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IMMUNO-

PHARMACOLOGY
Dr. Harshika Patel
Pharmacology and therapeutics II
Date:23/05/2018
Time : 11am – 1pm
Introduction
• Immune system plays an essential role to protect our body from
pathogens
• In certain instances its powerful destructive mechanisms do more harm
than good, example
1. Hypersensitivity reactions, Treated by
2. Autoimmune disorders, Immunosuppressive
3. Rejection reactions to transplanted tissues Drugs

• Drugs that suppress immune action  play a vital role to treat these
conditions.
• Now-a-days monoclonal Ab widely used as targeting proteins that count in
immunosupreesive agents

• In some case, Drugs that potentiate immune action  provide benefits


(vaccines, immunisation in infants and elders)
Elements of IS
Normal
immune Abnormal
responses immune
responses

Innate IS Adaptive IS

Autoimmunity
Hypersensitivit
y
Immunodeficiency
diseases
Normal Immune response
• Protect host from invading pathogens and
eliminate the diseases
• Functions: delicately responsive to invading
pathogens
• While  capacity to recognize "self" antigens
to which it is tolerant
• Protection by innate or adaptive immune
system
Innate immune system
• first line of defense against an antigenic insult

• Includes :
 physical (eg, skin)
 biochemical (eg, complement, lysozyme,
interferons)
 cellular components (neutrophils, monocytes,
macrophages)
Adaptive Immune System
• Arise when innate immune response is inadequate to cope
with infection
• the adaptive immune system is mobilized by signals from the
innate response
• has a many characteristics that contribute to eliminating
pathogens successfully :
1. To respond to a variety of antigens, each in a specific manner
2. To discriminate between foreign antigens and self antigens of
the host
3. To respond to a previously encountered antigen in a learned
way by initiating a vigorous memory response
• Response culminates in the
1. Production of antibodies, by activated B lymphocytes
which are the effectors of humoral immunity; and
2. Activation of T lymphocytes, which are the effectors of
cell-mediated immunity
• The subsets of lymphocytes that mediate different parts
of the immune response can be identified by specific cell
surface components or clusters of differentiation (CDs)
• Example :
• helper T (Th) cells bear the CD4 protein complex,
• whereas cytotoxic T lymphocytes express the CD8 protein
complex
• Induction of specific immunity requires the
participation of APCs (include macrophages, dendritic
cells, Langerhans cells, and B lymphocytes)

• These cells play pivotal roles in the immune response


 by enzymatically digesting protein antigens and
presenting the derived peptides in association with
class I and class II major histocompatibility complex
(MHC) proteins to the T cell receptor (TCR) expressed
on CD4 and CD8 T lymphocytes, respectively.
Cell- Mediated Immunity
• An immune response is initiated by internalization and
processing of antigen by an antigen-presenting cell such
as a macrophage
• The class II MHC-peptide complex is recognized by the
T-cell receptor (TCR) on T-helper (Th) lymphocytes,
• Resulting in T-cell activation
• Activated (Th) cells secrete cytokines such as IL-2 
cause proliferation and activation of Th1 and Th2 cells.
• Th1 cells produce IFN-γ and TNF-β, which activate
macrophages and NK cells
Humoral Immunity
• A humoral response is triggered when B
lymphocytes bind antigen via their surface
immunoglobulins (Ig)
• They are then induced by Th2-derived
cytokines (eg, IL-4, IL-5) to proliferate and
differentiate into memory cells and antibody-
secreting plasma cells
by activating complement to
stimulate an inflammatory
response  lysis
Down regulation of immune response

• by CD80/86 (on macrophage) bind to CTLA-4


on activated T cell provides a negative
feedback to regulate immune response
• By IL 10 (Th 1) and INF gamma (Th 2)
Abnormal Immune Responses
• Normal immune response eliminate pathogen
successfully but cause inappropriate responses

• These responses can lead


1. To extensive tissue damage (hypersensitivity)
2. Reactivity against self antigens (autoimmunity)
3. Conversely, impaired reactivity to appropriate
targets (immunodeficiency)
Hypersensitivity
• classified as
1. Immediate or
2. Delayed depending (time required for manifestate clinical
symptoms )

