Pharmacology Flashcards
(153 cards)
1
Q
Describe the physiology of the RAAS?
A
- short and long term blood pressure regulation
- regulation of plasma volume
- modulation of sympathetic NS
- stimulates thirst
2
Q
What is renin?
A
- proteolytic enzyme produced from the JG cells
- regulates the formation of Angiotensin II
3
Q
What endogenous chemicals cause increases in angiotensinogen synthesis?
A
- insulin
- estrogens
- glucocorticoids
4
Q
What is the relationship of renin and sodium intake?
A
- increases in sodium will cause decreases in renin release
5
Q
How is renin secretion controlled?
A
- Intrarenal baroreceptor pathway - measures blood vol.
- Macula densa pathway - increase NaCl flux across MD decreases renin release
- Beta adrenergic receptor pathway - increases release
6
Q
What are the feedback inhibition pathways?
A
- Ang II stimulates AT1 receptors on JG cells to decrease renin release
- Ang II increases BP which decreases renin release
7
Q
What are the effects of Ang II?
A
- increases total peripheral resistance - direct vasoconstriction, sympathetic activation
- alters renal funciton - aldosterone release, constriction of renal arterioles, contraction of mesangial cells
- ## alters cardiovascular structure (via AT1 receptor activation)
8
Q
What is the mechanism of action of ACE inhibitors?
A
- inhibits conversion of Ang I to Ang II
- inhibits degradation of bradykinin
9
Q
What are the pharmacological effects of ACE inhibitors?
A
- increases release of renin (without effect)
- increases circulating Ang I
- decreases aldosterone release
- prevents/reverses remodeling of cardiovasculature
10
Q
What are the pharmacokinetics of ACE inhibitors?
A
- cleared renally
11
Q
What are the therapeutic uses of ACE inhibitors?
A
- hypertension
- congestive heart failure
- acute myocardial infaction
- high risk cardiovascular events
- diabetic nephropathy - reduces glomerular capillary pressure, delays disease progression
12
Q
What are some adverse effects associated with ACE inhibitors?
A
- hypotension at first does
- cough
- angioedema
- hyperkalemia
- acute renal failure (w/ pre-existing bilateral renal arterial stenosis)
- never use in pregnant patients
- antacids reduce the bioavailability
- NSAIDS reduce efficacy
- NSAIDS, potassium sparing diuretics and potassium supplements can lead to hyperkalemia
13
Q
What is the mechanism of action of ARBs?
A
- competitive antagonist of the AT1 receptor
- high affinity for the AT1 over the AT2
- inhibits aldosterone secretion
14
Q
How are ARBs differing from ACE inhibitors?
A
- ARBs reduce AT1 receptor activation more effectively
- ARBs maintain the AT2 receptor beneficial effects from Ang II binding
- ARBs should have no effect on bradykinin
15
Q
What are the therapeutic uses for ARBs?
A
- hypertension
- Reno-protective in type 2 DM
- congestive heart failure
16
Q
What are the adverse effects associated with ARBs?
A
- slight cough and rare angioedema
- don’t give to pregnant patients
- hypotension and renal failure in pts w/ RAS-dependent BP (renal artery stenosis)
- hyperkalemia
17
Q
What is the mechanism of action of direct renin inhibitors?
A
- block conversion of angiotensinogen to Ang I
- increase in renin in plasma due to no Ang II feedback
- no effect on bradykinin
18
Q
What are the therapeutic uses of direct renin inhibitors?
A
- hypertension (alone or in combo)
19
Q
What some adverse effects associated with direct renin inhibitors?
A
- slight cough and rare angioedema
- don’t give to pregnant patients
- hypotension and renal failure in pts w/ RAS-dependent BP (renal artery stenosis)
- hyperkalemia
20
Q
What are the different drugs used to inhibit RAS function?
A
- Angiotensin Converting Enzyme Inhibitors (cptopril, enalapril and enalaprilat)
- Angiotensin Receptor Blockers (losartan)
- Direct Renin Inhibitors (aliskiren)
21
Q
What are the different classes of diuretic drugs?
A
- Carbonic anhydrase inhibitors (acetazolamide)
- Na-K-2Cl symport inhibitors (furosemide)
- Na-Cl symport inhibitors (hydrochlorothiazide, chlorothiazide)
- K-sparing diuretics - ENaC inhibitors (amiloride, triamterene), Aldosterone antagonists (spironolactone, eplerenone)
- Osmotic diuretics (mannitol)
- Vasopressin receptor antagonists (demeclocycline, tolvaptan)
22
Q
What are the functions of the kidneys?
