General Part-II

PHARMACODYNAMICS
 In Greek,
 Pharmakon = Drug
 Dynamics = Action/Power
 Pharmacodynamics deals with the study of the

biochemical and physiological effects of drugs and their
mechanisms of action.
 Study of what a drug does to the body.
General Pharmacology By: Biruk S. 1

Principles of Drug Action
The basic types of drug action are:
 Stimulation
 Enhancement of the level of a specific biological
activity (usually already ongoing physiological

process).
 E.g. Adrenaline stimulates heart
 Depression
 Diminution of the level of a specific biological activity
(usually already ongoing physiological process).

 E.g. barbiturate depress the CNS, Quinidine depresses
heart

Principles of Drug Action…
 Replacement
 Replacement of the natural hormones or enzymes (any
substance) in deficiency states

 E.g. Insulin in diabetes mellitus, iron in anemia
 Cytotoxic action
 Selective cytotoxic action on invading parasites or
cancer cells, attenuating them without significantly

affecting the host cells
 E.g. penicillin, chloroquine, zidovudine,
cyclophosphamide etc.

How does all this happen? /Mechanism of
drug action/
 A drug can produce all the said effects by virtue of any of
the following action:
 Physical action
 Bulk laxatives: physical mass
 Activated charcoal: adsorptive property
 Mannitol: osmotic activity
 Chemical action
 Chelating agents (EDTA, dimercaprol)—chelation
of heavy metals
 Antacids: neutralization of gastric HCl

Mechanism of drug action…
 Protein targets:
 Majority of drugs produce their effects by
interacting with a discrete target biomolecule, which

usually is a protein.
 Functional proteins that are targets of drug action
can be grouped into four major categories:

 Enzymes
 Ion channels
 Transporters and
 Receptors

 Receptors: is the most commonest way of producing
action.
 A drug produces its response by attaching itself to a
protein called as receptor which in turn regulates the

cell function.
 Enzymes: which may be inhibited (or, less commonly,
activated) by binding a drug
 Transport proteins: (e.g., Na+/K+ ATPase, the
membrane receptor for cardioactive digitalis glycosides)
 Ion channel: Ion channel- Ca2+ channel---calcium
channel blocker (Verapamil), local anesthetics block Na+
channel

1. Enzymes
 Drugs alter rate of enzyme catalyzed reactions by:
 Stimulation: increased substrate affinity to enzyme.
 Inhibition: is a common mode of drug action and could
be
 Competitive: where drug binds to catalytic site
(mostly non-covalently).
 Inhibition is reversed by increasing conc. of
substrate. Eg. Ach, AChE and neostigmine
 Noncompetitive: drug binds to a site adjacent to
catalytic site and as a result the catalytic property of

the enzyme is lost. E.g. ASA and cox

2. Ion Channels
 Ligand gated channels (e.g. nicotinic receptor)
 Voltage gated channels-Nifedipine & Verapamil blocks L-
type of voltage sensitive Ca2+ channel

 G-protein regulated channels (e.g. cardiac β1 adrenergic
receptor activated Ca2+ channel).

3. Transporters (Carrier molecules)
 Many drugs inhibit activity of transporters
 Proton pump inhibitor: omeprazole

4. Receptors
 Macromolecule or binding site located on the surface or
inside the effector cell that serves to recognize the signal

molecule/drug and initiate the response to it, but itself has
no other function

Receptors…
 Two essential functions:
 Recognition of specific ligand molecule
 Transduction of signal into response
 Two Domains:
 Ligand binding domain (coupling proteins)
 Effectors domain – undergoes functional
conformational change

Terms used in describing drug-receptor
interaction:
 Ligand: (Latin: ligare – to bind) - any molecule which
attaches selectively to particular receptors or sites (refers
only binding or affinity but no functional change)
 Drugs are also ligands
 When a drug binds to a receptor the following can occur

and based on this the drugs are classified.
 Affinity: It is the ability of a drug to bind to the
receptor (just bind)

 Intrinsic activity (IA): It is the ability of a drug to
activate a receptor following receptor occupation

Terms used in …
 Agonist
 Agonist: An agent/drug which activates a receptor to
produce an effect similar to that of the physiological

signal molecule.
 Example: Acetylcholine is agonist at muscarinic
receptor in heart cell.

