PHARMACODYNAMICS

PHARMACODYNAMICS: Pharmacodynamics means what drug does to the body .

PRINCIPLE OF DRUG ACTION:

What types of changes occur in our body by drug

MECHANISM OF DRUG ACTION

By which mechanism all the changes are occurred by drug

PRINCIPLE OF DRUG ACTION

When drug enter into the body it doesn’t impart any other function to system ,organ or cells.
It just alters the pace of ongoing or reaction.

Basic type of drug actions:

1.STIMULATION : refers to selective enhancement of the level of activity of specialized

cells.

e.g. adrenaline stimulates heart, pilocarpine stimulates salivary glands, caffine stimulates CNS

excessive stimulation is often followed by depression of that function.

e.g. high dose of picrotoxin, a central nervous system (CNS) stimulant, produces convulsions
followed by coma and respiratory depression stimulation is often followed by depression of
that function.

2.DEPRESSION : selective diminution of activity of specialized cells.

e.g. barbiturates depress CNS, quinidine depress heart, omeprazole depresses gastric acid
secretion.

Certain drugs stimulate one type of cells but depress the other

e.g. acetylcholine stimulates intestinal smooth muscle but depresses SA node in heart. Thus,
most drugs cannot be simply classed as stimulants or depressants

3. IRRITANT : Nonselective often noxious effect and is particularly applied to less

specialized cells

Act as counter irritant

Excessive use caused inflammation of skin (topical surface)

e.g senna used for constipation

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act as irritate and caused bowel movement

4. REPLACEMENT : used in case of deficiency state of natural metabolites , hormone

E,g. Iron for anemia, Levodopa in Parkinson, Insulin for diabetes

5. CYTOTOXIX: SELECTIVE cytotoxic action on parasite and cancer cell

Used in case of parasitic infection, Only killed the parasite cell and remain ineffective towards
the host cell.

Used in case of cancer to kill unwanted cell.

e.g. penicillin,chloroquine, antifolate etc

MECHANISM OF DRUG ACTION:

Mechanism of action means steps followed by drug to produce pharmacological action.

Drug shows pharmacological action by the help of four fuctional protein; i.e.

1. ENZYME

2. ION CHANNELS

3. TRANSPORTER

4. RECEPTOR

1.ENZYME :

• All the enzymes are protein.

• All the biological action carried out under catalytic influence of enzyme.
• Hence, enzymes play a very important role in target of drug action.
• Drug can either increase or decrease the effect or rate of enzymatically mediated
reaction .

• Several enzymes are stimulated through receptors and second messengers, e.g.
adrenaline stimulates hepatic glycogen phosphorylase through b receptors and cyclic
AMP.

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Enzyme inhibition:

Some chemicals (heavy metal salts, strong acids and alkalies, formaldehyde, phenol, etc.)
denature proteins and inhibit all enzymes nonselectively. They have limited medicinal value
restricted to external application only.

(i) Competitive (equilibrium type) The drug being structurally similar competes with
the normal substrate for the catalytic binding site of the enzyme so that the product
is not formed or a nonfunctional product is formed .
(ii) Noncompetitive The inhibitor reacts with an adjacent site and not with the catalytic
site, but alters the enzyme in such a way that it loses its catalytic property.

2.ION CHANNELS :

• Proteins which act as ion selective channels participate in transmembrane signaling and
regulate intracellular ionic composition are the ion channel.

• Ligand gated ions channels are a group of transmembrane ion channel proteins which
open to allow ions to pass through membrane in response to the binding of a chemical
messenger (i.e.ligand) such as neurotransmitter.

• Some of which are receptors, because they are operated by specific signal molecules
either directly and are called ligand gated channels (e.g. nicotinic receptor, or G-protein
regulated channels (e.g. cardiac β1 adrenergic receptor activated Ca2+ channel).

• Voltage gated ion channels are a class of transmembrane protein that form ion channels
that are activated by change in electric membrane potential near the channel.

• Drugs can also act on voltage operated and stretch sensitive channels by directly binding
to the channel and affecting ion movement through it, e.g. local anaesthetics which obstruct
voltage sensitive Na+ channels.

• Quinidine blocks myocardial Na+ channels.

• Dofetilide and amiodarone block myocardial delayed rectifier K+ channel.

• Nifedipine blocks L-type of voltage sensitive Ca2+ channel.

• Nicorandil opens ATP-sensitive K+ channels.

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 • Sulfonylurea hypoglycaemics inhibit pancreatic ATP-sensitive K+ channels.