• Immediate hypersensitivity : antibody-mediated, with symptoms


usually occurring within minutes or a few hours following the
patient's encounter with antigen

• Delayed-type hypersensitivity (DTH) : cell-mediated, and


responses occur 2–3 days after exposure to the sensitizing
antigen.
Autoimmunity
“Horror autotoxicus”
Literally, the horror of self-toxicity
• A term coined by the German immunologist Paul Ehrlich

• Autoimmunity is the failure of an organism in recognizing its


own constituent parts as non self, which allows an immune
response against its own cells and tissues.

• Any disease that results from such an aberrant immune


response is termed an autoimmune disease.

• Autoimmunity is often caused by a lack of germ development of


a target body and as such the immune response acts against its
own cells and tissues
• Autoimmunity results from a failure or
breakdown of the mechanisms normally
responsible for maintaining self- tolerance in B
cells, T cells, or both
• The major factors that contribute to the
development of autoimmunity are genetic
susceptibility and environmental triggers, such as
infections
• Autoimmune diseases may be either systemic or
organ specific
• Various effector mechanisms are responsible for
tissue injury in different autoimmune diseases
Major mechanisms involved in Autoimmunity

1. Exposure of self-reactive T lymphocytes to antigens previously


sequestered from the immune system (eg, lens protein, myelin basic
protein).

2. Molecular mimicry by invading pathogens, in which immune responses


are directed at antigenic determinants on pathogens that share
identical or similar epitopes with normal host tissue(rheumatic fever).

3. Inappropriate expression of class II MHC molecules on the membranes


of cells that normally do not express class II MHC (eg, islet B cells)
Immunodeficiency Diseases
“Is a result from abnormalities in the immune system”
• the consequences of these abnormalities include
increased susceptibility to infections and prolonged
duration and severity of disease
• Diseases initiated by:
1. Congenitally acquired
2. Arise from extrinsic factors (bacterial or viral
infections or drug treatment)
• Affected individuals  frequently succumb to
infections caused by  opportunistic organisms
that have low pathogenicity  immunocompetent
hosts
Example Of Diseases :
• congenitally acquired immunodeficiency diseases:
1. Xlinked agammaglobulinemia : failure of
immature B lymphocytes to mature into antibody-
producing plasma cells.
1. DiGeorge's syndrome: failure of the thymus to
develop, resulting in diminished T cell responses

2. severe combined immunodeficiency disease (due


to deficient adenine deaminase-ADA): normally
prevents the accumulation of toxic deoxy-ATP in
cells  which are toxic to lymphocytes and leads
to death of T and B cells
I.D. Diseases: By Extrinsic Factors
• AIDS caused by extrinsic factors the human
immunodeficiency virus (HIV)

• This virus exhibits a strong tropism for CD4 helper T


cells  these become depleted  rise to increased
frequency of opportunistic infections and
malignancies in infected individuals.

Ultimately, “ failure of T helper cells to maintain the


cytotoxic lymphocyte response”.
• Immunosuppressive agents have proved  to
useful in decreasing the occurrence or impact of
deleterious effects exaggerated or
inappropriate immune responses

FATE:
• They have the potentiality to cause: disease and
risk of infection ,malignancies
Tests of Immunocompetence
• Applied to test immunologic competence and drug-
induced immune dysfunction
• Simplest tests that can be used to detect:
Immunosuppressive, or
Immunostimulating agents effects

1. Delayed-type hypersensitivity testing with skin : test


to Ag to detect the ability to respond to recall
antigens

2. Measurement of serum (Ig, complement), and


specific Abs to various natural and acquired Ags.
3. Serial measurements of antibody response after primary
immunization or a secondary booster injection

4. Total circulating lymphocyte count

5. Measurement of the percentages of B cells, T cells, and subsets


such as CD4, CD8, CD11a, and CD56 (eg, with mAb) that comprise
the circulating blood lymphocyte count

6. In vitro lymphocyte proliferative responses to mitogens(tritiated


thymidine incorporation/ by cytokine production (IFN- , IL-2, TNF,
and others))