A
- filter large quantities of plasma
- maintain blood volume
- maintain acid-base balance
23
Q
What are the three components of the filter in the glomerular capillaries?
A
- fenestrated capillary
- basement membrane beneath the endothelial cells
- filtration slit diaphragms
24
Q
What is solvent drag?
A
- solutes are flowing with filtered water
25
What are the characteristics of the proximal tubule?
- 65% reabsorption of filtered Na
| - highly permeable to water
26
What are the characteristics of the Loop of Henle?
- Descending thin limb - highly permeable to water, low permeability to Na and urea
- Ascending thin limb - permeability to NaCl and urea but not water
- Ascending thick limb - actively reabsorbs NaCl and impermeable to water and urea
- 25% of filtered Na is reabsorbed
- Macula densa senses NaCl leaving the Loop
27
What is the significance of the Macula Densa?
- senses NaCl leaving the Loop of Henle
- when NaCl is high, constriction of the afferent arteriole of the nephron will occur
- constriction of the afferent arteriole will protect from salt and volume wasting
28
What are the characteristics of the distal convoluted tubule?
- actively transports NaCl
- impermeable to water
- "diluting segment of the nephron"
29
What are the characteristics of the collecting duct?
- fine adjustments in electrolyte composition are made
| - modulation done by aldosterone and ADH (modulating water permeability)
30
What are the seven mechanisms by which Na may cross the renal epithelium?
- sovent drag
- simple diffusion
- channel-mediated diffusion
- carrier-mediated diffusion
- ATP mediated transport
- symporters
- antiporters
31
Describe renal handling of Cl?
- reabsorption follows reabsorption of Na
- occurs paracellularly in the proximal tubule and thick ascending limb of the Loop
- occurs transcellularly in the proximal tubule, thick ascending limb, DCT and collecting duct
- symport, antiport and Cl channels
32
Describe renal handling of K?
- 80-90% reabsorbed in proximal tubule by diffusion and solvent drag
- secreted in DCT and collecting duct (channel mediated)
33
Describe renal handling of Ca?
- 70% is reabsorbed by proximal tubule by passive diffusion
- 25% is reabsorbed by the thick ascending limb
- 5% is reabsorbed in DCT
34
Describe renal handling of phosphate?
- 80% reabsorbed by proximal tubule
35
Describe renal handling of Magnesium?
- mainly reabsorbed in the thick ascending limb by a paracellular pathway due to a potential difference
36
Describe renal role in acid-base balance?
- reabsorb HCO3 and secrete protons
- substances not bound to protein are filtered
- substances bound to proteins are actively transported into nephron
37
Why is it important to know medications effects on ion transporters in the nephron?
- drug-drug interactions can occur because multiple drugs use same transporter (either for clearance or to get to activation site)
- will decrease efficacy of drugs that must cross these transporters to get to site of activation (furosemide)
38
What are the main concepts of diuretic action?
- disruption of sodium conservation (increase water excretion)
- sodium transporters and channels are targets
- will modify renal handling of other ions as well
- the nephron will try and compensate by reabsorbing Na downstream (leads to loss of potassium)
39
What is the mechanism of action of the carbonic anhydrase inhibitors (CAIs)?
- competitive inhibitor of carbonic anhydrase both within the cells and on the apical membrane
- blocks formation of protons to be exchanged for the reabsorption of Na
40
What are the effects on the urinary electrolytes that are excreted?
- increase in Na excretion
- increase in K excretion due to compensation for the early loss of Na in the tubule
- increase in HCO3 = decrease in urinary pH
41
What is the effect of CAIs on the macula densa?
- increases NaCl passing the macula densa
| - reducing GFR
42
What are the therapeutic effects of CAIs?
- open angle glaucoma
- altitude sickness
- Epilepsy
43
How does acetazolamide treat altitude sickness?
- makes the plasma more acidic which increases the breathing rate to try and bring back to homeostasis which will increase the amount of oxygen to the brain
44
What are the adverse effects of CAIs?
- hypokalemia - due to renal compensation
- urinary alkalization leading to renal stones, potassium wasting and worsen hepatic encephalopathy by diverting ammonia into systemic circulation
45
What is the mechanism of action of the Loop diuretics?
- inhibit the Na-K-Cl symporter
| - removes the potential across the epithelial cell stopping Ca++ and Mg++ reabsorption
46
What are the effects of Loop diuretics on the urinary electrolytes being excreted?
- major increase in Na
- increase in K
- increase in Cl
- no change in HCO3 excretion
- increase in Ca++ and Mg++
47
How does a Loop diuretic effect renal blood flow?
