Exam 3 Flashcards
3 producers of histamine
- Mast cells, stored in basophils
- Certain cells in gastric mucosa
- Certain CNS neurons (neurotransmitter)
How many receptors does histamine have, and what is the clinical use of each?
Histamine has 4 receptors:
H1: used clinically
H2: used clinically to reduced acid
H3: used clinically for narcolepsy
H4: not used clinically
3 places H1 is found in periphery
In periphery, H1 found primarily on:
1. Smooth muscle
2. Vascular endothelium
3. Sensory nerves
3 effects of peripheral H1 stimulation
- Smooth muscle contractions in intestine, bronchi, uterus
- Vasodilation and edema at small blood vessels
- Sensory nerve stimulation
2 effects of H1 receptors on CNS neurons
- Increase wakefulness
- Regulate emesis
Likely other functions as well
What are Type I hypersensitivity reactions, and what happens in the body?
Allergic reaction in which the stimulus is not in itself noxious but still promotes an immune response.
- Evokes the production of IgE antibody by cells of the immune system
- Subsequent exposure to allergen causes mast cell activation and histamine release
Describe the IgE mediated allergen response (initial and subsequent allergen exposure)
Initial allergen exposure:
1. Allergen enters the capillary
2. IgE antibodies are created
3. IgE antibodies create a mast cell that can fend off the allergen in future encounters
Subsequent allergen exposure:
1. Antibodies on the mast cell recognize the allergen, activating the mast cell and forming a crosslinked IgE
2. Mast cell releases histamine and becomes degranulated
Where in the body are mast cells found?
Connective tissues, especially in skin, lungs, intestines; also near blood vessels and peripheral nerves
Do H1 receptor antagonists (H1 antihistamines) act at other receptors (1st gen vs. 2nd gen)?
1st generation H1 antihistamines tend to have more effects at other non-histamine NT receptors than 2nd generation.
They can:
1. Act at muscarinic receptors
2. Block sodium channels in sensory neurons
Do H1 antihistamines cross the blood-brain barrier (1st gen vs. 2nd gen)?
1st generation H1 antihistamines tend to be more lipid soluble and therefore cross the BBB into CNS better than 2nd generation.
2nd generation tend to be substrates for P-glycoprotein transporter in the BBB, so they still cross.
Which generation of H1 antihistamines is cheaper?
1st generation tend to cost less because 2nd generation drugs are newer
2 prominent 1st generation H1 antihistamines
- Diphenhydramine (Benadryl)
- Doxylamine (Unisom)
2 prominent 2nd generation H1 antihistamines
- Cetirizine (Zyrtec)
- Loratadine (Claritin)
5 uses of H1 antagonists (H1 antihistamines)
- Allergies (both generations)
- Sedation (1st generation)
- Anti-emetic/anti-motion sickness (1st generation)
- Anti-muscarinic (1st generation)
- Local anesthesia (1st generation)
Are 1st or 2nd generation H1 antihistamines more efficacious?
Studies have found about equal efficacy in allergic diseases of 1st vs. 2nd generation H1 antihistamines
What is the first line of treatment for anaphylaxis?
epinephrine
What are the first 2 lines of treatment for hay fever?
- Intranasal glucocorticoids
- H1 antihistamines
Describe sedation as an effect of H1 antihistamines
In CNS, histamine actions at H1 receptors promote wakefulness, so H1 antihistamines naturally can cause sedation.
Sedation is most common with 1st generation H1 antihistamines (e.g., Benadryl used as OTC sleep aid).
Can cause tolerance.
Sedation does not always occur, as children and sometimes adults can occasionally experience excitation.
Describe H1 antihistamines as anti-emetics
1st generation H1 antihistamines can act as anti-emetic drugs for chemotherapy/radiation or for motion sickness prophylaxis.
H1 and muscarinic signals from the cerebellum, chemo-receptor trigger zone, solitary tract nucleus, and higher centers are transmitted to the emetic center, so naturally, blocking these signals via antihistamines has an anti-emetic effect.
