracellular domain with enzymetic
activity.
Role: control cell division, growth and differentiation also involved in inflammation.

Classes: the receptor could be linked to different type of effectors:

1. Tyrosine kinase (insulin like)
2. Serine/threonine kinase
3. Guanylyl cyclase linked receptor (stimulate cGMP)
4. C ytokine receptor; have no enzymatic activity of it’s own, when activated
they associate with and activate a cytosolic tyrosine kinase such as Jac.
enzymes

Activation:
when the ligand binds the receptor leads to dimerisation of two intracellular kinase
domains, this allows auto-phosphorylation of the kinase.
The phosphorylated residue (tyrosine/serine/guanylyl) will become a high affinity
docking site for intracellular proteins that form the next stage of the signal
transduction cascade.

The end result is to activate or inhibit transcription factors that migrate to the nucleus
and induce or suppress particular genes.

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 4. Nuclear receptors:
Are receptors for steroids such as sex hormones, glucocorticoids and
mineralocorticoids, vitamin A and D.
They are regarded as ligand activated transcription factors.
They also act as lipid sensors and regulate cell lipid metabolism.
They are important in the balance between diet metabolic status and deposition of fat.
Their malfunction is associated with inflammation, cancer, diabetes, cardiovascular
disorders and obesity. (class II)

Structure:
Nuclear receptors have distinct four parts:
a) N-terminal: with activation functions to bind to cell specific transcription factors.
b) core; is responsible for DNA recognition and binding -has a unique zinc fingers
structure-

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 c) hinge region: allows dimerization with other nuclear receptors.
d) C-terminal is the ligand binding site.

Classification:
Class I:
For steroids: the receptor is located in cytoplasm,
When bound to lignad, form homodimers, and translocate to the nucleolus,
They activates or suppresses genes by binging to (positive) or (negative) hormone
response elements.
Generally they mediate –ve feed back mechanisms.

Class II:
The receptor is located in the nucleous.
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 Ligands are generally lipids endogenous to the cell, like fatty acids, cholesterol, bile
acids.
They regulate metabolism of endogenous and exogenous subatances.
Form heterodimers
Mediate +ve feed back.
Associated with enzyme induction.

Hybrid class:
Ligands are encodrine hormones. –ve feed back
Form heterodimers.
Targets for drugs

Ion channels
Ion channels are targets for drug action
Ions are unable to penetrate the lipid bilayer of the cell membrane, can cross only
with the help of membrane-spanning proteins in the form of channels or transporters.
Ion channels consist of protein molecules designed to form water-filled pores that
span the membrane, and can switch between open and closed states. The rate and
direction of ion movement through the pore is governed by the electrochemical
gradient for the ion in question, and of the membrane potential.

Ion channels are characterised by:

• Selectivity:Channels are generally either cation-selective (Na+, Ca2+ or K+) or

anion-selective (Cl-).
• Gating (voltage gated) These channels open when the cell membrane is
depolarised (membrane excitability). The opening of the channel is usually
short even if the depolarization is maintained.

Structure: Ion channels are large and elaborate molecules. Consist of several (often
four) domains, which are identical to each other, organised either as an oligomeric
array of separate subunits, or as one large protein.
Each subunit or domain contains a bundle of two to six membrane-spanning helices.

Signaling on ion channels

Ligand activated (considered as receptors) e.g. nicotinic acetylcholine receptors
Voltage activated: e.g. Na channels is excitable tissues. Local anesthetic block
voltage gated Na channels.
Intracellular signals (channels open/close via intracellular components e.g. Ca,
nucleotides ATP…)

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 Enzymes
Drugs inhibit enzymes by:
• Being similar to the substrate and bind to the active site, thus blocking the
enzyme. E.g. aspirin on cycloxiginase enxyme.
• Binding to an alosteric site that negatively affect the enzyme e.g. angiotensin
converting enzyme inhibitors

Examples:
Angiotensin converting enzyme inhibitors (captopril) used to treat hypertension.
Xanthine oxidase inhibitors (allopurinol), used to treat gout.
Phosphodiesterase inhibitors (theophyllin) used to treat asthma.

More examples:

Drug Antagonism
Drug antagonism happens when two drugs used at the same time (concurrently) and
one of them (the antagonist) reduces the effect of the other (the agonist).

Types of drug antagonism

• By receptor block.
• Chemical antagonism
• Pharmacokinetic antagonism
• Physiological antagonism
• Chemical antagonism

1. Chemical antagonism: occurs when the two substances/drugs combine in

solution; as a result, the effect of the active drug is lost.
Examples:
- Tetracycline and cations (Ca, Fe, Al,…): the cations chelate tetracyline
rendering it inactive.

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 - Chelating agents (e.g. dimercaprol) that bind to heavy metals and thus reduce
their toxicity.

