Block 8 Flashcards
Which anti-TB agent is able to inhibit membrane-bound ATP synthase and block ATP production in mycobacteria?
Bedaquiline
Define the MOA of thiazide diuretics.
They affect the distal renal tubular mechanism of electrolyte absorption –> they reduce the amount of salt and wter in the body by reducing tubular reabsorption
How do polyene antifungal agents work?
They are membrane disruptors
- they are the broadest spectrum antifungals
- MOA: bind to ergosterol and form pores (making the membrane leaky); affinity for ergosterol > cholesterols
** the number of double bonds directly correlates with fungal toxicity and selectivity
Which NA inhibitor is a prodrug that is orally active? How is it activated to its active form and what is that active form?
Which one is given via inhalation?
Which one is given by IV?
Oseltamivir - orally active prodrug; cleaved by esterase to active drug (oseltamivir carboxylate)
Zanamivir - inhalation
Peramivir - IV
What are the primary and secondary insults associated with NSAIDs and gastric damage?
Primary - direct acid damage, an indirect contact effect, and a back diffusion of hydrogen ions
Secondary - inhibition of PG biosynthesis in the GIT, where PGs exert a cytoprotective effect (COX1 inhibition)
What is the purpose of the drug Kionex (polystyrene sulfonate)?
Identify its MOA.
Controls potassium levels
MOA - as the resin passes along the intestine or is retained in the colon after administration by an enema, the sodium ions on the molecule are partially released and replaced by potassium ions
What is a noticeable structural different between imidazoles and triazoles?
Triazoles have 3 nitrogens in a 5 member ring.
Imidazoles only have 2.
What is unique about triazole function when compared to imidazoles?
they exhibit more selective toxicity and are associated with fewer side effects
What is typically given alongside isoniazid? Why?
Vitamin B6 because INH is an antagonist of it; adding more vitamin B6 to the patient’s diet prevents the side effects associated with the antagonistic activity
identify the MOA of epinephrine.
adrenergic receptor agonist
acts on both alpha and beta receptors
- alpha activation causes vasoconstriction and decreases vascular permeability that occurs during anaphylaxis
Which two steps (enzymes) in ergosterol biosynthesis can be targeted?
1 - squalene epoxidase (it’s the last non-cyclic molecule in the synthesis pathway, so by inhibiting this enzyme with allylamine antifungals we can inhibit the first step in producing ergosterol)
2 - P450 14-alpha demethylase (CYP51) (lanosterol is eventually converted to ergosterol by this enzyme, so azole antifungals will prevent synthesis in the final stages)
What are the two drugs that belong to the “aryl and heteroarylacetic acids” category of NSAIDs?
How do they differ?
Diclofenac - most widely used NSAID; is more potent than aspirin in anti-inflammatory and antipyretic properties; MOA is COX inhibition and reduced production of PGs along with inhibition of the lipoxygenase pathway and arachidonic acid release
Nabumetone - prodrug of 6MNA, which is an effective inhibitor of COX in joints; more active than aspirin at inflammation reduction bu 1/2 as potent in analgesic properties; pro - less gastric irritancy
Identify the drug and its MOA.
Montelukast (Singulair)
MOA - high affinity CysLT1 receptor binder, so it inhibits the activity of LTD4 at the receptor
What are important mechanisms to resistance to antifungal agents?
- target alterations
- reduced access to targets
Drugs for herpes are broken down into what 3 categories?
1 - Nucleoside Analogs
2 - Nucleotide Analogs
3 - Pyrophosphate Analogs
Describe the ideal qualities of an antifungal agent.
- broad spectrum activity against a variety of yeast and mold
- fungicidal rather than fungistatic (we want to kill it, not just stop it from dividing because immunocompromised people still won’t be able to kill it off themselves)
- selectivity for fungal vs. human cells
- multiple delivery methods (particularly oral availability) to enable prolonged out-patient care
- minimal side effects/toxicities
- essential to identify biological targets that are unique to fungi!
Core structures of nucleoside-guanosine analogs contain _____________ instead of ____________.
What is required for activity of this drug class? Why is this important?