 Will have both Affinity and maximal Intrinsic activity

Terms used in …
 Antagonist
 An agent/drug which prevents the action of an agonist
on a receptor or the subsequent response, but does not

have any effect of its own.
 Example:
 Atropine is antagonist of Ach at Muscarinic

receptors.
 Will have only Affinity but no Intrinsic activity

Terms used in …
 Inverse agonist
 Inverse agonists are the chemicals/drugs that interact
with a receptor, but produces an effect in the opposite

direction to that of the agonist.
 Will have Affinity and negative Intrinsic activity
 Example: Flumazenil is an inverse agonist of

Benzodiazepine

Terms used in …
 Partial agonist
 An agent/drug which binds to the receptor and
activates it but produces a submaximal effect (by

antagonising the full effect of the agonist)
 Less response than a full agonist
 Partial agonist blocks the agonist action.
 Will have Affinity but sub maximal Intrinsic activity

Terms used in …
 If explained in terms of “Affinity and IA”:
 Agonist: Affinity + IA (1)
 Antagonist: Affinity + IA (0)
 Partial agonist: Affinity + IA (0-1)
 Inverse agonist: Affinity + IA (0 to -1)

Terms used in …

Types of Receptors and Signal Transduction
Mechanism
 Based on molecular structure and on the linkage between
the receptor occupation and the ensuing response,
receptors are classified into 4 types:
 Ion channels linked receptors
 G-protein-coupled receptors (GPCR)
 Kinase-linked receptors
 Nuclear receptors

1. Ion-channel-linked receptors
 There are two general classes of ion channels:
 Voltage gated and ligand gated.
 Voltage-gated ion channels are activated by alterations in

membrane voltage.
 For example, verapamil inhibits voltage-gated calcium
channels that are present in vascular smooth muscle and

reduce BP.

Ion-channel-linked receptors…
 Ligand-gated ion channels (ionotropic receptors)
 The activity of the channels is regulated by the binding of
a ligand to the channel.
 Response to these receptors is very rapid, (only a few
milliseconds).
 Agonist binding opens the channel and causes
depolarization /hyperpolarization/ changes in cytosolic
ionic composition, depending on the ion that flows
through
 E.g. The nicotinic cholinergic, GABA A, glycine…

Ligand-gated ion channels

2. G-Protein coupled receptors (GPCRs)
 AKA metabotropic receptors
 Is largest receptor family and includes the muscarinic
acetylcholine receptor, adrenoceptors and neuropeptide
receptors.
 Comprise seven membrane-spanning segments.
 One of the intracellular loops interacts with G-protein
 Stimulation of these receptors results in responses that
last several seconds to minutes

GPCRs…

3. Enzyme linked (Kinase-linked) receptors
 Comprise an extracellular ligand-binding domain linked

to an enzymatic intracellular domain by a single trans
membrane helix
 It takes minute to get cellular effect
 Activation involves dimerisation of receptors, followed
by autophosphorylation of tyrosine residues.
 The phosphotyrosine residues act as acceptors for a
variety of intracellular proteins, thereby allowing control
of many cell functions.

Kinase-linked receptors…
 The enzymatic activity
could be protein kinase or
guanylate cyclase.
 Examples are: insulin,
epidermal growth factor
(EGF), nerve growth factor
(NGF) and many other
growth factor receptors.

4. Intracellular (cytoplasmic or nuclear)
receptors
 Are intracellular (cytoplasmic or nuclear) soluble proteins
which respond to lipid soluble chemical messengers that
penetrate the cell
 Receptors are intracellular proteins, so ligands must first
enter cells
 Receptors consist of a conserved DNA-binding domain
attached to variable ligand-binding and transcriptional
control domains.

Intracellular receptors…
 Effects are produced as a result of altered protein
synthesis and, therefore, are slow in onset (30 minutes to
several hours).
 Ligand include all steroidal hormones (glucocorticoids,
mineralocorticoids, androgens, estrogens, progesterone),
thyroid hormones, vit. D and vit. A function in this
manner

Intracellular receptors…

Summary

Drug-Receptor Interactions
 Receptors are highly specific and selective in that they
choose drugs that exactly fits on them.
 Thus, the molecular size, shape and electrical charge of a
drug determines whether, and with what affinity it will
bind to a particular receptor
 In most cases, a drug (D) binds to a receptor (R) in a
reversible bimolecular reaction