7. Mixed lymphocyte reaction, (in which the lymphocytes of one


individual are mixed with and proliferate in response to allogeneic
lymphocytes of another individual)
Calcineurin inhibitors
Cyclosporine :a lipophillic cyclic polypeptide composed of 11
amino acids
• drug is extracted from a soil fungus
Uses:
• prevent rejection of kidney, liver, and cardiac allogeneic
transplants
• Prevent acute rejection of transplanted organs : In double
or triple drug regimen (corticosteroids & antimetabolite
such as mycophenolate mofetil)
• alternative to methotrexate  severe, active rheumatoid
arthritis.
• recalcitrant psoriasis that does not respond to other
therapies
• MOA: preferentially suppresses cell-mediated
immune reactions
• Both (cyclosporin and tacrolimus) Inhibit the
cytoplasmic phosphatase, calcineurin  necessary
for the activation of a T-cell-specific transcription
factor  cNF-AT, is involved in the synthesis of
interleukins (eg, IL-2) by activated T cells.
Explanation of cascade activation
Pharmacokinetics/toxicity
• Oral/IV administration, ophthalmic solution(severe dry eye syndrom)
• metabolized by the P450 3A4 enzyme system in the liver (with resultant
multiple drug interactions).
• Metabolites are excreted thr’ bile in feces (lesser via urine)

A/E: dose- dependent (so monitored blood level of the drug)

Narrow therapeutic window


Levels too high: toxicities (i.e. nephrotoxicity, mental confusion, hyperglycemia
and hypertension)
Levels too low: transplant rejection.

• Increased incidence of lymphoma and other cancers (Kaposi's sarcoma,


skin cancer) have been observed in transplant recipients receiving
cyclosporine,
Cyclosporine
Monitoring Parameters:
• Cyclosporine trough levels (blood drug level)
• Serum electrolytes  hyperkalemia*
• Renal function.
• Hepatic function.
• Blood pressure.
• serum cholesterol.
Tacrolimus
• a macrolide that is isolated from a soil fungus
• prevention of rejection of liver and kidney
transplants (with methotrexate)

• Because of the effectiveness of systemic tacrolimus


in some dermatologic diseases, a topical
preparation is now available.

• Tacrolimus ointment is currently used in the


therapy of atopic dermatitis and psoriasis.
• MOA: same as cyclosporine but has different
immunophilin site is Fk-BP

• PK: oral/ IV * ()
• More potent than cyclosporine, highly serum protein
bound even concentrated well in RBCs
• Same metabolism and elimination as cyclo. (one of
metabolite have immunosuppressive action)

• A/E: nephro & neurotoxicity (higher than cyclo.)


• Development of posttransplant, insulin-dependent
diabetes mellitus (hispanic/ black pt.)
• Others side effects same as cyclo.
Sirolimus (mTOR inhibitor)
• macrolide obtained from fermentations of a soil mold

• Use: in renal transplantation, with CsA and corticosteroids)


with their lower dose  so by that lowering the toxicity
potential
• combination of SRL and CsA is apparently synergistic
because SRL works later in the immune activation cascade
• Limit the long term toxicity calcinurine inhibitor in
posttransplant pt
• Antiproliferative action served to treat cardiological
condition*
• MOA: Inhibits immune cell growth through
inhibiting the kinase activity of mammalian
target of rapamycin (mTOR) and decreasing IL-
2 activities

• A/E: hyperlipidemia, nephrotoxic (monitored


blood level of drug)
• headache, nausea and diarrhea, leukopenia,
and thrombocytopenia. Impaired wound
healing, diabetes (rare and common)
IL-2-receptor antagonists
• Ab specific for the high-affinity IL-2 receptor is expressed only on
activated T-cell, blocks proliferation of T-cells activated in response to
the alloantigens of the graft.

• Basiliximab is said to be “chimerized” because it consists of 25% murine


and 75 percent human protein.

• Daclizumab is 90 %human protein, and is designated “humanized.”