Acyclic side chain instead of a ribose sugar
They have to undergo phosphorylation by a viral kinase for activity –> meaning this class is relatively nontoxic because they cannot be activated in uninfected host cells
The four types of asthma therapeutic agents are:
Adrenergic Agonists (alpha and beta)
Antimuscarinics
Adrenocorticoids
Leukotriene Modifiers
Match each drug with the appropriate description:
acyclovir, ganciclovir, foscarnet, cidofovir, oseltamivir, zanamivir
1 - this drug is administered by intravitreal injection to treat CMV retinitis
2 - a pyrophosphate analog which does not require activation by viral kinase
3 - an obligate DNA chain terminator
4 - is a nucleotide analog
5 - drugs of choice in ganciclovir resistant CMV as well as acyclovir resistant HSV
6 - orally effective prodrug used against flu virus
1 - Ganciclovir
2 - Foscarnet
3 - Acyclovir
4 - Cidofovir
5 - Foscarnet and Cidofovir
6 - Oseltamivir
How do corticosteroids reduce mucus secretion?
They inhibit the release of secretagogue from macrophages. They also inhibit the late phase reaction by inhibiting the inflammatory response and interfering with chemotaxis
How do PDE inhibitors help with COPD?
They increase cAMP and cGMP levels in cell types associated with release of inflammatory chemicals (such as T cells, B cells, monocytes, neutrophils, and eosinophils)
(COPD is associated with neutrophils)
What characteristics are needed for a good topical antihistamine?
- slow rate of receptor dissociation (long duration of action)
- logD ~1.0 +/- 0.5 at pH 7.4 (drugs with logD in this range are most efficacious and their water-soluble salts also show a low incidence of causing ocular irritation)
Give an example of a non-selective NSAID and its therapeutic benefits.
Salicylic Acid
Benefits: antipyretic, analgesic, and anti-inflammatory properties, promotes the excretion of uric acid (gouty arthritis); inhibits COX in platelet membranes, so irreversibly blocks formation of TXA2
Why can COX inhibitors be useful against fungi?
mPGES = microsomal PGE2 synthase (only in fungi)
COX inhibitors prevent the formation of PGE2, so COX inhibitors may reduce the activity that produces biofilms
Identify the drug. What are its proprietary names? Describe the MOA.
Hydroxyzine
Vistaril and Atarax
1st gen antihistamine
H1 receptor antagonist. (histamine allows fluid to escape from the capillaries into the tissues and this fluid is what is found with runny noses and water eyes during allergic reactions; histamine also induces swelling and the production of wheels in rashes)
What types of mutations are already being seen in response to antifungal agents?
Polyenes - resistance is rare and includes decreased ergosterol content in membranes
Azoles - low affinity to target enzyme (modified binding site, overexpression of enzyme, reduced accumulation of drug (efflux))
Allylamines - none detected, expected soon
Echinocandins - target mutation
5FC - inhibition of the transformation of 5-fluorocytosine to 5-florouracil
How can fungi become resistant to 5-FU?
they can block the reaction that cleaves 5-FU from its prodrug form to its active drug form.
What are the uses of foscarnet?
What is its MOA?
It is active against all types of herpes and HIV
- clinically used in ganciclovir resistant CMV and acyclovir resistant HSV
MOA: selective inhibitor of DNA polymerase (blocks pyrophosphate binding site)
__________ drugs prevent increases in cGMP levels, which are caused by interaction of ______ with the _______ receptors on bronchial smooth muscle.
Antimuscarinics
Acetylcholine
Muscarinic
__________ is a pyrofosphate analog
FOScarnet
The first NSAID to be marketed as a selective COX-2 inhibitor was ______. What other property needs to be taken into account when using this drug?
Celecoxib
It also inhibits CYP2D6, so it can affect the PK of other drugs (drug-drug interaction)
Identify the drugs.
Top - prednisolone
Middle - also prednisolone (putnam put it on this slide twice)
Bottom - fluticasone
Hydrocortisone looks like prednisolone, but the bottom left ring structure with the ketone does not possess two double bonds in hydrocortisone, it only has one.
Identify the drug. Which isomer is more active?
Naproxen
What is erythropoietin (EPO)?
- hormone produced by healthy kidneys that stimulates the bone marrow to make RBCs
(if your kidneys aren’t working properly, you won’t make enough EPO and you become anemic)
Which drugs are triazoles?
Fluconazole
Voriconazole
Itraconazole
Identify the drug and its MOA.