3. TRANSPORTER:

Several substrates are transloncated across membranes by binding to specific transporters

(carriers) which either facilitate diffusion in the direction of the concentration gradient or
pump the metabolite/ion against the concentration gradient using metabolic energy.

• Desipramine and cocaine block neuronal reuptake of noradrenaline by interacting with

norepinephrine transporter (NET)

• Amphetamines selectively block dopamine reuptake in brain neurons by dopamine

transporter (DAT).

4.RECEPTOR:

Receptors are the macromolecule or binding site located on the surface or inside the effector
cell.

It serves to recognize the signal molecule/drug and initiate the response to it (to action)

But receptor itself has no other function.

IMPORTANT TERMS:

Agonist: Activates a receptor to produce an effect similar to that of the physiological signal
molecule.

Inverse agonist :Activates a receptor to produce an effect in the opposite direction to that of
the agonist.

Antagonist :prevents the action of an agonist on a receptor or the subsequent response, but
does not have any effect of its own.

Partial agonist :activates a receptor to produce submaximal effect but antagonizes the action
of a full agonist.

Ligand (Latin: ligare—to bind)

Any molecule which attaches selectively to particular receptors or sites.

NATURE OF RECEPTOR:

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Receptors are regulatory macromolecules, mostly proteins (nucleic acid serves as receptor)

Several receptor protein have been isolated, purified ,cloned and their primary amino acid has
been worked out.

The polar portion of amino acid comes out as aqueous medium where as the nonpolar portions
bury within the cell membrane .

ROLE OF RECEPTOR :

Chemical messenger recognize the binding of receptor

This causes intermolecular bond formonation

Bindings results induction of receptor protein

Caused change in receptor

This change in receptor Results domino effects

(also known as Transduction )

Leads to chemical signal being received inside the cell

THEORIES OF RECEPTORs :

Receptor Occupation Theory

• Propounded by Clark (1937), a theory of drug action based on occupation of receptors by

specific drugs.

• He perceived the interaction between the two molecular species, viz. drug (D ) and receptor
(R) to be governed by the law of mass action, and the effect (E) to be a direct function of the
drug-receptor complex (DR) formed:

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 • It has been realized that occupation of the receptor is essential but not itself sufficient to
elicit a response, the agonist must also be able to activate (induce a conformational change in)
the receptor. • Competitive antagonists occupy the receptor but do not activate it. Moreover,
certain drugs are partial agonists which occupy and submaximally activate the receptor.

• A theoretical quantity (S) denoting strength of stimulus imparted to the cell was interposed
in the Clark’s equation

• Depending on the agonist, DR could generate a stronger or weaker S, probably as a function

of the conformational change brought about by the agonist in the receptor

Agonists have both affinity and maximal intrinsic activity (IA = 1), e.g. adrenaline, histamine,
morphine.

Competitive antagonists have affinity but no intrinsic activity (IA = 0), e.g. propranolol,
atropine, chlorpheniramine, naloxone.

Partial agonists have affinity and submaximal intrinsic activity (IA between 0 and 1), e.g.
dichloroisoproterenol (on β adrenergic receptor), pentazocine (on μ opioid receptor).

Inverse agonists have affinity but intrinsic activity with a minus sign (IA between 0 and –1),
e.g. DMCM (on benzodiazepine receptor), chlorpheniramine (on H1 histamine receptor.

Two states receptor model :

This models explains the action of Agonist, Antagonist, Partial agonist, Inverse agonist

Receptor exists in two interchangeable states: Ra (active) and Ri (inactive) which are in
equilibrium.

• Ri state is favoured at equilibrium— no/very weak signal is generated in the absence of the
agonist. • The agonist (A) binds preferentially to the Ra conformation and shifts the equilibrium
→ Ra predominates and a response is generated depending on the concentration of A.

• The competitive antagonist (B) binds to Ra and Ri with equal affinity

the equilibrium is not altered

no response is generated and when the agonist is applied fewer Ra are available to bind it ans
response to agonist is being decreased.

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• If an agonist has only slightly greater affinity for Ra than for Ri, the equilibrium is only
modestly shifted towards Ra even at saturating concentrations and a submaximal response is
produced and the drug is called a partial agonist (C).