• Both agents have been approved for prophylaxis of acute rejection in


renal transplantation in combination with cyclosporine/tacrolimus and
corticosteroids.
• To treat donor’s bone marrow before it is transplanted.
- Both antibodies are given intravenously.

- The serum half-life of daclizumab is about 20 days, and the


blockade of the receptor is 120 days.

- The serum half-life of basiliximab is about 7 days. Usually, 2


doses of this drug are administered—the first at 2 hours prior
to transplantation, and the second at 4 days after the surgery.
• 5 doses of daclizumab (serum half life 20day) are
administered  1st at 24 hours before transplantation, and
the next 4 doses at 14-day intervals

- well tolerated, Their major toxicity is gastrointestinal.


Infliximab/adalimumab:TNF- α
inhibitors
• Anti TNF-α: Blocking TNF- from binding to TNF
receptors on inflammatory cell surfaces results in
suppression of downstream inflammatory cytokines
such as IL-1 and IL-6 and adhesion molecules involved
in leukocyte activation and migration

• Approved by the FDA in 1998

• Designated for use in patients who did not respond to


methotrexate.

• Proven to slow the clinical progression of rheumatoid


arthritis (Crohn's disease of the colon)
Side effects

• Infection
– Tuberculosis
– Serious resulting in death
• Neurologic
– Multiple Sclerosis, seizures, inflammation of the ocular
nerve
• Worsening of Congestive Heart Failure

• Remember
STOP if develop a fever, have an infection,
• Tendency to cause lymphomas
Etanercept
• Dimeric fusion protein composed of human IgG1
constant regions fused to TNF receptor.
• Binds to both TNF- alpha and TNF- B have same
effect as infliximab  inhibition of TNF-alpha
-mediated inflammation,
• Dissimilarity from:
 half-life is shorter due to its physical form (fusion
protein)
 the route of injection(SC twice weekly)
Antimetabolites
• In immunotherapy, they are used in smaller
doses than in the treatment of malignant
diseases.

• They affect the proliferation of both T cells


and B cells.
Methotrexate
• is a folic acid analogue. It binds dihydrofolate
reductase and prevents synthesis of
tetrahydrofolate.

• It is used in the treatment of autoimmune


diseases (for example rheumatoid arthritis or
Behcet's Disease) and in transplantations.
Azathioprine and mercaptopurine
• Azathioprine is the main immunosuppressive cytotoxic
substance.
• immunosuppressive effects of drug are due to this
nucleotide analog.
• In autoimmune condition (Nucleotides ) :  rapid
proliferation in the immune response and their
dependence on the de novo synthesis of purines
required for cell division, lymphocytes are
predominantly affected by the cytotoxic effects of drug
• It is extensively used to control transplant rejection
reactions.
• Azathioprine # allopurinol (inhibit the
metabolism required dose reduction)
• Bone marrow depression
Mycophenolate mofetil (MMF)
• MMF replaced Azathioprine because its more potent and
efficacious than latter
• successfully used in heart, kidney, and liver transplants

MOA: rapidly hydrolyzed in the GIT to MPA:


a potent, reversible, uncompetitive inhibitor of inosine
monophosphate dehydrogenase(IMPDH)  blocking the de
novo formation of guanosine phosphate  Thus, like 6-MP 
deprives the rapidly proliferating T and B cells of a key
component of nucleic acids
• PK: oral absorption,
 MPA & its glucuronidated metabolites are plasma
albumin bound
 Eliminate thr’ urine

• A/E: N/V/D, abdominal pain, leukopenia, and


anemia, higher doses cause risk of CMV infection

• Drug interaction: antacids


(Mg/aluminium/cholestyramin)  red’ absorption
 More effective than Azathioprine in preventing acute
rejection
 It is used in combination with cyclosporine and
prednisolne