Benadryl (Diphenhydramine HCl)
1st gen antihistamine
H1 receptor antagonist; has anticholinergic (drying) and sedative effects (competes with histamine for H1 sites on effector cells)
Echinocandins are used to target _____________.
What limitations do they face?
Describe their MOA.
They target the cell wall and are used to treat resistant Candida and azole-resistant Aspergillus
limitations - need for daily IV administration because they have limited bioavailability and they are destroyed quickly
MOA: inhibition of the catalytic subunit of 1,3-beta-D-glucan synthase
Which drugs are members of the allylamine antifungal class?
Naftifine, Terbinifine, Butenafine, Tolnaftate thiocarbamate
Which drugs are classified as potassium-sparing diuretics?
Amiloride
Eplerenone (Inspra)
Spironolactone (Aldactone)
Triamterene (Dyrenium)
Identify the drug. Which isomer is more active?
Ibuprofen
S isomer
what’s the purpose of using antimuscarinics for asthma treatment?
Drugs that block the muscarinic fibers will cause cardiovascular, mydriatic, antispasmodic, antisecretory, and bronchodilatory effects
Describe the antibacterial activity of rifamycin antibiotics.
- broad spectrum (G+ and G- activity)
- bactericidal against intracellular and extracellular bacteria
- active aginst semi-dormant bacteria (sterilizing effect)
- resistance develops when used alone so is always used in combination with other agents
What is SRS-A?
SRS-A is slow-reacting substance of anaphylaxis.
- it’s a mixture of triene-containing lipids (LTC4, LTD4, and LTE4; all of which are cysteine-leukotrienes)
Which drugs are selective COX 2 inhibitors?
Celecoxib, Valdecoxib, and Meloxicam
Meloxicam was moved to the class for COX2 inhibitors
What properties do most 2nd gen antihistamines possess that prevent them from crossing the BBB?
- most are zwitterionic at physiological pH
and/or
- substrates for efflux (p-glycoprotein)
Ethanolamine Ethers belong to which generation of antihistamines?
1st generation
Describe the MOA and SAR of bedaquiline.
MOA: inhibits membrane-bound ATP synthase and blocks ATP production in mycobacteria
SAR: the tertiary amine, tertiary alcohol, ether oxygen, and bromine exert antibacterial activity by binding with amino acids of ATP synthase
In a culture positive for herpes simplex virus infection, parenteral therapy with acyclovir was started. The patient was at increased risk of develping what adverse side effect as a result?
Crystalluria
Identify the drug.
Nabumetone
Define the MOA of loop diuretics.
They inhibit sodium reabsprtion in the ascending loop of Henle. Reabsorption of chloride is also blcoked.
This causes the kidneys to get rid of more urine, lowering the amount of water in the body.
Describe the cell wall of Mycobacteria.
Thick, waxy cell wall that contains long chains of fatty acids called mycolic acid.
The mycolic acid is attached to the next cell wall component, a type of oligosaccharide called arabinogalactan
Identify the drug.
Amphotericin B
Why aren’t chitin and chitosan inhibitors used?
A common response to cell wall damage is strengthening of the cell wall by the production of excess chitin.
This mechanism is triggered when fungi are treated with echinocandin drugs.
Thus, enhanced chitin levels will then reduce susceptibility to echinocandin drugs
Because there are several ways to produce chitin, blocking one way will just result in excess production through the other way
What are the key points to remember about pyrazinamide?
- it’s a prodrug of nicotinamide
- it’s pH dependent and exhibits optimal activity under pH ~5
- is bactericidal against semi-dormant intracellular tubercle bacilli (sterilizing effect)
- decreases the pH and inhibits pH sensitive enzymes inside the cell
- prevents energy production
The most common Aspergillus mold species are…
A. fumigatus
A. niger
A. flavus
Allergy therapeutic agents are typically _________, which include…
H1 receptor antagonists
Ex. Diphenhydramine
Hydroxyzine
Cetirizine
Levocetirizine
Loratadine
Fexofenadine
What modification made the lead compound (in the development of zanamivir) selective for viral NA?
4-amino substitution
the 4-OH was replaced with a basic amine substitute.
It was then replaced with a guanidinium group (forms more H bonds and ionic bonds)
What may result from acute kidney failure? How can this be treated?
Acute kidney failure may result in too much fluid in the body, leading to swelling in the arms and legs. In these cases, medications (diuretics) may be used to expel extra fluids.