- stimulation of renin release leads to increase of RBF (GFR)
48
How is a Loop diuretic delivered to its site of action?
- bound to proteins so it is not filtered
| - passes through anionic transporters
49
What are the therapeutic uses for Loop diuretics?
- Acute pulmonary edema (increasing venous capacitance)
- Congestive heart failure (depleting volume)
- Hypercalcemia (removing gradient)
50
What are some adverse effects of Loop diuretics?
- hyponatremia and hypokalemia
- hypocalcemia
- ototoxicity - alteration in inner ear electrolytes
- hyperuricemia
- hyperglycemia
- NSAIDs will reduce efficacy
51
What is the mechanism of thiazides and thiazide-like diuretics?
- inhibition of the Na-Cl symporter
| - weakly inhibits the carbonic anhydrase
52
What effect does thiazides have on urinary excretion of electrolytes?
- increase Na
- increase K - due to renal compensation
- increase Cl
- small increase in HCO3 - due to weak CAI
- decreases excretion of Ca++
53
How is a thiazide drug brought to its site of action?
- delivered via an anion transporter
54
What are the therapeutic uses of thiazides?
- Hypertension
- mild edema
- Nephrogenic diabetes insipidus
- Calcium nephrolithiasis and osteoporosis
55
What are some adverse effects of thiazides?
- hypokalemia, hyponatremia
- hyperuricemia
- hyperglycemia and hyperlipidemia
- erectile dysfunciton
- NSAIDs will reduce efficacy
56
What are two types of Potassium sparing diuretics?
- ENaC inhibitors (triamterene and amiloride)
| - Aldosterone antagonists (spironolactone and eplerenone)
57
What are the mechanisms of action of ENaC inhibitors?
- block Na reabsorption by blocking the Na channels on the apical side of the cell
58
What are the mechanisms of action of Aldosterone antagonists?
- block cytosiolic mineralocorticoid receptors and reduces expression of the ENaC transporters
59
What are the therapeutic uses for potassium sparing diuretics?
- prevent hypokalemia
- Liddle syndrome and cystic fibrosis
- primary hyperaldosteronism, hepatic cirrhosis, CHF
60
What are some adverse effects associated with potassium sparing diuretics?
- hyperkalemia
- gynecomastia, impotence, hirsutism, dicreased libido
- metabolic acidosis
61
What is an example of an osmotic diuretic and where does it effect the nephron?
- mannitol
| - entire nephron length
62
What is the mechanism of action of osmotic diuretics?
- increases the osmolality of tubular fluid
- reducing passive reabsorption of NaCl in ascending lip of the Loop
- inhibits the release of renin
63
How does mannitol effect urinary excretion and renal hemodynamics?
- increases all electrolytes being excreted
| - increases RBF and maintains GFR
64
How is mannitol used therapeutically?
- minimize acute tubular necrosis
| - reduces pre/post op CSF and intraocular pressure
65
What are some adverse effects associated with osmotic diuretics?
- contraindicated in heart failure and active cranial bleeding
- flash pulmonary edema
66
What are the effects of vasopressin (ADH)?
- vasoconstriciton with V1a stimulation
- increase Na and urea reabsorption transporters as well as the movement of aquaporins in the collecting duct (with V2)
- net result is increased water retention and concentration urine
67
What are some vasopressin receptor antagonists?
- demeclocycline
| - tolvaptan
68
What is the mechanism of aciton of vasopressin receptor antagonists?
- competitive antagonists of the V2 receptors
| - increase water excretion without change in electrolyte excretion
69
How is a vasopressin receptor antagonist used therapeutically?
- hyponatremia associated with SIADH
70
What adverse effects are associated with demeclocycline and tolvaptan?
- demeclocycline - all tetracycline side effects and diabetes insipidus
- tolvaptan - hyperglycemia
71
Losartan
- ARB
72
Aliskiren
- direct renin inhibitor
73
Captopril, Enalipril, Enaliprilat
- ACE inhibitor
74
Acetozolamide and Methazolamide
- Carbonic Anhydrase Inhibitors
75
Demeclocycline and Tolvaptan
- Vasopressin receptro antagonists
76
Furosemide
- Loop diuretic
77
Chlorothiazid and Chlorothiadone
- Na-Cl inhibitor
78
Triamterene and amiloride
- ENaC inhibitor
79
Spironolactone and eplerenone
- aldosterone antagonist
80
Mannitol
- osmotic diuretic
81
What are some drugs that are used as anti-influenza medications?
- amantadine
- oseltamivir
- zanamivir
82
What are some drugs that are used as anti-herpes medications?
