Immunopharmacology Flashcards
Why is it important to understand the mediators of the immune response?
So we know potential targets for immune therapy
What two events underlie the innate immune response?
Vascular events
Cellular events
Examples of vascular events of the innate immune system
Vasodilation
Increased permeability of the postcapillary venules
Exudation of fluid
Examples of cells involed in the innate immune system
WBC - accumulate in the area of inflammation and are activatedto ingest microbes or kill infected cells
Tissue cells - vascular endothelial cells, mast cells, macrophages
What mediators are released by the immune cells?
Eicosanoids
Cytokines
Histamine
Neuropeptides
What two outcomes can arise following an infection?
Resolution and healing
Development of a chronic infection
Important enzyme involved in the formation of eicosanoids and platelet-activating factors
COX enzyme
Exists in two forms:
- COX-1
- COX-2
What is COX-1 important for?
Tissue homeostasis
What is COX-2 important for?
Induced in activated inflammatory cells
Which drugs target the COX enzyme?
Non-steroidal inflammatory drugs
Glucocorticoids
Examples of eicosanoids
Prostaglandins
Leukotrienes
Thromboxane
How are COX enzymes involved in the production of eicosanoids?
Catalyse the oxidation of arachidonic acids into eicosanoid sub-classes
Effect of bradykinin
Vasodilation
Increased vascular permeability
Stimulation of pain nerve endings
Effect of NO
Vasodilation
Increased vascular permeability
Stimulates PG release
Which cells produce NO?
Most inflammatory cells
Express NO synthase upon activation by cytokines
Examples of cytokines
Interleukins
Chemokines
Colony-stimulating factors
How do NSAIDs vary?
NSAIDs vary in the degree that they inhibit COX-enzymes
From highly - very - weakly - COX-1 selective
From very - weakly COX2 selective
How selective are aspirin and ibuprofen?
Weakly COX-1 selective
Characteristic of weakly COX-2 selective agents
They also inhibit COX-1
What are the 3 pharmacological actions of non-steroidal inflammatory drugs?
Anti-inflammatory
Analgesic
Antipyretic
Describe the anti-inflammatory action of NSAIDs
Inhibit COX-2 actions in inflammation
Promote vasodilation
Vasodilation facilitates increased permeability
Describe the analgesic actions of NSAIDs
Reduce pain caused by tissue damage or inflammatory mediators that act on nerve endings
Indirectly decrease the production of prostaglandins which sensitise nerve endings to pain-inducing mediators
Describe the antipyretic actions of NSAIDs
Reduce fever
Fever is induced by IL1, which generates E-type prostaglandins in the hypothalamus
This disturbs the natural thermostat and results in an elevation of the set-point
NSAIDs interrupt the synthesis of the relevant PGs
What is the mechanism of action of NSAIDs?
Inhibit the COX enzyme
Which NSAID is irreversible?
Aspirin
What is the difference between COX-1 and COX-2?
Both are found in the site of inflammation
But COX-1 is constitutively expressed, and is necessary for the production of the protective mucosa in the GI and kidneys
COX-2 has no endogenous role and is only found in sites of inflammation
How are newer COX drugs different from the classical forms of the drug?
Newer COX drugs are selective to COX-2, leading to fewer side effects since COX-1 is required for the formation of protective mucosa
Suppression of which COX enzyme leads to most of the side-effects of NSAIDs?
COX-1
Side-effects of NSAIDs
GI disturbances
Skin reactions
Adverse renal effects
Bone marrow depression and liver disorders
Encephalitis
Bronchospasms
Adverse cardiovascular effects
How do COX-1 NSAIDs lead to mucosal damage?
COX-1 is involved in the formation of PGs that play a role in stimulating the formation of the protective mucosal lining of the stomach
How do NSAIDs cause adverse renal effects?
Decrease local renal PG levels
PGs are used to increase blood flow and promote natriuresis
What is gout?
Chronic disease
Caused by the overproduction of purines
Crystals of sodium urate precipitate in the joints causing an inflammatory response
Strategies for gout therapy
Reducing uric acid synthesis
Inhibiting migration of immune cells to the site
Reduce pain
What are the two phases of the immune response?