What are the two types of azoles? Why is there a risk of toxicity associated with these drugs?
Imidazoles and Triazoles
Azoles target CYP450, so many can also inhibit human CYP450 and cause toxicity
(Triazoles are more selective than Imidazoles)
Once isoniazid is activated, what is its specific MOA?
It forms an adduct with NAD, which then inhibits enoyl ACP reductase (InhA), a component of fatty acid synthase complex (FAS2) that helps make mycolic acid
Xyzal (generic name _______) is the active enantiomer of ________. Its principle effects are mediated via selective inhibition of ____________.
Levocetirizine
Cetirizine
H1 receptors
________ inhibits dCTP incorporation into viral DNA. Similar to guanosine analogs, it causes…
Why is the active form the diphosphate form?
Cidofovir
causes a slowing and subsequent cessation of viral DNA chain elongation
the active form is the diphosphate form because the phosphonate is not considered a phosphate (just a phosphate equivalent)
Compare acyclovir and ganciclovir in terms of spectrum coverage and clinical uses.
Acyclovir: HSVI > HSV2
*Note - HSV strains that are resistant to acyclovir are resistant to otehr guanosine analogs (cross resistance)
Ganciclovir: active againts CMV and most widely used in CMV infection (this is because phosphotransferase enzyme is the enzyme that works to activate ganciclovir, and it’s only found in CMV)
Identify the drug. What is it a metabolite of?
Cetirizine HCl (zyrtec)
It’s a metabolite of hydroxyzine
_________ is the mediator of influenza viral attachment to host cells by binding to _________.
______ cleaves the attachment and promotes release from cells.
HA (hemagglutinin)
Sialic Acid
Neuraminidase
What is parsabiv? How does it work?
Parsabiv (etelcalcetide) is a synthetic peptide calcium-sensing receptor agonist.
Its MOA is to allosterically modulate the calcium sensing receptor in the parathyroid gland by binding to the CaSR and enhancing activation of the receptor (which normally responds to extracellular calcium). This activation on parathyroid chief cells decreases PTH secretion, thus decreasing calcium levels.
How do first and second generation anti-histamines compare to one another?
1st gen - act at cholinergic, adrenergic, dopaminergic, and serotonergic receptors (low specificity); cause drowsiness and some peripheral side effects (blurred vision, dry mouth)
2nd gen - have improved H1 selectivity, little to no sedative effect, selective peripheral effects (don’t cross BBB), and less cholinergic activity
Why would you not use rifampin and isoniazid together?
The hepatotoxic metabolite of isoniazid is made through the function of CYP2E and rifampin is a CYP2E inducer (thus increasing the levels of the hepatotoxic metabolite)
List the common uses of the various imidazoles.
- fungal skin infections (ringworm)
- athlete’s foot
- jock itch
- tinea corporis
- miconazole is predominantly for yeast infections
- ketoconazole is for tina versicolor and dandruff (both are caused by Malassezia)
How is TB identified?
Through acid-fast staining (NOT gram staining)
Give examples of both DNA and RNA viruses.
Which RNA viruses replicate in the nucleus? Which DNA virus replicates in the cytoplasm?
DNA - HAPPy (Herpes, Adeno, Pox, Papilloma)
Pox - does not replicate in nucleus
RNA - influenza and HIV (both replicate in the nucleus actually)
Summarize viral replication
1 - attachment
2 - capsid enters by receptor mediated endocytosis or fusion (entry)
3 - enzymatic removal of capsid proteins (uncoating)
4 - biosynthesis (in nucleus or cytoplasm)
5 - release (enveloped viruses bud out; non-enveloped viruses rupture the membrane)
optional - chronic infection/latency
What are the 4 R’s of Rifampin?
RNA Polymerase Inhibitor (DDRP)
Rapid Resistance if used alone
Red/orange color of body fluids
Ramps up CYP450
What structural feature makes zanamivir a potent neuraminidase inhibitor?
Guanidinium group
Identify the MOA of aspirin.
Aspirin is the only NSAID that covalently modifies COX by acetylating Ser530 (COX1) and Ser516 (COX2)
_______ inhibits the migration of polymorphonuclear cells into inflammatory sites, the release of lysosomal enzymes from these sites, platelet aggregation, AND COX.