Doxylamine + vitamin B6 (Diclegis) is an H1 antihistamine that can be used for severe morning sickness.
What is doxylamine + vitamin B6 (Diclegis)?
Doxylamine is an H1 antihistamine, and combining it with vitamin B6 can be used to treat severe morning sickness.
Makes sense given the anti-emetic properties of H1 antihistamines.
Describe the anti-muscarinic effects of H1 antihistamines
Several 1st generation antihistamines can be used as anti-muscarinics, which potentially contributes to the anti-emetic effects.
Anti-muscarinic effects can have clinical utility (e.g., treating acute dystonia caused by antipsychotics).
Describe the sodium channel blocking effects of H1 antihistamines
Several 1st generation H1 antihistamines block sodium channels.
This can be clinically used for local anesthetic effects.
Describe the pharmacokinetics of H1 antihistamines (duration, distribution, metabolism)
Duration: many are 4-6 hours, some 12-24 hours, peak concentrations in 1-3 hours after oral administration.
(Mostly) widely distributed throughout the body, some cross the placenta, others not specifically studied.
Some are extensively metabolized, mostly by CYP450, and some drugs have active metabolites.
Virus vs. Virion
A virus is a non-living infectious agent that replicates only inside living cells. It consists of genetic material (DNA or RNA) surrounded by a protein coat.
A virion is a complete, infectious virus particle outside a host cell. It is the form of a virus that can spread and infect other cells.
The virion is essentially the vehicle that allows the virus to move from one host cell to another.
Endemic vs. Epidemic vs. Pandemic
Endemic - disease is constantly present in a certain geographic area or amongst a certain group of people
Epidemic - an unexpected increase in the number of disease cases in a specific geographical area
Pandemic - when disease spreads over a wide geographical area, usually affecting a large number of people
Are virus genomes DNA or RNA?
Virus genomes can be either DNA or RNA, allowing viruses to make copies of themselves once they enter a susceptible cell
How many viruses are there?
> 400 different viruses known to infect humans
200 known to cause disease in humans
What was the first successful vaccination?
Smallpox vaccine by Edward Jenner in 1798
Are vaccines available for all viruses?
Vaccines available for some (but not all) disease-causing viruses
Describe the 3 types of antiviral drugs
- Virus targeted: these drugs directly target specific viral components or processes, such as viral enzymes, proteins, or genetic material
- Broad-spectrum virus targeted: these drugs have activity against a wider range of viruses, often by interfering with essential viral functions like replication or assembly
- Broad-spectrum host targeted: these drugs target cellular processes or pathways that are essential for viral replication but not for normal host cell function
Describe the characteristics of influenza A virus
- wild waterfowl are natural reservoir for virus
- can infect humans, pigs, birds, horses, cats, dogs
- multiple subtypes (e.g., H1N1, H5N1 - current “bird flu”)
- can cause pandemic (widespread, affecting large number of people) flu
Describe the characteristics of influenza B virus
- primarily a human disease
- generally milder than A
- no subtypes, but 2 lineages: B/Yamagata and B/Victoria
- though tsequence of viral genoe changes more slowly than influenza A
Describe the characteristics of influenza C virus
- human major host
- causes mild or even no symptoms in healthy adults
- rather different from A and B
Describe the characteristics of influenza D virus
primarily infects cattle
What type of genome do influenza viruses A and B have?
RNA genome, but segmented!
2 major virion surface proteins of influenza viruses A and B
- Hemagglutinin
- Neuraminidase
What is influenza reassortment?
Process where two or more different influenza viruses co-infect a single host cell and exchange RNA segments.
This leads to new virus strains with novel gene combinations, potentially resulting in significant changes in the virus’s behavior and immune system recognition.
What is unique about the origin of swine-origin H1N1 influenza viruses?
They were created from a quadruple reassortment, meaning 4 different influenza viruses co-infected a single host cell and exchanged RNA segments, yielding H1N1
Can influenza A reassort with influenza B?