 Mycophenolate mofetil is used in solid organ transplant


patients for refractory rejection and,

 In combination with prednisone, as an alternative to


cyclosporine or tacrolimus in patients who do not tolerate
those drugs

 In renal transplants, it’s used with low-dose cyclosporine


to reduced cyclosporine-induced nephrotoxicity.
Enteric-coated mycophenolate sodium:
• To reduced GIT effcets of MMF
• delayed-release formulation designed to
• release in the neutral pH of the small intestine.
• Equivalent effects with 720 mg dose with
1000mg of MMF  phase III study in acute
rejection episodes in kidney transplant
recipients  still found same GIT adverse
events
Immunosuppressive antibodies
• Pivotal role in prolonging allograft survival
• Polyclonal Ab (immunisation of rabbit/horse
with human lymphocytes Ag)
Inexpensive and variable
• Monoclonal Ab(hybridoma tech./ recombinant
DNA technology)
homogeneous , specific n economic
Antithymocyte globulins
• Polyclonal Ab
• Thymus cell, serve as T-cell precursors
• Use in combination :
 as immunosuppressive agents, at the time of
transplantation to prevent early allograft
rejection,
 they may be used to treat severe rejection
episodes or corticosteroid-resistant acute
rejection.
• MOA: The antibodies bind to the surface of circulating T
lymphocytes  various reactions, such as complement-
mediated destruction, antibody-dependent cytotoxicity,
apoptosis, and opsonization

• The antibody-bound cells  are phagocytosed in the liver


and spleen  cause lymphopenia & impaired T-cell
responses

• PK: IV infusion, t1/2: 3-9 days


• A/E: chills and fever, leukopenia and thrombocytopenia,
infections due to CMV or other viruses, and skin rashes
Antilymphocyte Ab: (polyclonal Ab)
• ALG + mAb in the induction of
immunosuppression  in the treatment of initial
rejections
• bone marrow transplantation
• steroid-resistant Rejections
• AE: Local pain and erythema
Immune Globulin Intravenous (IGIV)
• quite different approach to immunomodulation
• IV use of polyclonal Ab

• PPn : prepared from pools of thousands of healthy donors, and no


specific antigen is the target of the therapeutic antibody. Rather,
one expects that the pool of different antibodies will have a
"normalizing" effect upon the patient's immune network.

• 2g/Kg IGIV high dose used in: asthma to autoimmune disorders


• Kawasaki's disease*: proved to be safe and effective, reducing
systemic inflammation and preventing coronary artery aneurysms
• Sub acute lupus erythematosus and refractory idiopathic
thrombocytopenic purpura (autoimmune disorders)
RhO (D) Immune Globulin Micro-Dose
• Prevent Rh hemolytic disease of the newborn
• The technique is based on the observation that  primary antibody
response to a foreign antigen can be blocked  if specific antibody
to that antigen is administered passively at the time of exposure to
antigen
• Sensitization of Rh-negative mothers to the D antigen usually
occurs at the time of birth of an Rho(D)-positive infant  when
fetal red cells may leak into the mother's bloodstream
• Cause erythroblastosis fetalis (hemolytic disease of the newborn)
• Prophylactic rx, also adviced for Rh-negative mothers who
have had miscarriages, ectopic pregnancies, or abortions
when the blood type of the fetus is unknown
• Rho(D) immune globulin is administered to the mother and
must not be given to the infant.
• IM administration, local discomfort at the injection site
/slight temperature elevation (rare)

Hyperimmune Immunoglobulins:
Various hyperimmune IGIVs are available for treatment:
• infections with respiratory syncytial virus, cytomegalovirus,
varicella-zoster virus, human herpes virus 3, hepatitis B
virus and
• for patients with rabies, tetanus, and digoxin overdose.
Monoclonal Antibodies
1. Trastuzumab
2. Rituximab :patients with relapsed or refractory low-
grade or follicular B cell non-Hodgkin's lymphoma
3. Ibritumomab tiuxetan is an anti-CD20 murine
monoclonal antibody labeled with either Yttrium-90 or
Indium-111 approved for use in relapsed or refractory
low-grade or follicular B cell non-Hodgkin's lymphoma pt.
4. Daclizumab
5. Basiliximab
6. Abciximabthat binds to the integrin GPIIb/IIIa receptor
on activated platelets, inhibiting fibrinogen, Von
Willebrand factor (coagulation diseases)
•7. Palivizumab: binds to the fusion protein of
respiratory syncytial virus, preventing infection in
susceptible cells in the airways(neonates: dec’d
hospitalization, infection frequency)
8. Infliximab, etanercept, and adalimumab :
inhibition of TNF
9. Alemtuzumab: binds to CD52 found on normal &
malignant B and T lymphocytes, NK cells,
monocytes, macrophages, and a small population
of granulocytes* (whats may go down?)
Anti-CD3 Ab
• To suppress the activity of subpopulation of T-cells.
• To block co-stimulatory signals.