Piroxicam
What are the first line agents for TB infections and what does each one target?
RIPE
R - Rifampin; targets mRNA synthesis (DDRP)
I - Isoniazid; targets mycolic acid synthesis
P - Pyrazinamide; targets intracellular (mechanism unclear)
E - Ethambutol; targets arabinogalactan synthesis (specifically arabinosyl transferase)
Identify each of the drugs in the picture.
top left - epinephrine
top right - albuterol
middle - terbutaline
bottom - salmeterol
What are the typical targets for antifungal agents?
1 - fungal cell membrane and cell wall
2 - fungal nucleic acid and protein biosynthesis
3 - miscellaneous (yeah yeah)
Identify the two drugs.
Left - piroxicam
Right - meloxicam
List examples of thiazide diuretics.
Chlorothiazide (Diuril)
Methyclothiazide (Enduron)
Hydrochlorothiazide (Microzide)
Chlorthalidone (Thalitone)
Inadpamide (Lozol)
Metolazone (Zaroxolyn)
If AKI is caused by a lack of fluids in the blood, ________________ may be administered. What types of disease states would be associated with this phenomenon?
IV fluids may be administered
Heart Failure or COVID-19
Which two NSAIDs are heteroarylproprionic acids? Describe them.
Iburpofen - forms a racemic mixture (S is more active); is more potent than aspirin in anti-inflammatory and PG inhibition, causes moderate GI irritation
Naproxen - S isomer is more active; inhibits PG biosynthesis 12x more than aspirin and 3-4x more than ibuprofen; is also less irritating than aspirin; longer duration of action than ibuprofen
Identify the drugs.
Top - ipratroprium hydrobromide
Bottom - tiotropium bromide
Describe the binding of Sialic acid with NA.
C1 carboxylate group binds with 3 arginine residues through ionic interaction
C2 hydroxyl group forms hydrogen bonds with asp-151
C4 hydroxyl group, C5 acetamido group, and C6 glycerol group are also important (H, VDW, and H)
Which drugs are imidazoles?
Ketoconazole, Clotrimazole, Miconazole
Allylamine antifungals have limited activity and are mostly used againts _________. Their use is localized to which region of the body?
Describe the MOA.
Dermatophytes
Skin and nails
MOA there are two outcomes of inhibition of squalene epoxidase:
1 - the decrease in ergosterol concentration in membranes leads to malfunction of transport proteins involved in nutrient transport and pH balance
2 - build up of hydrocarbon squalene within fungal cells, which is toxic in high concentrations
How are ethanolamine ethers (such as diphenhydramine) metabolized?
Dealkylation of the amine (metabolites have short half-life) and deamination (COOH metabolite, inactive)
Identify the drug.
Roflumilast (PDE4 inhibitor)
Describe the structure of cidofovir and how that impacts its MOA.
It is a cytidine monophosphate (nucleotide) analog
it has phosphonomethylene as its side chain instead of a ribose phosphate
Cidofovir does not require phosphorylation by viral kinase because it already has a phosphate equivalent
Once inside the cell, it’s instead converted to a diphosphate form by a cellular kinase (meaning, unlike nucleoside analogs, this one doesn’t require a viral kinase and can be activated by cells)
Describe the SAR of diclofenac.
Dichloro-substituents force the anilino-phenyl rings out of the acid moiety plane, increasing binding to COXs
Compare the functions of COX1 and COX2.
COX1 - production of PGs that are part of normal cellular activity (protecting GI mucosa, maintenance of kidney function)
COX2 - production of PGs at inflammatory sites
What types of treatments are available for AKI (acute kidney injury)?
- treatments to balance the amount of fluids in the blood
- medications to control blood potassium
- medications to restore blood calcium levels
- dialysis to remove toxins from the blood
What enzyme is required to activate the prodrug isoniazid?
Why is this drug safe for humans?
KatG (mycobacterial catalase-peroxidase)
Humans don’t have KatG
How do alkyl amines compare to ethanolamine ethers in terms of antihistamine properties?
- more selective to H1
- less sedative effect
- less CNS depression
- decreased antiemetic effect
- longer half-life (up to 24 hours)
- deamination is the major metabolic pathway
Kionex (sodium polystyrene sulfonate) can be given if…
What else could be given?