2. Pharmacokinetic antagonism
The 'antagonist' effectively reduces the concentration of the active drug (agonist) at
its site of action. This can happen in various ways:
- The rate of metabolic degradation of the active drug may be increased (e.g. the
reduction of the anticoagulant effect of warfarin when an agent that
accelerates its hepatic metabolism, such as Phenobarbital is used at the same
time.
- The rate of absorption of the active drug from the gastrointestinal tract may be
reduced.
- Or the rate of renal excretion may be increased.

* Interactions of this sort can be important in the clinical setting.

3. By receptor block
This can be:
• Reversible competitive antagonism
• Irreversible competitive antagonism
• Non competitive antagonism.
a. Reversible competitive antagonism
Competitive antagonism describes the common situation whereby a drug (antagonist)
binds selectively to a particular type of receptor without activating it, but in such a
way as to prevent the binding of the agonist. The two drugs compete with each other.
Because the receptor can bind only one drug molecule at a time. At a given agonist
concentration, the agonist occupancy will be reduced in the presence of the
antagonist.
Raising the agonist concentration can restore the agonist occupancy
(surmountable/reversable).
In the presence of a fixed concentration of the antagonist, the log concentration-effect
(dose- response) curve for the agonist will be shifted to the right, without any change
in slope or maximum.
The shift is expressed as a dose ratio (the ratio by which the agonist concentration
has to be increased in the presence of the antagonist in order to restore a given level
of response).
The surmountability of the block by the antagonist may be important in practice,
because it allows the functional effect of the agonist to be restored by an increase in
concentration.
E.g. atropine and acetylcholine.

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 b. Irreversible competitive antagonism
Irreversible, or non-equilibrium, competitive antagonism occurs when the antagonist
dissociates very slowly, or not at all, from the receptors. No change in the antagonist
occupancy takes place when the agonist is applied. Efficacy is reduced. And the dose
response curve shifts downwards.

Irreversible competitive antagonism occurs with drugs that possess reactive groups
that form covalent bonds with the receptor.

These are mainly used as experimental tools for investigating receptor function, and
few are used clinically.Irreversible enzyme inhibitors that act similarly are clinically
used, e.g. aspirin, omeprazole and monoamine oxidase inhibitors.

c. Non-competitive antagonism
The antagonist blocks at some point the chain of events that leads to the production
of a response by the agonist.
For example, drugs such as verapamil and nifedipine prevent the influx of Ca2+
through the cell membrane and thus block non-specifically the contraction of smooth
muscle produced by other drugs (agonist)
The effect will be to reduce the slope and maximum of the agonist log concentration-
response curve.

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 4. Physiological antagonism
Is a term used loosely to describe the interaction of two drugs whose opposing
actions in the body tend to cancel each other. Usually both drugs are agonists.
For example, histamine (agonist) acts on receptors of the parietal cells of the gastric
mucosa to stimulate acid secretion , while omeprazole Agonist) inhibits the proton
pump;
The two drugs can be said to act as physiological antagonists.

* Physiological antagonist is responsible for tolerance of many drugs

Desensitization
Desensitization: Is the gradual loss of pharmacological response with repeated use of
a drug.
Examples for drug that develop desensitization:
Nicotine, caffeine, alcohol, morphine, cocaine. (non medical use)
Diazepam, Glecerlyl trinitrate, thiazide diuretics. (medical use)

Tachyphylaxis is a term used to describe desensitization which develops in the course

of a few minutes (usually on isolated tissues)

The term tolerance is conventionally used to describe a more gradual decrease in

responsiveness to a drug, taking days or weeks to develop.

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 Refractoriness is synonyms with tolerance. Drug resistance is a term used to
describe the loss of effectiveness (tolerance) of antimicrobial or antitumour drugs.
Many different mechanisms can cause resistance for example B lactamase enzyme
produced by bacteria to break penicillin.

Causes of desensitization
• Change of receptors
• Loss of receptors
• Exhaustion of mediators.
• Increased metabolic degradation.
• Physiological adaptation.
• Active extrusion of the drug.
There are other mechanism but poorly understood, for example tolerance to morphine, alcohol…
etc.

1. Change in receptors
Usually happens on receptors directly coupled to ion channels. The desensitized state
is caused by a conformational change in the receptor, resulting in tight binding of the
agonist molecule without eliciting response. (e.g. opening of the ionic channel) or
phosphorylation of intracellular regions of the receptor protein.

Phosphorylation can also lead to desensitization in G- protein coupled receptors

2. Loss of receptors
Prolonged exposure to agonists often results in a gradual decrease in the number of
receptors expressed on the cell surface, as a result of internalisation of the receptors.
This is termed down regulation. Example β-adrenoceptors, and hormone receptors
like gonadotrophin-releasing hormone.