Drug-Receptor Interactions…
 Drugs interact with receptors by means of chemical
forces:
 Covalent: (very strong, usually irreversible, not
common)
 Electrostatic: (ionic and hydrogen bonds - relatively
strong)
 Hydrophobic interactions: (weak bonds)
 Van der Waal forces: (very weak)

Receptor Regulation
 Receptors are in dynamic state.
 The affinity of the response to drugs is not fixed.
 It alters according to situations
 Receptor up regulation:
 Prolonged deprivation of agonist (by denervation or
antagonist) results in supersensitivity of the receptor as well
as to effector system to the agonist.
 Receptor down regulation:
 Continued exposure to an agonist or intense receptor
stimulation causes desensitization or refractoriness
 Receptor become less sensitive to the agonist
 Examples – beta adrenergic agonist

Dose – Response Relationship
 The relationship between intensity of drug effect and
drug level
 Quantification of drug level at the site of action is
difficult
 Hence either the dose administered or plasma
concentration are considered during quantification.

Dose – response relationship…
 The degree of effect produced by a drug is generally a
function of the amount administered: this expressed in
dose-response curve.
 Response ~ concentration of drug in receptor
 Concentration of drug in receptor ~ concentration of
drug in plasma

Dose – response relationship…
 Two types of dose response curve
 Graded dose response
 Quantal dose response

Graded (individual) Dose–Response
Relationships
 Demonstrates the effect of a drug as a function of its
concentration in a single individual
 Are measured by exposing an individual or a specific
organ or tissue to increasing (graded) amounts of drug and
quantifying the resulting effect on a continuous scale
 With graded responses, one can obtain a complete dose–
response curve in a single animal or patient
 Since an entire dose-response relationship is determined
from one animal, the curve cannot tell us about the

degree of biological variation inherent in a population
of such animals.

Graded (individual) …
 A good example is the effect of the drug norepinephrine
on heart rate.
 Two important parameters: potency and efficacy can be
deduced from the graded dose–response curve

 Potency: refers to the amount of drug needed to produce a
certain response.
 Relative potency of two drugs is generally defined by
comparing the dose (concentration) of the agonists at
which they elicit half maximal response (EC50).
 A DRC positioned rightward indicates lower potency.

 If 10 mg of morphine = 100 mg of pethidine as analgesic,
morphine is 10 times more potent than pethidine.
 However, drug potency does not necessarily mean
therapeutic superiority. Other factors such as adverse drug
reactions associated with the drug need to be considered.
 Drug potency is clearly a factor in choosing the dose of a
drug.

 Efficacy: refers to the maximal response that can be
elicited by the drug, e.g. morphine produces a degree of
analgesia not obtainable with any dose of aspirin---
morphine is more efficacious than aspirin.
 Efficacy is a more critical factor in the choice of a drug.
 Potency and efficacy can vary independently:


Fig.: Illustration of drug potency and drug efficacy.

 Dose-response curve of four drugs producing the same qualitative effect
 Note:
 Drug B is less potent but equally efficacious as drug A.
 Drug C is less potent and less efficacious than drug A.
 Drug D is more potent than drugs A, B, & C, but less efficacious than drugs A & B, and
equally efficacious as drug C.

Individual variation
 Drug response curves of same effect (response) from
different individuals is made and compared for EC50

 EC50 - is the dose at half maximum response
 Sensitive individuals display smaller EC50 value
indicating that smaller dose of a drug produces higher
response in this individuals.

Quantal Dose–Response Relationships
 Quantal dose-response relationships describe the
concentrations of a drug that produce a given effect in a
population.
 Effect is either present or absent (all or none response)
 E.g. protection of convulsion or death
 Relates dose to the frequency of the all-or-none effect in a

population of individuals
 The construction of a quantal dose-response curve
requires data to be obtained from many individuals
(population of species).

Quantal Dose–Response …
 Any given patient (or animal) either will or will not
respond to a given dose.
 The responses are defined as either present or not present
(i.e., quantal, not graded).
 This variability can be expressed as a curve in which the
dose (X-axis) is evaluated against the percentage of
animals in the experimental population that is protected
by each dose (Y-axis).

 F I G U R E.: Quantal dose–response curves based on all-or-none responses.

 A. Relationship between the dose of phenobarbital and the protection of groups of rats
against convulsions.
 B. Relationship between the dose of phenobarbital and the drug’s lethal effects in groups
of rats. ED50, effective dose, 50%; LD50, lethal dose, 50%.