Induction phase
Effector phase
What does the effector phase consist of?
Antibody-mediated component
Cell-mediated component
What controls the phases of the immune response?
Cytokines
Describe the maturation of the adaptive immune response
ThP cells give rise to Th0 cells
Th0 cells develop into Th1 and Th2 cells
Which part of the immune system are Th1 cells involved in?
Cell-mediated immunity
Which part of the immune system are Th2 cells involved in?
Humoral immunity
What do Th1 cells do once activated by pathogen peptides presented on the MHC of APCs?
Produce cytokines that activate macrophages which kill intracellular organisms
Stimulate CD8+ T cells to proliferate, driving the production of cytotoxic T cells which kill virally infected host cells
How does the humoral immune response effectively fight a pathogen?
Antibodies contain two Fab and one Fc portion
Fab = recognise and interact with parts of the pathogen
Fc = trigger host defences
Which cells contain receptors for the Fc portion of the antibodies?
Many inflammatory host cells
What do antibodies represent?
A direct link between the invading pathogen and the host
Which interleukin is important in Th1 development?
IL-2
What immune defect do inappropriate Th1 responses trigger?
RA
MS
Anaemia
Insulin-dependent diabetes
Allograft rejection
What immune defect do inappropriate Th2 responses trigger?
Hypersensitivities
3 classes of drugs used for unwanted immune responses
Antihistamines
Anti-rheumatoid agents
Immunosuppressants
What is the importance of histamine in the immune response?
Mediator of both acute inflammation and hypersensitivity
Released by granulocytes and mast cells
What are the two types of histamine receptor?
H1 - ileum contraction, systemic vasodilation, bronchoconstriction, vestibular nucleus and vomiting center
H2 - gastric acid secretion, smooth muscle relaxation
How can histamine responses be targeted for therapy in hypersensitivities?
H1-receptor antagonists
Unwanted effects include: sedative CNS actions, GI disturbances and antimuscarinic effects
What are DMARDs?
Disease modifying anti rheumatoid agents
Alleviate symptoms of RA without stopping the progress of disease
How do glucocorticoids target the immune response?
Decrease transcription of genes for IL-2 and macrophage-activating cytokines
What is the main action of immunosuppressants?
Inhibit clonal expansion
What is the main target for most immunosuppressants?
IL-2 signal transduction/gene transcription
Clinical uses of immunosuppressants
Inhibit rejection of transplanted organs and tissues
Suppress graft-versus-host disease
Treatment of autoimmune conditions
What are pathogens?
Bacteria that cause disease
Which aspect of a healthy host prevents pathogens from causing infection?
The immune inflammatory response
What are the two effects of antibacterial drugs?
Bactericidial
Bacteriostatic
What are bactericidial antibiotics?
Kills the bacterium
What are bacteriostatic antibiotics?
Stops the bacterium from growing through the use of the host’s defense mechanisms
Are antibacterial agents and antibiotics the same thing?
No
Antibacterial agents are chemicals produced by one microorganism that kills or prevents the growth of another agent
How are antibacterial agents specific?
Target metabolic processes that are different in bacteria
So no major side effects due to ineffectiveness in host cells
How are antibacterial agents and antibiotics different?
Antibiotics inhibits the replication or survival of cellular pathogens
Antibacterial agents actively and selectively kill bacteria
What are the targets for antibacterial drugs?
Cell wall
Plasma membrane
Protein synthesis
Nucleotide metabolism
Bacterial genome
What is the specificity of antibacterial drugs targeting protein synthesis?
30s and 50s subunits of bacterial ribosomes are different from those in human hosts
What is the specificity of antibacterial drugs targeting nucleotide metabolism?
Unlike humans which take up dietary folates, bacteria synthesise folic acid required for nucleotide synthesis using PABA
This can be targeted by drugs
What is the specificity of antibacterial drugs targeting the bacterial genome?
Bacterial topoisomerase II differs from that of humans and is a good target
Bacterial RNA polymerase inhibitors
What is the difference between gram positive and gram negative bacteria?
Gram positive bacteria = stain with Gram’s stain
Main difference is the structure of cell wall
- negative = single layer
- positive = can be up to 40 layers thick
Why is the composition of the cell wall important?