Why would this situation be bad?
the kidneys aren’t filtering potassium from blood
Calcium or glucose
too much potassium in the blood can cause dangerous irregular heartbeats (arrhythmias) and muscle weakness
Identify the drug. True or false: it causes sedative effects as a side effect of its MOA.
Loratadine (Claritin)
False - it has antiallergic properties without sedative effects
Compare the MOAs of phosphate binders Fosrenol and Renagel.
Fosrenol - reduces absorption of phosphate by forming insoluble lanthanum phosphate complexes that pass through the GIT unabsorbed
Renagel - taken with meals has been shown to decrease serum phophorous concentrations (not described in further detail)
Identify the drug and its MOA.
Zafirlukast (aka Accolate)
MOA: selective and competitive antagonist of LTD4 and LTE4 (components of SRS-A)
Prednisolone primarily has _______ (gluco/mineralo)corticoid properties.
Glucocorticoid
How can PKD (polycystic kidney disease) be treated?
there are few therapeutic interventions, but one is Jynarque (tolvaptan). Its MOA is as a selective vasopressin V2-receptor antagonist. It causes:
- decreased binding of vasopressin to the V2 receptor in the kidney, which lowers AC activity resulting in decreased intracellular cAMP concentrations (less constriction)
- in human ADPKD cyst epithelial cells, it inhibited in vitro cyst growth and chloride dependent fluid secretion into cysts
What are the various classes of diuretics?
- thiazide diuretics
- loop diuretics
- potassium-sparing diuretics
What is the most common target for antifungal agents?
Why?
Fungal Cell Membrane
Fungi have a slightly different pathway in sterol biosynthesis (also, they have ergosterol instead of cholesterol)
True or false: all guanosine analogs show dual MOAs.
True:
DNA polymerase inhibition and DNA chain termination
List the sates involved in inflammation.
1 - initial injury causes release of inflammatory mediators (histamine, serotonin, prostaglandins, leukokinins, and others)
2 - Vasodilation
3 - Increased vascular permeability and exudation
4 - Leukocyte migration, chemotaxis, and phagocytosis
5 - Proliferation of connective tissue cells
A patient with CMV infection was prescribed a parenteral anti-herpes medication. The drug must be phosphorylated first by a virus-specific enzyme, then by host cell enzymes to become active. What drug was most likely given?
Ganciclovir
Describe the MOA of azoles.
- they inhibit CYP450, leading to accumulation of lanosterol
- this causes permeability changes in the membrane, leading to a leaky membrane and malfunctioning proteins
What are the 3 primary respiratory disease states?
Allergies
Asthma
COPD (chronic obstructive pulmonary disease)
Identify the drugs in the picture.
Top left - bumetanide (bumex)
Top right - ethacrynic acid (edecrin)
Bottom left - furosemide (lasix)
Bottom right - torsemide (demadex)
Why are acyclovir and penciclovir inactive against CMV?
CMV lacks thymidine kinase
Substitution of aromatic rings at the 5-position of salicylic acid has what effect?
Increases anti-inflammatory activity (drug = diflunisal)
Identify the drugs in the picture.
Top left - amiloride
Top right - eplerenone (Inspra)
Bottome left - spironolactone (Aldactone)
Bottom right - triamterene (Dyrenium)
Identify the location in which each of the following herpes virus is able to establish latency:
- Herpes Simplex
- Varicella-Zoster
- Cytomegalovirus
- Epstein-Barr
Herpes Simplex - sensory nerve ganglion
Varicella-Zoster - sensory nerve ganglion
Cytomegalovirus - myeloid stem cells
Epstein-Barr - B cells
The GI side effects from salicylic compounds are caused by which moiety?
What happens if the drug is in its amide form?
What happens if the OH is moved to the meta or para position on the ring? If it’s removed altogether?
- carboxylic acid moiety
- the amide form maintains the analgesic property but eliminates anti-inflammatory properties (salicylamide)
- moving the OH to the meta or para position abolishes its activity
- removing the OH gives it weak anti-inflammatory activity
Identify examples of loop diuretics.
Bumetanide (Bumex)
Ethacrynic Acid (Edecrin)
Furosemide (Lasix)
Torsemide (Demadex)
What is rayaldee?
Rayaldee (calcifediol) is a prohormone of the active form of vitamin D3
It’s converted to the active form by CYP450 and will activate the vitamin D receptros in target tissues. this increases the levels of vitamin D and calcium in the body, thus decreasing PTH synthesis.