 The goal is to generalize a result to a population, rather
than to examine the graded effect of different drug doses
on a single individual.
 Types of responses that can be examined using the
quantal dose–response relationship include effectiveness
(therapeutic effect), toxicity (adverse effect), and lethality
(lethal effect).
 The doses that produce these responses in 50% of a
population are known as the median effective dose

(ED50), median toxic dose (TD50), and median lethal
dose (LD50), respectively.

 ED₅₀ (Median effective dose): the dose at which 50% of
individual exhibit the specified quantal effect
 TD₅₀ (Median toxic dose): The dose required to produce
a particular toxic effect in 50% of test animals.
 LD₅₀ (Median lethal dose): The dose required to
produce death in 50% of experimental animals

Therapeutic Index (TI)
 Quantal dose-effect curves are used to generate
information regarding the margin of safety (Therapeutic

index)
 An estimate of a drugs margin of safety

Therapeutic index
 Therapeutic index is the ratio between the median lethal
dose and the median effective dose.

 So, therapeutic index =LD₅₀/ED₅₀
[In experimental animal]

 Or, Therapeutic index is the ratio between median toxic
dose and the median effective dose.

 So, therapeutic index =TD₅₀/ED₅₀
[In clinical medicine]

 Therapeutic index is determined using laboratory
animals
 Having high therapeutics index = good safety (safe
drug).
 Low therapeutic index drug = there should be caution
in its use.

 Clinical significance
 Drugs with a low TI should be used with caution and
needs a periodic monitoring (less safe)

 E.g. warfarin, digoxin, theophylline
 Drugs with a large TI can be used relatively safely and
does not need close monitoring (highly safe)

 E.g. Penicillin, Paracetamol
 Other terms used: wide safety margin, narrow safety
margin


Factors affecting dose-response relationship
1. Body weight
 Affect the concentration of drug at the site of action.
 The average adult dose refers to individuals of medium
built.
 Individual dose= BSA (m3) X average adult dose
1.7
 Individual dose = BW(Kg) X average adult dose
70
55
Factors affecting …
2. Age
 The dose of drug for children often calculated from the
adult doses
 Pediatric
 Child dose = age X adult dose (Young’s formula)
age +12
 Child dose = weight X adult dose (Clark’s formula
70
Factors affecting …
 However, infants and children have important
physiological differences
 Higher proportion of water
 Lower plasma protein levels
 More available drug
 Immature liver/kidneys
 Liver often metabolizes more slowly
 Kidneys may excrete more slowly
 Old people: deteriorated body functions
3. Sex: Women respond faster due to their relative small

body size.
57
Factor affecting ...
4. Route of administration: Governs the speed and
intensity of drugs response
5. Time of administration: More of a hypnotic drug is
required to induce hypnosis during day time than during
night.
6. Genetic factors- Pharmacogenetic
7. Pregnancy: physiological changes
8. Environmental: Exposure to insecticides, carinogens,
tobacco smoke induce drug metabolism.
58
Factor affecting ...
9. Nutritional state: Starvation causes decreased protein
synthesis (drug metabolizing enzymes), hence enhanced
drug effect.
10. Pathological factors: Alter PK and PD parameters.
Special attention is given to renal and hepatic problems
11. Simultaneous administration of two or more drugs
 Due to drug interaction
59
Drug Interaction
 Modification of the effect of one drug by the prior/
concomitant administration of another drug, food, or
herb, or by pre-existing disease.
 The knowledge of drug interactions is essential for safe
and effective drug therapy.
 Drug interaction could be in-vitro or in-vivo.

Drug interaction…
 Type of interaction: based on type of agents that
interact
 Drug-drug interaction (DDI)
 E.g. Antacid Vs ketoconazole --- ketoconazole needs
an acidic environment for better absorption-antacid

alkalinize the media--so ↓absorption
 Drug – Food interaction (DFI)
 Efaverenz Vs fatty food ---the absorption of efaverenz
↑ in presence of fatty food.

 Grape fruit juice Vs phenytoin --- grape fruit juice are
CYP3A4 enzyme inhibitor—which ↓metabolism →
↑Toxicity

Drug interaction…
 Drug – beverage interaction (DBI)
 E.g. Benzodiazepine Vs Alcohol---both have CNS
depression, sedation, effect---additive sedative effect

 Drug – herbal interaction (DHI)
 E.g. St’jhons Vs warfarin ---St’jhons is liver
microsomal enzyme inducer---increase metabolism of

the other drug---decrease therapeutic outcome.