Influenza reassortment has never been observed between influenza A and influenza B, but both viruses can reassort within their own types
What is the efficacy of the influenza vaccine?
Vaccine effectiveness can vary year to year, but when “well matched” it can reduce illness by about 40-60%
When are influenza antivirals used?
CDC recommends treatment begin ASAP (best efficacy) for hopsitalized people, people with severe, complicated, or progressive illness, and people at risk for complications from influenza.
More or less used in those that or more susceptible.
In certain circumstances, can even be used for chemoprophylaxis.
4 effects of influenza antivirals
When taken as early as possible is best:
1. Can lessen symptoms
2. Can shorten illness duration
3. May reduce risk of complications
4. Some studies have found benefit in hospitalized patients
Describe the influenza life cycle
- Entry into host cell and disassembly of the infectious virus particle (virion)
- Replication of the viral genome/transcription of viral mRNA
- Synthesis of the viral proteins by the host cell translation machinery
- Reassembly of these components into progeny virus particles and exit from host cell
What are the functions of hemagglutinin and neuraminidase?
Hemagglutinin and neuraminidase are the two major virion surface proteins of influenza viruses A and B.
Hemagglutinin promotes binding and entry of influenza at sialic acid receptors, which hold the virus particles to the host cell.
Neuraminidase allows budding and release of influenza from the cell. It acts as a sialidase enzyme, breaking down sialic acid molecules that hold the virus particles to host cells.
What are neuraminidase inhibitors (+ 3 common drugs)?
Neuraminidase allows budding and spread of influenza progeny from the host cell, so neuraminidase inhibitors are antivirals that prevent this process and are active against influenza A and influenza B.
3 common neuraminidase inhibitors:
1. Oseltamivir (Tamiflu)
2. Zanamivir (Relenza)
3. Peramivir (Rapivab)
What is oseltamivir (Tamiflu) (mechanism, who should take, route of administration, duration, side effects, efficacy)?
Oseltamivir (Tamiflu) is an antiviral neuraminidase inhibitor that is recommended by CDC for hospitalized patients, those with complicated/progressive illness, and pregnant women with influenza A or B.
-Orally bioavailable
-Usually taken for 5 days (can be more)
-Side effects: nausea, vomiting
Only 2 of 2800+ viral samples tested this year had reduced susceptibility to oseltamivir (but both were susceptible to zanamivir, an inhaled powder).
How is zanamivir (Relenza) administered?
Zanamivir (Relenza) is an antiviral neuraminidase inhibitor antiviral used to treat influenza, and it is taken as an inhaled powder (major limitation)
What is baloxavir marboxil (Xofluza) (mechanism, who should take, administration, side effects, efficacy, main issue)?
Baloxavir marboxil (Xofluza) is an antiviral that acts as an inhibitor of one of the subunits of the influenza RNA polymerase complex in influenza viruses A and B, blocking RNA synthesis.
- taken by those 5+, within 48 hours of symptoms
- Not studied in pregnant/nursing, hospitalized, those with complicated/progressing illness
- Given as single oral dose (very long half life)
- Side effects: diarrhea, bronchitis
Effects on symptoms similar to oseltamivir (Tamiflu), but reduces viral load more quickly than oseltamivir.
1 of 2700+ viral samples tested had reduced susceptibility to baloxavir marboxil (Xofluza).
Main issue: it chelates with polyvalent cations (like calcium), decreasing the amount of drug that gets absorbed; shouldn’t be taken with products like milk
What is recombinant DNA (rDNA)?
artificial DNA created by joining two or more pieces of DNA that are normally not found together in nature (e.g., typical plasmid used for research)
Recombinant DNA technology allows new types of drugs to be manufactured (field of Biotechnology).
4 types of rDNA-based drugs
- rDNA-based versions of human proteins like insulin or erthyropoietin (EPO)
- Synthetic proteins that combine pieces of human proteins with other sequences (as in the anti-cancer drug Herceptin)
- rDNA-based micro-organism proteins that act as vaccines (like Gardasil for HPV)
- rDNA-based vectors for gene therapy
How is insulin produced?