• The inverse agonist (D) has high affinity for the Ri state therefore it can produce an opposite
response, provided the resting equilibrium was in favour of the Ra state

Receptor subtypes

The delineation of multiple types and subtypes of receptors for signal molecules has played an
important role in the development of a number of targeted and more selective drugs. Even at
an early stage of evolution of receptor pharmacology, it was observed that actions of
acetylcholine could be grouped into ‘muscarinic’ and ‘nicotinic’ depending upon whether they
were mimicked by the then known alkaloids muscarine or nicotine. Accordingly, they were
said to be mediated by two types of cholinergic receptors, viz. muscarinic (M) or nicotinic (N);
a concept strengthened by the finding that muscarinic actions were blocked by atropine, while
nicotinic actions were blocked by curare.

TRANSDUCER MECHANISMS:

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Transducer mechanism means after drug binging with receptor it’s form a complex and various
conformational changes are occurred .

1. G-Protein couple receptor

2. Ion channel
3. Transmembrane
4. Transmembrane JAK SAT
5. Receptor regulatory gene expression

1.G-PROTEIN COUPLE RECEPTOR(GPCRs):

It also called as seven transmembrane domain receptor ( as they pass cell membrane 7 time),
7TM receptor, heptahelical receptor, serpentine receptor, G-protein linked receptor (GPLR)

• All such receptors has has 7 α-helical membrane spanning hydrophobic amino acid (AA)
segments which run into 3 extracellular and 3 intracellular loops.

The agonist binding site is located somewhere between the helices on the extracellular face,
while another recognition site formed by cytosolic segments binds the coupling G-protein.

• The G-proteins float in the membrane with their exposed domain lying in the cytosol, and
are heterotrimeric in composition (α, β and γ subunits).

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• In the inactive state GDP is bound to the α subunit at the exposed domain, activation through
the receptor leads to displacement of GDP by GTP.

• The activated α-subunit carrying GTP dissociates from the other two subunits and either
activates or inhibits the effector.

• The βγ diamer has also been shown to activate receptor-operated K+ channels, to inhibit
voltage gated Ca2+ channels and to promote GPCR desensitization at higher rates of activation.

• A number of G proteins distinguished by their α subunits have been described. The important
ones with their action on the effector are:

Gs : Adenylyl cyclase activation, Ca2+ channel opening

Gi : Adenylyl cyclase inhibition, K+ channel opening

Go : Ca2+ channel inhibition

Gq : Phospholipase C activation

There are three major effector pathways through which GPCRs function.

(a) Adenylyl cyclase: cAMP pathway

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• Adrenaline (Adr) binds to β-adrenergic receptor (β-R) on the cell surface inducing a
conformational change which permits interaction of the G-protein binding site with the
stimulatory G-protein (Gs).

• The activated Gs now binds GTP (in place of GDP), causing its active subunit to dissociate
and in turn activate the enzyme adenylyl cyclase (AC) located on the cytosolic side of the
membrane, ATP is hydrolysed to cAMP which phosphorylates and thus activates cAMP
dependent protein kinase (PKA).

• The PKA phosphorylates many functional proteins including troponin and phospholamban,
so that they interact with Ca2+, respectively resulting in increased force of contraction and
faster relaxation.

• Calcium is made available by entry from outside (direct activation of myocardial membrane
Ca2+ channels by Gs and through their phosphorylation by PKA) as well as from intracellular
stores.

• Action of acetylcholine (ACh) on muscarinic M2 receptor (M2-R), also located in the

myocardial membrane, can similarly activate an inhibitory G-protein (Gi) which then opposes
the action of AC by Gs.

(b) Phospholipase C: IP3-DAG pathway

• The agonist, e.g. histamine binds to its H1 receptor (H1 R) and activates the G-protein Gq,
which in turn activates membrane bound phospholipase C (PLc) that hydrolyses phosphatidyl
inositol 4, 5-bisphosphate (PIP2), a membrane bound phospholipid.

• The products inositol 1, 4, 5-trisphosphate (IP3) and diacylglycerol (DAG) act as second
messengers.

• The primary action of IP3 is facilitation of Ca2+ mobilization from intracellular organellar
pools, while DAG in conjunction with Ca2+ activates protein kinase C (PKc) which
phosphorylates and alters the activity of a number of functional and structural proteins. Page14

• Cytosolic Ca2+combines with calmodulin (CAM) to activate myosin light chain kinase
(MLCK) inducing contraction, and another important regulator calcium-calmodulin protein
kinase (CCPK). (c) Channel regulation.