Drug-Drug Interactions (DDIs)
 When two or more drugs are given together or in quick
succession they might interact.
 Action of one drug is facilitated by the other
 Action of one drug may decrease or inhibit the action
of other drug
 Nothing (indifferent to each other)

Drug-Drug Interactions…
1. In-vitro interaction: out side the living organism
 Pharmaceutical interactions
 Direct physico-chemical interactions
 Occur commonly when drugs are combined in IV
solutions.
 Never combine two or more drugs in the same
container unless it has been established that a direct

interaction will not occur
 E.g. Penicillin G and Aminoglycosides

2. In-vivo: inside the living organism
 Pharmacokinetic: interaction at level of
 Absorption
 Distribution
 Biotransformation
 Excretion
 Pharmacodynamic:
 Agonize or antagonize drugs’ action

1. Pharmacokinetic Interactions
 Alter the basic PK processes
 One drug alters the rate or extent of ADME of the
other
 Affects serum concentration of the interacting drugs
 Absorption
 Tetracyclines chelate metals → ↓ absorption of Ca 2+,
Mg2+, & Al3+ containing antacids.

 Drugs that change the pH of the gut contents can also
affect the rate of absorption of other drugs by

affecting drug ionization.

PK interactions…
 Distribution
 A drug with higher affinity for plasma proteins will
displace another drug with less affinity ↑ its free

concentration and hence its effect
 Aspirin displaces warfarin → bleeding.
 Metabolism
 Enzyme Induction by enzyme inducers
 Rifampicin →↑ metabolism of COC→ pregnancy

 Enzyme inhibition by enzyme inhibitors
 Ciprofloxacin inhibits metabolism of theophylline

PK interactions…
 Excretion
 Alkalinization of urine → ↑ ionization of acidic drugs
(aspirin) → ↓ tubular reabsorption → ↑ excretion

(useful in treatment of toxicity)
 Acidification of urine → ↑ ionization of basic drugs
(amphetamines) → ↓ tubular reabsorption →↑

excretion (useful in treatment of toxicity)
 Probenecid competes with penicillin for renal tubular
excretion → inhibits its excretion → prolongs its

action.

2. Pharmacodynamic interactions
A. Agonizing interaction (Synergism)
 When the action of one drug is facilitated or increased by
the other, they are said to be synergistic.

1. Additive Synergism (1+1=2)
 Effect of (A+B) = Effect of A + Effect of B
 Two drugs eliciting same response and their combined
effect is equal to their summation


2. Supra-additive Synergism:
 The effect of combination is greater than the individual
effects of the components.

2.1. Potentiation: (1+ 0 > 1)
 This is always the case when one component given
alone produces no effect, but enhances the effect of the

other (potentiation)
 Effect of (A+B) > Effect of A + Effect of B
 Especially if one is inactive as such
 E.g. Amoxicillin + clavulanic acid

2.2. Synergistic (true supra additive): (1+1 >2)
 E.g. Sulfamethoxazole + trimethoprim
 Is synergistic owing to the inhibition of sequential steps
in microbial folate synthesis

B. Antagonizing interaction
 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
I. Physical antagonism
 Based on the physical property of the drugs,
 E.g. charcoal adsorbs alkaloids and can prevent their
absorption - used in alkaloidal poisonings.

II. Chemical antagonism
 The two drugs react chemically and form an inactive
product
 E.g. Chelating agents (Dimercaprol, Calcium disodium
edetate) complex toxic metals (As, Pb).

III. Physiological/functional antagonism
 The two drugs act on different receptors or by different
mechanisms, but have opposite overt effects on the same

physiological function.
 i.e. have pharmacological effects in opposite direction.
 Glucagon and insulin on blood sugar level.

IV. Receptor antagonism
A. Competitive antagonism
 Antagonist is chemically similar to agonist and binds to
same receptor molecules.

 Affinity (1) but IA (0), Result – no response.
 But, antagonism is reversible – increase in concentration
of agonist overcomes the block.