Determines the effects of antibiotics on them
Do gram positive or gram negative bacteria have more complex cell walls?
Gram negative bacteria
Contain transmembrane water-filled channels called porins which hydrophilic antibacterial agents can move freely through
What two categories of resistance exist?
Genetic determinants of resistance
Biochemical mechanisms of resistance
Examples of genetic determinants of resistance
Chromosomal determinants - mutations of chromosomal genes
Extrachromosomal determinants
Transfer of resistance genes between bacteria
Describe extrachromosomal determinants of resistance
Many bacteria have genetic elements that can replicate on their own
These are called plasmids
Plasmids can carry resistance genes
Some stretches of plasmid DNA can be transported from one plasmid
The stretches are called transposons and can spread resistance
How can resistance genes be transferred between bacteria?
Conjugation
Sex pili connect two bacteria, allowing transfer of plasmids between them
Also transferred by phages
Examples of biochemical mechanisms of resistance
Production of enzymes that inactivate the drug
Modification of the drug-binding sites
Decreased accumulation of the drug in the bacterium - efflux mechanisms
Alteration of the target enzymes
Example of enzymes that inactivate a drug
Beta-lactamases
What are b-lactams examples of?
Drugs that affect peptidoglycan synthesis
Bactericidial
Mechanism of action of b-lactams
Inhibit the synthesis of the peptidoglycan corset by inhibiting the enzyme that inserts the cross-links
Examples of b-lactams
Penicillins
Cephalosporins
How do bacteria develop resistance to penicillins?
B-lactamases disrupt the b-lactam ring
Can overcome this using b-lactamase inhibitors
But there are also other mechanisms of resistance = modification of binding sites, reduced permeability to the outer membrane
Main type of drugs affecting DNA synthesis in bacteria
Fluoroquinolones
Inhibit topoisomerase II
Essential for transcription and replication
Main problem with antituberculosis drugs
Development of multi-drug resistant strains
What is the prevalence of TB?
World’s main cause of death from a single agent
First-line drugs of TB
Isoniazid
Rifampicin
Pyrazinamide
What is done to reduce the emergence of resistant organisms in TB?
Compound therapy
Long-term
What disease, apart from TB, does rifampicin also treat?
Leprosy
Structure of viruses
DNA or RNA
Protein coat
Some contain enzymes
How do viruses replicate?
By taking over the metabolic processes of the host
Virtually become part of the host cells
Therefore, selective chemotherapy is difficult
Where can a virus bind to its host cell through?
Receptors for cytokines
Neurotransmitters
Ion channels
Membrane glycoproteins
Describe the pathogenic life cycle of viruses
Virus binds to receptor
Entry
Uncoating
Reverse transcription to make double stranded DNA copy of viral RNA
DNA copy enters nucleus and integrates with host cell
Transcription of provirus
Translation by host ribosomes
Protease action
Assembly and budding
New virions
How do many viruses enter the host cell?
Through receptor-mediated endocytosis
How are RNA retroviruses special?
Use reverse transcriptase that makes a DNA of the viral RNA
This DNA copy is integrated into the host genome and directs the generation of new viral particles
What are the two main groups of anti-HIV drugs?
Reverse transcriptase inhibitors
Protease inhibitors
What are the two main types of reverse transcriptase inhibitors?
Nucleoside RTIs
Non-nucleoside RTIs
Mechanism of action of nucleoside RTIs
Inhibit the action of viral reverse transcriptase
Mechanism of action of non-nucleoside RTIs
Denature the catalytic site of reverse transcriptase
Mechanism of action of protease inhibitors
Protease cleaves the precursor polyproteins to make the structural and functional proteins of the new virions
Protease inhibitors prevent this step
What are targets of antiviral drugs?
Inhibit penetration of host cell
Inhibit transcription of the viral genome
What type of immunomodulators can be used in treating viral infections?
Interferon-a - induces host cell enzymes with antiviral activity
Immunoglobulins - specific for viruses
Clinical uses for non-anti-HIV antiviral agents
Aciclovir = herpes
Foscarnet = CMV