List the available nucleoside-guanosine analogs and indicate which ones are prodrugs.
Which type of diuretic is much less potent than the others?
Potassium-sparing diuretics
What combinations are generally used to treat COPD?
Adrenergic agonists (alpha & beta), Antimuscarinics, and Adrenocorticoids
(you don’t typically use H1 receptor antagonists, but you do sometimes)
Identify the drug
Diclofenac
What class of antifungal is amphotericin B? What are some characteristics associated with it?
- polyene antifungal
- adverse effects: chills, hypotension, severe kidney toxicity
- cannot cross BBB so has to be administered intrathecally to treat CNS-located fungal infections
- it’s able to get to sites of infection despite being liposomally encapsulated because the inflammation increases permeability at the infection site
the rate of absorption/bioavailability/metabolism of salicylates is dependent upon
dosage formulation, gastric pH, food contents of the stomach, and particle size
What are the main points to remember about ethambutol?
- blocks arabinogalactan synthesis
- delays emergence of resistant TB
- lacks sterilizing effect
- affects eyes (optic neuritis, diminished visual acuity, and color blindness [red/green])
- contraindicated in children under 12
identify the compounds in the picture.
Top middle - salicylic acid
bottom middle - salicylamide
bottom left - acetylsalicylic acid (aspirin)
bottom right - diflunisal dolobid
________ are nitrogen isosteres of salicylic acid
Fenamic acids
Albuterol and Salmeterol Xinafoate both act on
beta-2 adrenoreceptors
What are the 4 I’s of Isoniazid?
Inhibits InhA (enoyl ACP reductase)
Inhibits CYP450
Inactivated by N-acetylation (NAT2)
Injures nerves and hepatocytes
True or False: triazoles are orally active.
True. they can be administered orally or IV for treatment of several types of systemic yeast infections (including oral thrush and cryptococcal meningitis)
Any condition that causes reduced kidney function over a period of time is known as
Chronic Kidney Disease (CKD)
Describe the 5 stages of CKD.
Stage 1 - kidney damage with normal kidney function (GFR > or = 90mL/min per 1.73m2) and persistent (>3 months) proteinuria.
Stage 2 - kidney damage with mild loss of kidney function (GFR 60-89 mL/min) and persistent (>3 months) proteinuria
Stage 3 - mild-to-severe loss of kidney function (GFR 30-59 mL/min)
Stage 4 - severe loss of kidney function (GFR 15-29 mL/min)
Stage 5 - kidney failure requiring dialysis or transplant for survival; also known as ESRD (GFR < 15mL/min)
Identify the drug in the picture and describe some of its characteristics.
Loratidine (claritin)
- is a non-sedating, 2nd generation antihistamine
- its metabolite on the right is desloratidine, which is more active H1 antagonist and antagonist of histamine release
- it does not cross the BBB even though it’s not a zwitterion
True or false: very few clinically encountered fungi have been shown to produce biofilms.
False - the majority have been shown to produce biofilms, including: Aspergillus, Saccharomyces, Cryptococcus, and Candida
Oseltamivir, Zanamivir, and Peramivir are all _______
Neuraminidase inhibitors
Is isoniazid more bactericidal or sterilizing?
Bactericidal
It has little sterilizing effect
A man had recurrent genital herpes that was effectively rtreated each time by acyclovir. The patient asked his physician why the treatment was not able to prevent recurrence. What would be the most appropriate answer for the physician to give?
Antiviral drugs have no effect on the latent state of viral disease.
Why would you use the prodrug form of a guanosine analog?
The prodrugs all have higher oral availability than their respective active drugs.
Therefore, IV formulations of the active drugs should only be used for serious infections and the prodrugs are preferred for oral indications
What cell surface receptors do influenza and herpes simplex bind to?
Flu - Sialic Acid
Herpes - HVEM (herpes virus entry mediator)
AKI is…
acute kidney injury - sudden and temporary loss of kidney function
What is the basis for selectivity for COX2 selective inhibitors?
COX-1 has a larger Ile residue at the active site, which restricts access by larger, relatively rigid side chain substituents such as sulfamoyl or sulfonyl side chains.
Thus, these side chains are characteristic of COX-2 inhibitors (they tend to be bigger structures)
This will be on the exam.