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• The activated Gproteins (Gs, Gi, Go) can also open or inhibit ionic channels specific for Ca2+
and K+, without the intervention of any second messenger like cAMP or IP3, and bring about
hyperpolarization/depolarization/changes in intracellular Ca2+.

• The Gs opens Ca2+ channels in myocardium and skeletal muscles, while Gi and Go open K+
channels in heart and smooth muscle as well as inhibit neuronal Ca2+ channels.

(C ) Channel regulation:

• The activated Gproteins (Gs, Gi, Go) can also open or inhibit ionic channels specific for
Ca2+ and K+, without the intervention of any second messenger like cAMP or IP3, and bring
about hyperpolarization/depolarization/changes in intracellular Ca2+.

• The Gs opens Ca2+ channels in myocardium and skeletal muscles, while Gi and Go open K+
channels in heart and smooth muscle as well as inhibit neuronal Ca2+ channels.

2.ION CHANNEL RECEPTOR:

These cell surface receptors, also called ligand gated ion channels, enclose ion selective
channels (for Na+, K+, Ca2+ or Cl¯) within their molecules.

• Agonist binding opens the channel and causes depolarization/hyperpolarization/ changes in

cytosolic ionic composition, depending on the ion that flows through.

• The nicotinic, cholinergic, GABA-A, glycine (inhibitory), excitatory AA (kainate, NMDA

or N-methyl-D-aspartate, quisqualate) and 5HT3 receptors fall in this category.

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3. TRANSMEMBRANE ENZYME-LINKED RECEPTOR:

• This class of receptors are utilized primarily by peptide hormones

On binding the peptide hormone to the extracellular domains, the monomeric receptors move
laterally in the membrane and form diamers.

• Dimerization activates tyrosine-kinase (RTK) activity of the intracellular domains so that

they phosphorylate tyrosine (t) residues on each other, as well as on several SH2 domain
substrate proteins (SH2-Pr).

• The phosphorylated substrate proteins then perform downstream signalling function.

4.TRANSMEMBRANE JAK-STAT BINDING RECEPTORS

• These receptors differ from RTKs in not having any intrinsic catalytic domain.

• Agonist induced dimerization alters the intracellular domain conformation to increase its
affinity for a cytosolic tyrosine protein kinase JAK (Janus Kinase). Transducer mechanism:

• On binding, JAK gets activated and phosphorylates tyrosine residues of the receptor,
which now bind another free moving protein STAT (signal transducer and activator of
transcription).

• This is also phosphorylated by JAK. Pairs of phosphorylated STAT dimerize and

translocate to the nucleus to regulate gene transcription resultingin a biological response.

• Many cytokines, growth hormone, prolactin, interferons, etc. act through this type of
receptor.

5.RECEPTORS REGULATING GENE EXPRESSION (TRANSCRIPTION

FACTORS, NUCLEAR RECEPTORS)

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 • In contrast to the above 3 classes of receptors, these are intracellular (cytoplasmic or
nuclear) soluble proteins which respond to lipid soluble chemical messengers that
penetrate the cell.
• The glucocorticoid (G) penetrates the cell membrane and binds to the glucocorticoid
receptor (GR) protein that normally resides in the cytoplasm in association with heat
shock protein 90 (HSP90) + other proteins. Page16
• The GR has a steroid binding domain near the carboxy terminus and a mid region DNA
binding domain joined by a ‘hinge region’.
• The DNA binding domain has two ‘zinc fingers’, each made up of a loop of amino
acids with chelated zinc ion. Binding of the steroid to GR dissociates the complexed
proteins (HSP90, etc) removing their inhibitory influence on it.
• A dimerization region that overlaps the steroid binding domain is exposed, promoting
dimerization of the occupied receptor.
• The steroid bound receptor diamer translocates to the nucleus, binds co-
activator/corepressor proteins and interacts with specific DNA sequences called
‘glucocorticoid responsive elements’ (GREs) within the regulatory region of
appropriate genes.
• The expression of these genes is consequently altered resulting in promotion (or
suppression) of their transcription.
• The specific mRNA thus produced is directed to the ribosome where the message is
translated into a specific pattern of protein synthesis, which in turn modifie cellfunction.

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COMBINED EFFECT OF DRUGS

• When two or more drugs are given simultaneously or in quick succession, they may be either
indifferent to each other or exhibit synergism or antagonism. SYNERGISM (Greek: Syn—
together; ergon—work):

• When the action of one drug is facilitated or increased by the other, they are said to be
synergistic.