3. Exhaustion of mediators
Desensitization is associated with depletion of an essential intermediate substance.
Drugs such as amphetamine, which acts by releasing noradrenalin from nerve
terminals show marked tachyphylaxis because the amine stores become depleted.

4. Altered metabolism
Tolerance to some drugs, for example barbiturates and ethanol, occurs partly
because repeated administration of the same dose produces a progressively lower
plasma concentration, because of increased metabolic degradation. Such drugs are
termed enzyme inducers.
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 5. Physiological adaptation
The drug's effect is reduced because it is nullified by a homeostatic response.
For example, the blood pressure-lowering effect of thiazide diuretics is limited
because of a gradual activation of the renin-angiotensin system.

Many side effects of drugs, such as nausea or sleepiness, tend to subside when drug
administration is continued.

Variation in responses to drugs

People have variable responses to the same drug. Variation could be;
- Quantitative: different people require different concentrations to produce the
same effect.
- Qualitative (idiosynchratic): people produce different Reponses to the same
drug.

Factors causing variation in responses

Ethnicity
Genetic
Age
Pregnancy
Idiosyncratic reactions
Disease
Drug interactions

Ethnicity
Example African-American with heart failure benefit better from hydralazine +
nitrate compared to white.
Chinese people metabolize alcohol faster resulting in higher levels of acetaldehyde
thus they get more side effects (flushing and palpitation)
Afro-Carebians are less responsive to beta blockers than Whites and Asians.
Asians (Chinese) are more sensitive to beta blockers than White, they get more side
effects

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 Genetic factors
This is caused by gene mutations and polymorphism. In some situations there is a
balance between different forms of a gene; this is called “balanced polymorphism”
Examples:
• Mutation in glucose-6-phosphate dehydrogenase G6PD makes the
individual resistant to malaria. It is popular in areas were the disease is
endemic. However this affects the metabolism of many drugs e.g.
sulphonamides.

• Slow and fast acetylators: have varying metabolism of isoniazide (TB

drug)
• Altered buterylcholine esterase results in prolonged action of
suxamethonium
(muscel relaxant in anaesthesia)
• Mutation in CYP2D6 facilitates the conversion of codeine (not euphoric) into
morphine (euphoric).

Idiosynchratic reactions
These are qualitatively abnormal, usually harmful drug effects that occur in a small
proportion of the population.
• Example: chloramphenicol causes aplastic anaemia in 1: 50, 000 individuals
• Primaquine cuses haemolysis leading to severe anaemia (linked to G6PD
deficiency)
• Penicillin causes anaphylactic shock.

Age
Drug metabolism and elimination is much slower in neonates and elderly people
therefore it causes prolonged action of the drug and more side effects.

Also sensitivity to some drugs varies in these groups, e.g. benzodiazepines produce
more confusion and less sedation in elderly compared to young adults

Pregnancy
In pregnancy many physiological factors that affect drugs are changed like:
- Plasma albumin is increased (more protein binding less free drug)
- Cardiac output is increased, increases GFR and renal elimination of drugs
- Metabolic rate is increased
- Drugs that cross the placenta (lipophylic) are excreted much slowly (the fetus
metabolism and renal elimination are very deficient).

Diseases
Dr. Nuha Pharmacology Lecture Notes 2017 Page 28
 Drug absorption is affected in migraine, diabetic neuropathy, heart failure …
Hypothyroidism increases the sensitivity of many drugs e.g. pethidine.
Hypothermia (in elderly) reduces the elimination of many drugs.

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 Types of Adverse Drug Reactions

As a general rule; all drugs can produce harmful as well as beneficial effects. Adverse
effect could be related to the mechanism of action or not.

Adverse effects related to the mechanism of action are sometimes termed

“augmented” responses.
For example, postural hypotension occurs with α1-adrenoceptor antagonists, bleeding
with anticoagulants, sedation with anxiolytics. In many instances, this type of
unwanted effect is reversible, and the problem can often be dealt with by reducing the
dose. Some are not easily reversible, for example drug dependence produced by
opiate (morphine) analgesics.

Adverse effects not related to the mechanism of action are sometimes termed
“bizarre” reactions e.g. anaphylaxis to penicillin

Adverse effects may be predictable when:

- a drug is taken in excessive dose: e.g. paracetamol → hepatotoxicity, aspirin
→ tinnitus, aminoglycoside → Ototoxicity.
Dr. Nuha Pharmacology Lecture Notes 2017 Page 30
 - during pregnancy (e.g. thalidomide teratogenicity)
- patients with a predisposing disorder: e.g. primaquine-induced haemolysis in
patients with glucose 6-phosphate dehydrogenase deficiency,

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Dr. Nuha Pharmacology Lecture Notes 2017 Page 32