• Ab to the CD3 molecule of TCR (T cell receptor) complex results


in a rapid depletion of mature T-cells from the circulation.

• It is used for treatment of acute rejection of renal allografts


as well as for corticosteroid-resistant acute allograft
rejection in cardiac and hepatic transplant patients.

• It is also used to deplete T cells from donor bone marrow


prior to transplantation.
• Initial binding of muromonab-CD3 to the antigen
transiently activates the T cell and results in
cytokine release (cytokine storm).

• It is therefore customary to premedicate the


patient with methylprednisolone,
diphenhydramine, and acetaminophen to
alleviate the cytokine release syndrome.
Glucocorticoids
• Glucocorticoids suppress the cell-mediated immunity.
inhibiting genes that code for the cytokines, the most
important of which is IL-2.

• Smaller cytokine production reduces the T cell proliferation.

• Glucocorticoids also suppress the humoral immunity, causing


B cells to express smaller amounts of IL-2 and IL-2 receptors.

• Cellular immunity is more affected than humoral immunity.

• Anti-inflammatory effects
Clinical use
• Glucocorticoids are first-line immunosuppressive therapy for
both solid organ and hematopoietic stem cell transplant
recipients and graft-versus-host disease (GVHD). (combination
therapy)

• idiopathic thrombocytopenic purpura and rheumatoid arthritis.

• Glucocorticoids modulate allergic reactions and are useful in


the treatment of diseases like asthma or as premedication for
other agents (eg, blood products) that might cause undesirable
immune responses.
Immunostimulants
• Increase the immune responsiveness of
patients who have either selective or
generalized immunodeficiency.

• Use for immunodeficiency disorders, chronic


infectious diseases, cancer and HIV.
Cytokines
• Interferon (INF): INF-α,β,γ
– Antiviral, anticancer, immunomodulating effects.
– Antiviral effects : INF-α,β > INF-γ
– immunomodulating effects: INF-γ
– Adverse Effects: flu-like symptoms, fatigue, malaise
• Interleukin-2 (IL-2)
– T cell proliferation, TH, NK, LAK cell activation
– Treatment of malignant melanoma, renal cell carcinoma,
Hodgkin disease
– Adverse Effects: fever, anorexia, etc .
• Hematopoietic cofactor (HCF): Plays some role, but not the
central role, in growth and differentiation of bone marrow
derived cells
Cancer Immunotherapy
• Immune checkpoints refer to inhibitory pathways of
the immune system that are crucial for maintaining
self-tolerance and modulating the duration and
amplitude of physiological immune responses in
peripheral tissues in order to minimize collateral
tissue damage.

• Tumors misuse immune-checkpoint to evade the


immune system clearance, in particular to avoid
tumor-antigen specific T-cell responses
Levamisole
• first synthesized for the treatment of parasitic infections

• it increases the magnitude of delayed hypersensitivity / T


cell-mediated immunity in humans
• By inducing macrophase activity  tumor cell kill

• immunodeficiency with Hodgkin's disease


• rheumatoid arthritis causes agranulocytosis (stop the use)
• in adjuvant therapy of colorectal cance*r with 5-FU
• Replaced by leucovorine-5-FU regimen bcz of its high
effectivess (diseases free)
BCG (Bacille Calmette-Guérin) & Other Adjuvants