• In a synergistic pair, both the drugs can have action in the same direction. Synergism can be:
(a) Additive : • The effect of the two drugs is in the same direction and simply adds up:

Effect of drugs A + B = Effect of drug A + Effect of drug B

(b) Supraadditive (potentiation)

• The effect of combination is greater than the individual effects of the components: Effect of
drug A + B > Effect of drug A + Effect of drug B

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ANTAGONISM

• When one drug decreases or abolishes the action of another, they are said to be antagonistic:
Effect of drugs A + B < Effect of drug A + Effect of drug B Depending on the mechanism
involved, antagonism may be: (a) Physical antagonism

• Based on the physical property of the drugs, e.g. charcoal adsorbs alkaloids and can prevent
their absorption—used in alkaloidal poisonings. (b) Chemical antagonism

• The two drugs react chemically and form an inactive product, e.g. functional antagonism

• The two drugs act on different receptors or by different mechanisms, but have opposite effects
on the same physiological function, i.e. have pharmacological effects in opposite direction, e.g.

• Histamine and adrenaline on bronchial muscles and BP.

• Glucagon and insulin on blood sugar level. (d) Receptor antagonism

• One drug (antagonist) blocks the receptor action of the other (agonist). • Which can produce
specific and often profound pharmacological effects.

• Receptor antagonists are relatively selective. Receptor antagonism can be competitive or non-
competitive.

Competitive antagonism (equilibrium type):

• The antagonist is chemically similar to the agonist, competes with it and binds to the same
site of the agonist molecules. No response is produced.

Non competitive antagonism:

The antagonist is chemically unrelated to the agonist, binds to a different allosteric site
altering the receptor in such a way that it is unable to combine with the agonist or is unable to
transduce the response.

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• This is also called allosteric antagonism. Because the agonist and the antagonist are
combining with different sites, there is no competition between them.

Nonequilibrium antagonism:

• Certain antagonists bind to the receptor with strong bonds or dissociate from it slowly (due
to very high affinity) so that agonist molecules are unable to reduce receptor occupancy of the
antagonist molecules—law of mass action cannot apply— an irreversible or non-equilibrium
antagonism is produced.

• Phenoxybenzamine is a non-equilibrium antagonist of adrenaline at the α-adrenergic

receptors.

FACTORS MODIFYING DRUG ACTION

1. Body size
• It influences the concentration of the drug attained at the site of action.
• For exceptionally obese or lean individuals and for children dose may be calculated
on body weight (BW) basis:

• Body surface area (BSA) provides a more accurate basis for dose calculation.

• The BSA of an individual can be calculated from Dubois formula:

2.AGE:

The dose of a drug for children is often calculated from the adult dose;

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In case of New born :

• gastric acid secretion low

• liver microsomal enzymes (glucuronyl transferase) less

• Plasma protein binding low

• GFR & tubular secretion is slow

• Immaturity of BBB in neonates

This results in following :

• GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric
acidity

• Chloramphenicol cause Grey baby syndrome (Inadequate glucouronidation of

chloramphenicol with drug accumulation)

• Sulfonamides cause Hyperbilirubinemia & Kernicterus CHILDREN

• Tetracyclines cause Permanent teeth staining

Corticosteroids cause Growth & development retardation.

In case of Old Age:

• Liver function ( diazepam, theophylline) reduced

• Kidney function( Gentamycin ,Digoxin ,Pencillins are contraindicated in old people) slow
down

• Plasma protein binding less

• sensitivity to CNS depressants ( diazepam, morphine) high

3.Sex

• Females have smaller body size and require doses that are on the lower side of the range

• A number of antihypertensives (clonidine, methyldopa, β-blockers, diuretics) have potential

to interfere with sexual function in males but not in females.

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 • Gynaecomastia is a side effect (of ketoconazole, metoclopramide, chlorpromazine, digitalis)
that can occur only in men.

• Ketoconazole causes loss of libido in men but not in women.

PREGNANCY

• Drugs given during pregnancy can affect the foetus.

• Gastrointestinal motility is reduced which cause delayed absorption of orally administered

drug.

• Plasma and extracellular fluid volume expand so volume of drug distribution may increase.

• Plasma albumin level falls —the unbound fraction of acidic drugs increases but that of basic
drugs decreases.

• Renal blood flow increases which cause polar drugs are eliminated faster.

• Hepatic microsomal enzymes undergo induction—many drugs are metabolized faster.

5.species and race

• Rabbits are resistant to atropine, rats and mice are resistant to digitalis and rat is more
sensitive to curare than cat.