- acyclovir
- valacyclovir
- ganciclovir
- valganciclovir
- cidofovir (with probenecid)
- foscarnet
83
What are some drugs that are used as anti-viral hepatitis medications?
- interferon alpha
- ribavirin
- simeprevir
- sofosbuvir
- entecavir
84
What are three general properties of antiviral drugs?
- often have higher host toxicity than antibiotics
- most are nucleosides, used to prevent replication of viral nucleic acids
- they are predominantly virustatic and host immune system clears the infection
85
What is the most effective approach to prevent influenza infection?
- vaccination
86
What is the mechanism of action of amantadine?
- blocks influenza A M2 ion channel
| - interferes with viral uncoating
87
What are the pharmacokinetics of amantadine?
- orally available and well absorbed in GI
| - eliminated renally
88
WHat are the therapeutic uses of amantadine?
- not currently recommended because of resistance
89
What are the adverse effects associated with amantadine?
- lowers the seizure threshold
- no use in pregnancy
- interacts with anticholinergics
90
What is the mechanism of action of oseltamivir?
- competitive inhibitor of neuraminidase
| - interferes with spread by preventing release
91
What are the pharmacokinetics of oseltamivir?
- orally available
- metabolized in the liver
- excreted by the kidneys
92
What are the therapeutic effects of oseltamivir?
- prevention/treatment of influenza A and B
| - must be given with 48 hours of symptom onset
93
What are the adverse reactions and degree of resistance for oseltamivir?
- slight nausea and bomiting
| - variable resistance in seasonal flu
94
What are some characteristics of zanamivir?
- neuraminidase inhibitor
- low or bioavailability
- inhalation administration - can cause bronchospasms
95
What are the characteristics of HSV infection?
- genital warts
- infection in mouth
- miningitis
- encephalitis
96
What are the characteristics of VZV infection?
- chickenpox
| - shingles
97
What are the characteristics of CMV?
- infects immunocompromised
| - retinitis, lung and GI infection
98
What is the drug type of acyclovir?
- nucleoside analog for HSV and VZV
99
What is the mechanism of action of acyclovir?
- conversion by viral kinase into acyclo-GMP
- conversion of acyclo-GMP by host kinase into acyclo-GTP
- acyclo-GTP will cause chain termination by inhibiting viral DNA polymerase
100
How does resistance develop for acyclovir?
- viral kinase deficiency or mutation
101
What are the pharmacokinetics of acyclovir?
- orally effective with low bioavailability
| - widely distributed and eliminated unchanged by kidneys
102
What are the characteristics of valacyclovir?
- it is a prodrug that increases the bioavailability
103
What are the therapeutic uses of acyclovir?
- HSV all infections
- VZV can lessen the infection time
- used for more severe cases
104
What are the adverse effects associated with acyclovir?
- neurotoxicity
| - reversible renal dysfunction
105
What type of medication is ganciclovir?
- nucleoside analog for CMV
106
What is the mechanism of action of ganciclovir?
- converted by the viral kinase and then by host kinase and then inhibits viral DNA polymerase
107
What are the pharmacokinetics of ganciclovir?
- orally effective with low bioavailability
| - eliminated unchanged in the kidneys
108
What are the characteristics of valganciclovir?
- increased oral bioavailability
109
What are the therapeutic uses of ganciclovir?
- restricted due to toxicity
- treats CMV retinitis
- prevention of CMV in transplant pts
110
What are the adverse effects associated with ganciclovir?
- myelosuppression (neutropenia, thrombocytopenia)
| - CNS (fever, convulsions)
111
What type of drug is cidofovir?
- nucleotide analog for CMV
112
What is the mechanism of action of cidofovir?
- converted only by host kinase
| - inhibits viral DNA polymerase
113
What are the pharmacokinetics of cidofovir?
- poor oral bioavailbility
| - used with probenecid to increase efficacy
114
What is the therapeutic use of cidofovir?
- CMV retinitis in AIDS pts
115
What are the adverse effects associated with cidofovir?
- nephrotoxicity because of probenecid use
- neutropenia
- possible carcinogen
116
What type of drug is forcarnet?
- non-nucleoside analog for HSV and CMV
117
What is the mechanism of action of forcarnet?
- effective on all herpesviruses and HIV
- inhibits herpes DNA polymerase
- inhibits HIV reverse transcriptase
118
What are the pharmacokinetics of forcarnet?
- poor oral bioavailability
| - most eliminated unchanged by the kidney
119
What is the therapeutic effect of forcarnet?
- only for drug resistant herpes viruses
120
What are the adverse effects associated with forcarnet?