Describe how the MOA of nucleoside-analogs works.
After the initial phosphorylation by a viral kinase, each analog is phosphorylated twice more by cell kinases. At this point, they are now triphosphate molecules.
Ex. Acyclovir-triphosphate will then be used instead of a normal guanine (by herpes simplex’s DNA polymerase) during replication. Once the PPi is removed, there’s no 3’ position on the acyclovir for another connection to the growing deoxyribose-phosphate backbone, so there will be termination of the replication sequence (yay!)
Define the MOA of potassium sparing diuretics.
They work through various mechanisms that have an overall affect of increasing sodium and water secretion.
(reduces the amount of water in the body, but while otehr diuretics cause the body to lose potassium in the process, this kind does not)
Isoniazid is metabolized by ________ into the form of __________. In patients that are slow acetylators, _________ is the biproduct of the minor pathway. What is the problem that can arise from this pathway metabolite?
N-acetylation (NAT2)
Diacetyl hydrazide (non-toxic normal metabolite)
Hydroxy-hydrazide (hepatotoxic minor pathway metabolite)
The minor metabolite (HH) is hepatotoxic
_______ is a genetic disease causing uncontrolled growth of cysts in the kidney, eventually leading to kidney failure.
Polycystic kidney disease
Describe the MOA of terbutaline sulfate.
- Adrenergic receptor agonist
- is a beta adrenergic agonist
- stimulates AC, which increases intracellular cAMP levels
- increased cAMP is associated with relaxation of bronchial smooth muscles and inhibition of release of mediators of immediate hypersensitivity (like from mast cells)
What type of drug is specific to use in treating COPD?
Phosphodiesterase inhibitors - ex. Roflumilast
Identify each of the structures in the picture.
Top left - base thiazide structure
top right - methyclothiazide (enduron)
bottom left - hydrochlorothiazide (microzide)
bottom right - chlorothiazide (diuril)
To what class of drugs do these belong?
Allylamine Antifungals
In most cases, RNA viruses replicate in the ______, while DNA viruses replicate in the ______.
Cytoplasm
Host nucleus
_______ serve as viral attachment proteins (VAPs) that bind to specific host cell receptors for infection.
Viral glycoproteins (spikes)
identify the drug in the photo and describe some of its characteristics.
Cetirizine
long duration, 2nd gen antihistamine
highly selective for H1
no cardiotoxicity
levocetirizine (R-isomer) has a higher affinity and slower dissociation rate than the S-isomer
Identify the drug. Describe its MOA.
Allegra (fexofenadine)
It’s a peripheral H1-blocker
- blockage prevents the activation of H1 receptors
The picture below illustrates some of the groups present in sialic acid. How does the C1 carboxylate group interact with the binding site on neuraminidase?
It binds by ionic interactions
Identify the drugs and their class.
Left - Celecoxib
Right - Valdecoxib
Selective COX-2 Inhibitors
List exams of topical antihistamines.
Olopatadine
Ketotifen
Bepotastine
List examples of drugs used for herpes and influenza.
Herpes - Acyclovir, Ganciclovir, Cidofovir
Influenza - Oseltamivir, Zanamivir, Peramivir
What causes the red/orange color of urine, tears, sweat, and saliva that you see when taking rifamycins?
The extended conjugated double bonds
identify the drugs in the picture.
Top left - indapamide (thiazide-like diuretic)
Top right - metolazone (thiazide-like diuretic)
Bottom - chlorthaladone (thiazide-like diuretic)
Describe the MOA of rifamycins.
What is the SAR?
- *MOA:** They block transcription (DNA to mRNA) by inhibiting bacterial DNA-dependent RNA polymerase (DDRP)
- *SAR:**
- the naphthalene ring of rifamycins interact with the aromatic amino acids of DDRP through pi-pi bonding
- C1 and C8 phenolic groups form chelate with Zn ion of DDRP
- C21 and C23 alcohols form hydrogen bonds with DDRP
- reduction of any double bond in the structure reduces activity
Which organism is the most common opportunistic pathogenic fungus?
Candida albicans
Describe the purpose of dialysis.
During dialysis, a machine pumps blood out of the body through an artificial kidney (dialyzer) that filters out waste. The blood is then returned to the body.
Dialysis can be used to remove toxins and excess fluids from the body, as well as excess potassium.