• Blacks require higher and mongols require lower concentrations of atropine and ephedrine to
dilate their pupil.

• β-blockers are less effective as antihypertensive in Afro-Caribbeans.

• Indians tolerate thiacetazone better than whites. 5. Route of administration

• It governs the speed and intensity of drug response.

• Parenteral administration is often resorted to for more rapid, more pronounced and more
predictable drug action.

• A drug may have entirely different uses through different routes.

• Magnesium sulfate given orally causes purgation, applied on sprained joints—decreases

swelling, while intravenously it produces CNS depression and hypotension.

6.Environmental factors and time of administration

• Several environmental factors affect drug responses.

• Exposure to insecticides, carcinogens, tobacco smoke and consumption of charcoal broiled

meat are well known to induce drug metabolism.

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• Food interferes with absorption of ampicillin, but a fatty meal enhances absorption of
griseofulvin

• Hypnotics taken at night and in quiet, familiar surroundings may work more easily

7.Psychological factor

• Efficacy of a drug can be affected by patient’s beliefs, attitudes and expectations

• This is particularly applicable to centrally acting drugs.

Placebo

• Placebo is a Latin word meaning ‘I shall please’.

• This is an inert substance which is given in the garb of a medicine.

• It works by psychodynamic rather than pharmacodynamic means and often produces

responses equivalent to the active drug

• Some individuals are more suggestible and easily respond to a placebo: and are called
‘placebo reactors’.

• Placebos are used in two situations:

1. As a control device in clinical trial of drugs (dummy medication).

2. To treat a patient who, in the opinion of the physician, does not require an active drug.

Nocebo

• It is the converse of placebo, and refers to negative psychodynamic effect evoked by the
pessimistic attitude of the patient, or by loss of faith in the medication and/or the physician.

• Nocebo effect can oppose the therapeutic effect of active medication.

8. Pathological states

GASTROINTESTINAL (G.I.) DISEASES

• Certain g.i. diseases can alter absorption of orally administered drugs absorption can
increase or decrease,

e.g. In celiac disease absorption of amoxicillin is decreased but that of cephalexin and
cotrimoxazole is increased.

• Achlorhydria decreases aspirin absorption by favouring its ionization.

• NSAIDs can aggravate peptic ulcer disease. Liver disease

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 • Bioavailability of drugs having high first pass metabolism is increased due to loss of
hepatocellular function.

• Serum albumin is reduced.

• Metabolism and elimination of some drugs (morphine, lidocaine, propranolol) is

decreased—their dose should be reduced

. • Prodrugs needing hepatic metabolism for activation -should be avoided.

• The sensitivity of brain to depressant action of morphine and barbiturates is markedly

increased in cirrhotics—normal doses can produce coma.

KIDNEY DISEASE

• Antihypertensive drugs produce more postural hypotension in patients with renal

insufficiency.

• Tetracyclines have an anti-anabolic effect and accentuate uraemia.

• NSAIDs cause more fluid retention.

• Nephrotoxic drug should be avoided

• Urinary antiseptic likely to produce systemic toxicity

THYROID DISEASE

• The hypothyroid patients are more sensitive to digoxin, morphine and CNS depressants.

• Hyperthyroid patients are relatively resistant to inotropic action but more prone to
arrhythmic action of digoxin.

9. Cumulation

• Any drug will cumulate in the body if rate of administration is more than the rate of
elimination.

• However, slowly eliminated drugs are particularly liable to cause cumulative

• Prolonged use of chloroquine causes retinal damage.

• A course of emetine should not be repeated within 6 weeks.

10. Tolerance

• It refers to the requirement of higher dose of a drug to produce a given response.

• Often called ‘refractoriness’. Drug tolerance may be:

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 Natural : The species/individual is inherently less sensitive to the drug, e.g. rabbits are
tolerant to atropine; black races are tolerant to mydriatics.

Acquired : This occurs by repeated use of a drug in an individual who was initially
responsive.

• Tolerance need not develop equally to all actions of a drug. e.g. Tolerance develops to
the sedative action of chlorpromazine but not to its antipsychotic action.

• Tolerance occurs to the sedative action of phenobarbitone but not as much to its
antiepileptic action.

Tachyphylaxis (Tachy-fast, phylaxis-protection)

• It refers to rapid development of tolerance when doses of a drug repeated in quick

succession result in marked reduction in response.

• This is usually seen with indirectly acting drugs, such as ephedrine, tyramine, nicotine.

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