- nephrotoxicity
| - electrolyte disturbances (hypocalcemia)
121
What are some characteristics associated with HCV?
- considered curable because no genomic integration
- no vaccine
- major risk for hepatocellular carcinoma
122
What is the standard treatment for HCV?
- 24-48 week treatment with combination of interferon alpha and ribavirin
123
What is the mechanism of action of Ribavirin?
- broad spectrum against DNA and RNA viruses
- converted by host kinases
- depletes GTP pools within cells
- unknown causing lethal mutations in RNA viruses
124
What are the pharmacokinetics of Ribavirin?
- given orally or inhalation
- high Vd and long half life
- eleminated by hepatic metabolism and renal excretion
125
What are the therapeutic uses of Ribavirin?
- in fixed dose with INF alpha for HCV
| - pediatric RSV brochiolitis and pneumonia
126
What are the adverse effects associated with Ribavirin?
- hemolytic anemia
| - contraindicated during pregnancy
127
What is the mechanism of action of INF-alpha2a?
- not directly acting on viral proteins
- activates Jak-STAT signalling to increase immune response to stop viral replication
- stimulates MHC class I and II
128
What are the characteristics of pegylated INF-alpha2a?
- interferon attached to large polyethylene glycol
| - increases the half life
129
What are the pharmacokinetics of INF-alpha2a?
- well absorbed in SC or IM injection
| - pegylation increases serum concentration and prolongs duration
130
What are the therapeutic uses for INF-alpha2a?
- chronic HCV and HBV in combo with other drugs
- genital warts associated with HPV
- cancers - Kaposi's, lymphomas, melanoma
131
What are some adverse effects associated with INF-alpha 2a?
- Flu-like syndrome
- Neuropsychiatric - depression
- Myelosuppression
132
What type of drug is simeprevir?
- direct acting antiviral for HCV
133
What is the mechanism of action of simeprevir?
- inhibits viral protease
| - analogous to HIV protease inhibitors
134
What are the pharmacokinetics of simeprevir?
- given in combo with ribavirin/INF
| - metabolized by CYP3A4
135
What are the adverse effects associated with simeprevir?
- photosensitivity and rash
| - contraindicated in pregnancy
136
What type of drug is sofosbuvir?
- direct acting antiviral for HCV
137
What is the mechanism of action for sofosbuvir?
- nucleotide prodrug metabolized to inhibit viral RNA polymerase
138
What are the pharmacokinetics of sofosbuvir?
- in combo with ribavirin and INF
| - efficacy across all HCV genotypes and low resistance
139
What are some characteristics of HBV?
- DNA virus that integrates into host genome
- vaccination available and effective
- therapy used for persistant elevated serum ALT and HBV DNA
140
What are the treatment options for HBV?
- Pegylated INF
- entecavir
- Tenofovir
- Lamivudine
141
What is the mechanism of action of Entecavir?
- converted by host cell kinase
| - inhibits HBV DNA polymerase
142
What are the pharmacokinetics of entecavir?
- orally available
| - excreted unchanged in urine
143
What are the therapeutic uses of entecavir?
- first line treatment for chronic HBV (administered for 1 year)
- not active against HIV
144
What are the adverse effects associated with entecavir?
- risk of lactic acidosis and hepatomegaly when fatty liver
145
What drugs are classified as nucleoside revers transcriptase inhibitors?
- zidovudine
- lamivudine
- emtricitabine
- tenofovir
146
What drugs are classified as non-nucleotide revers transcriptase inhibitors?
- efavirenz
| - nevirapine
147
What drugs are classified as protease inhibitors?
- lopinavir/ritonavir
| - atazanavir
148
What drugs are classified as integrase inhibitors?
- raltegravir
149
What drugs are classified as fusion inhibitors?
- enfuvirtide
| - maraviroc
150
What are the goals for antiretroviral treatment?
- maximal suppression of plasma HIV RNA
- restoration and/or preservation of immune function
- limitation of drug adverse effects
- reduction in HIV-associated morbidity and mortality
151
What are the antiretroviral treatment guidlines?
- treatment recommended for all symptomatic and asymptomatic HIV infected patients
- a 3 drug regimine is the minimum standard of care
- therapeutic failure is an increase in viral load
- treatment failure requires initiation of a completely new regimen
152
What are some consequences of antiretroviral therapy?
- lifelong therapy
- HIV lipodystrophy syndrome
- complex pharmacokinetics with drug associations
- immune reconstitution inflammatory syndrome
153
What is IRIS?
- reversal of immunodeficiency in pts with low CD4 counts
- usually occurs in initial treatment phase
- usually due to opportunistic infection with an accelerated inflammatory reaction