• viable strain of Mycobacterium bovis  been


used for immunization against tuberculosis.
• nonspecific adjuvant or immunostimulant in
cancer therapy
• intravesical therapy only possible for superficial
bladder cancer
• Action: activation of macrophages to make them
more effective killer cells in concert with lymphoid
cells in the cellular efferent limb of the immune
response (lymph node/organ)
• Lipid extracts of BCG as well as nonviable
preparations of Corynebacterium parvum
• BCG cell wall, [Lys18]-muramyl dipeptide  enhance
bone marrow recovery after cancer chemo (in japan,
approved drug)
• In Japan : whole org / extracts used as I. modulators
in standard cancer rx
• Such as,
 picibanil (OK432),
 lentinan, and
 pachymaran
Other agents
Inosiplex (isoprinosine) :
• immunomodulating activities in various
experimental and clinical settings.
• This agent increased natural killer cell cytotoxicity
as well as T cell and monocyte functional activities
(investigantional drugs for AIDS )
• THYMOSIN: protein hormones synthesized by the
epithelioid component of the thymus (bovine +
human)
• Treat: low Serum levels in DiGeorge's syndrome of
T cell deficiency (under trial)
Immunologic Reactions to Drugs & Drug
Allergy
• Drugs also activate the immune system in undesirable
ways  which are manifested  as adverse drug
reactions "drug allergy.“
• Eg. penicillin, iodides, phenytoin, and sulfonamides
• skin eruptions
• edema,
• anaphylactoid reactions,
• glomerulonephritis,
• fever, and
• Eosinophilia
Hypersensitive allergic reaction
• Type I:
• IgE-mediated acute allergic reactions to stings,
pollens, and drugs
• Ab fixed with Tissues Mast cell and blood
basophil then interact with Ag  release
potent mediators
• anaphylaxis, urticaria, and angioedema
• Type II:
• allergic responses involve IgG or IgM  induced ADCC,
CDC mechanism and suppress the reaction
• modify host proteins by drug

• Type III: Drugs may cause


• serum sickness (Immune complex containing IgG)
• Vasculitis (multisystem complement-dependent)

• Type IV: cell mediated allergy


• contact dermatitis from topically applied drugs
• Induration (hardness) of the skin at the site of an antigen
injected intradermally
Drug Treatment of Immediate Allergy
• Type I allergy
• a simple scratch test with a very dilute drug solution  observe the
immediate wheal (edema) and flare (increased blood flow) will occur
• Prednisolone : highly used drug in severe conditions
• By blocking proliferation of IG E producing clone by inhibition of IL 4
production.
• Isoproterenol, epinephrine, and theophylline reduce the release of
mediators from mast cells and basophils and produce bronchodilation
• Epinephrine :
• relaxation of bronchiolar smooth muscle  bronchospasm
• contraction of vascular muscle  hypotension
Desensitization of drugs
• Absent of alternative , have to used(in life threatening
condition) the drugs in the presence of allergic reaction
such as, penicillin and insulin
• It is thought that
• slow and progressive administration of the drug gradually
binds all available IgE on mast cells, triggering a gradual
release of granules. Once all of the IgE on the mast cell
surfaces has been bound and the cells have been
degranulated, the therapeutic doses of the offending drug
may be given with minimal further immune reaction.
Autoimmune (Type II) Reactions to Drugs

• systemic lupus erythematosus following


hydralazine or procainamide
• autoimmune hemolytic anemia resulting from
methyldopa
• thrombocytopenic purpura due to quinidine
• agranulocytosis due to a variety of drugs
Serum Sickness & Vasculitic (Type III)
Reactions
• type II and type III hypersensitivities often overlap
(involved Ig M n Ig G Ab)
• Manifestation of serum sickness : urticarial and
erythematous skin eruptions, arthralgia or
arthritis, lymphadenopathy, peripheral edema,
and fever (6-12 days or untill offending drug will
not eliminate fully)
• Glucocorticoids and plasmapheresis (severe case)
to removes the offending drug from circulation
References
• Katzung pharmacolgy
• Lippincott’s illustrated reviwed 4th edition –
immunopharmacolgy
• Internet sources
• https://accesspharmacy.mhmedical.com/cont
ent.aspx?bookid=1568&sectionid=95705051
(introduction theory)
Thank you
?

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