The human pancreas contains ~1 million islets of Langerhans (total mass ~1 gram) that produce insulin
Why do endocrine hormones make good drugs?
Endocrine hormones make good drugs because they function normally if they are delivered into the bloodstream
What is the role of insulin?
Insulin is one part of the system that maintains glucose in a normal range:
1. After a meal, blood glucose increases
2. Insulin level increases in response to increased blood glucose
3. Insulin causes cells of the body to take-up glucose, reducing the blood glucose level
4. Blood glucose levels are maintained in a normal range in healthy individuals due to this process
What is the mechanism of action of insulin?
- Insulin binds to cell surface receptors on target cells when blood glucose is high (after meal)
- Insulin increases expression of glucose transporters, especially GLUT4 on muscle and fat cells
- Glucose uptake then increases, and glucose is used to build and store glycogen and fatty acids
Without insulin, glucose builds up outside cells (in bloodstream) and can cause hyperglycemia
What is hyperglycemia, and what are its 5 consequences?
Failure to produce or respond to insulin leads to hyperglycemia, or high blood glucose
Consequences of hyperglycemia:
1. Ketoacidosis (can be fatal)
2. Decreased consciousness or confusion
3. Dehyration due to glycosuria and osmotic diuresis
4. Acute hunger/thirst
5. Long term health problems such as heart disease, kidney disease, eye damage, nerve damage, etc.
What is diabetes mellitus type 1?
Diabetes mellitus type 1 is an autoimmune disease that destroys islet beta cells (cells that produce insulin). This causes an inability of the body to produce insulin and causes chronic hyperglycemia.
Sometimes called juvenile diabetes but can also arise later in life.
Cause(s) are uncertain but are likely a combination of environmental exposures and genetic susceptibility.
Describe the progression of diabetes type 1
Destruction of iselts of Langerhans (producers of insulin) in diabetes type 1 may take months to years.
As insulin production drops, blood glucose will increase from normal value of 70-120 mg/dL, and the disease is largely asymptomatic until blood glucose surpasses ability of the kidneys to clear the ~200 mg/dL threshold (renal threshold).
- Once blood glucose is above the renal threshold, symptoms can come on rapidly and severely, typically in younger children but can occur in adulthood
Describe the history of insulin procurement (+ 4 concerns)
From 1920s-1980s all insulin was isolated from animal sources (cow, pig, horse, fish etc.), but there are concerns for animal-derived (or human-derived) drugs:
1. May contain pathogens
2. Treatment to kill pathogens often not possible because it would damage the drug
3. Difficult to control health status of donors and other aspects of supply chain
4. Finite supply of raw materials available
What is the solution to the risks of human and animal-derived drugs?
recombinant DNA (rDNA) technology
What are the benefits of using recombinant DNA (rDNA) technology to produce biomolecule-based drugs, like insulin?
Uses naturally occurring proteins or synthetic designs, and manufacturing typically occurs in a factory setting where it is straightforward to achieve FDA-mandated Good nufacturing Practices.
Contamination risks for rDNA drugs are very low compared to human or animal-derived products.
Human proteins used as drugs often have very high specificity for their targets, so they can produce a very specific medical outcome with few side effects (as compared to small molecule drugs that often have many potential targets and side effects).
Describe the 5 enzymes that make rDNA technology possible
endonuclease: enzyme that cleaves NA in the middle of the polymer
exonuclease: enzyme that cleaves nucleotides from the end of the polymer
terminal transferase: enzyme that adds nucleotides randomly to the end of the polymer (no template needed)
DNA polymerase: enzyme that synthesizes complementary sequence DNA using a template strand
DNA ligase: enzyme that covalently joins two pieces of DNA
Describe the work of Paul Berg
Paul Berg’s laboratory made the first rDNA in the early 1970s.
SV40 genome was manipulated to carry foreign DNA segments (initially from a bacterial virus, later from mammalian genes).
- Refinements of this approach allowed expression of proteins from the hybrid genome