 Parallel shift of curve to the right side
 Reduce agonist potency
 Ach. Vs Atropine

B. 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.

 No competition between them – no change of effect even
agonist concentration is increased

 Reduce agonist efficacy

Adverse drug reactions
 WHO: Definition:
 “Any response to a drug which
is noxious, unintended and

occurs at doses used in man for
prophylaxis, diagnosis or
therapy.”
 The term "adverse reactions" is
used for harmful effects of a

drug, which require reduction of
dose, drug withdrawal or
immediate treatment

ADRs…
Classification of ADRs
 Depending on….
 Onset of event: Acute (<60 minutes), Sub-acute (1-24
hrs.) and Latent (>2 days)

 Type of reaction: (Wills and Brown)
 Type A (Augmented), B (Bizarre), C (Chronic), D
(Delayed), E (End of treatment)

 Severity: Minor, Moderate, Severe, Lethal ADRs
 Mild: no intervention
 Moderate: change in drug
 Severe: life threatening, needs drug withdrawal
 Lethal: contribute to death

ADRs…
1. Type A (Augmented) reactions
 Related to pharmacological action of drug
 Predictable
 Dose dependent
 Can be alleviated by a dose reduction
 common
 Skilled management reduces their incidence.

ADRs…
Type A…
 E.g.
 Anticoagulants → Bleeding
 Beta blockers → Bradycardia
 Nitrates → Headache
 Insulin → Hypoglycemia

ADRs…
Type A…
 Side effect (occurs at therapeutic dose)
 Nearly unavoidable secondary drug effect produced by
therapeutic doses
 Intensity is dose dependent
 Occur immediately after initially taking drug or may
not appear until weeks after initiation of drug use

ADRs…
Type A…
 Overdose (at doses slightly > therapeutic):
 E.g., Seizure with lidocaine.
 Toxic effect (at very high doses)
 E.g., Hepatotoxicity with acetaminophen,
hypoglycemia with sulfonylurea

ADRs…
2. Type B (Bizarre) reactions
 Unrelated to known pharmacological actions of drug
 Unpredictable, unrelated to dosage
 Often related to patient factors such as genetic
predisposition and allergy caused by immunological &

pharmacogenetic mechanisms
 Comparatively rare & cause serious illness or death
 These account for most drug fatalities.
 Penicillin → Anaphylaxis

ADRs…
Drug allergy/Hypersensitivity reactions
 Are adverse effects mediated by immunogenic
mechanisms.
 Most drugs are simple chemicals acting as incomplete
antigens
 Drug allergy is dose-independent and occurs in minority
of patients
 Cross-allergy may occur within a group of chemically
related drugs.
 Chief target organs are skin, respiratory tract, GIT, blood
& blood vessels.

ADRs…
Types of hypersensitivity reactions
 Type I reactions (immediate type)
 Symptoms occur within minutes ⇒immediate
reactions
 IgE antibody mediated
 Occur on blood basophils/tissue mast cells ⇒release
of histamine, PGs, leukotrienes

 Usual targets include GIT (diarrhea), BV
(anaphylactic shock), respiratory tract (rhinitis,

asthma), and skin (dermatitis)
 E.g., asthma, anaphylaxis, angioedema (with
penicillins).

ADRs…
 Type II reactions (cytotoxic)
 Mediated through IgM or IgG
 Targeted to blood cells
 Ag-Ab reaction leads to cell destruction ⇒ cytotoxic
(cytolytic) reactions
 On RBC cause hemolytic anemia, e.g., penicillins
 On WBC cause agranulocytosis, e.g., sulfonamides
 On platelets cause thrombocytopenia, e.g., aspirin

ADRs…
 Type III reactions (immune complex)
 Forms Ag-Ab complex ⇒immune complex reactions
 The complex deposited in vascular endothelium ⇒
destructive inflammatory response (serum sickness)

and glomerulonephritis
 Symptoms include: Urticaria, skin eruption, arthritis,
lymphadenopathy, fever
 The reactions persist for 6-12 days then subside after
removing drug, e.g., penicillins, sulfonamides

ADRs…
 Type IV reactions (delayed, cell mediated)
 Direct interaction between drug and sensitized T
lymphocytes ⇒ release of digestive enzymes

(lymphokins) ⇒ tissue destruction ⇒delayed reactions
 It is involved in allergic contact dermatitis from
topically applied drugs

 E.g., contact dermatitis with topical antihistamines
 Response occurs 2-3 days after exposure

ADRs…
 Diagnosis and measurement against drug allergy
 Diagnosis of drug allergy
 History and type of reaction
 Intradermal and conjunctival tests
 Measures against allergy

 Treatment: epinephrine, hydrocortisone,
antihistamines.
 Prophylaxis:
 Cromolyn (inhibits histamine release)

 Anti-IgE monoclonal antibodies.
 Desensitization

ADRs…
3. Type C (chronic) Reactions
 Adverse effects that only occur during prolonged
(chronic) treatment and not with single dose

 Colonic dysfunction due to laxatives
 Analgesic - nephropathy
 Corticosteroids - induced osteoporosis, diabetes and
hypertension.
 Aminoglycosides - ototoxicity, renal toxicity

ADRs…
4. Type D (delayed) Reactions
 Delayed in onset: This adverse effect may occur even
after stopping drug

 Mutagenic, carcinogenic & teratogenic effects
 Very rare
 Mutagenicity: drug-induced gene abnormalities
 Carcinogenicity: drug-induced neoplasm; with alkylating
agents, radioactive drugs.

 Medication lead to cancer; take >20 y to develop

ADRs…
Type D…
 Teratogenic Effect
 Drug- induced birth defects (short term exposure at a
critical time)
 It can be caused by some drugs when given early in
pregnancy
 The most vulnerable period is weeks 3-10 of
intrauterine life
 E.g. Tetracyclines: dental hypoplasia
 Antiepileptics: cleft palate

ADRs…
5. Type E (End of use) reactions
 Occur on withdrawal especially when drug is stopped
abruptly
 E.g.
 Abstinence (withdrawal syndrome) in drug-dependent
persons (addicts) following withdrawal of narcotics,

alcohol, hypnotics
 Phenytoin withdrawal → Seizures

ADRs…


General Part-II

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General Part-II

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PHARMACODYNAMICS

 Pharmacodynamics deals with the study of the

General Pharmacology By: Biruk S. 1

 Enhancement of the level of a specific biological

activity (usually already ongoing physiological

 Diminution of the level of a specific biological activity

(usually already ongoing physiological process).

General Pharmacology By: Biruk S. 2

substance) in deficiency states

cancer cells, attenuating them without significantly

General Pharmacology By: Biruk S. 3

 Bulk laxatives: physical mass

 Activated charcoal: adsorptive property

 Mannitol: osmotic activity

 Chelating agents (EDTA, dimercaprol)—chelation

General Pharmacology By: Biruk S. 4

interacting with a discrete target biomolecule, which

can be grouped into four major categories:

General Pharmacology By: Biruk S. 5

protein called as receptor which in turn regulates the

General Pharmacology By: Biruk S. 6

catalytic site and as a result the catalytic property of

General Pharmacology By: Biruk S. 7

type of voltage sensitive Ca2+ channel

receptor activated Ca2+ channel).

General Pharmacology By: Biruk S. 8

 Proton pump inhibitor: omeprazole

General Pharmacology By: Biruk S. 9

inside the effector cell that serves to recognize the signal

General Pharmacology By: Biruk S. 10

 Transduction of signal into response

 Effectors domain – undergoes functional

General Pharmacology By: Biruk S. 11

 When a drug binds to a receptor the following can occur

receptor (just bind)

activate a receptor following receptor occupation

General Pharmacology By: Biruk S. 12

produce an effect similar to that of the physiological

receptor in heart cell.

General Pharmacology By: Biruk S. 13

on a receptor or the subsequent response, but does not

 Atropine is antagonist of Ach at Muscarinic

General Pharmacology By: Biruk S. 14

with a receptor, but produces an effect in the opposite

 Example: Flumazenil is an inverse agonist of

General Pharmacology By: Biruk S. 15

activates it but produces a submaximal effect (by

 Partial agonist blocks the agonist action.

 Will have Affinity but sub maximal Intrinsic activity

General Pharmacology By: Biruk S. 16

General Pharmacology By: Biruk S. 17

General Pharmacology By: Biruk S. 18

 G-protein-coupled receptors (GPCR)

General Pharmacology By: Biruk S. 19

 Voltage-gated ion channels are activated by alterations in

channels that are present in vascular smooth muscle and

General Pharmacology By: Biruk S. 20

General Pharmacology By: Biruk S. 21

General Pharmacology By: Biruk S. 22

General Pharmacology By: Biruk S. 23

General Pharmacology By: Biruk S. 24

 Comprise an extracellular ligand-binding domain linked