Term
|
Definition
| Blood levels of ( ) can estimate GFR and kidney function. |
|
|
Term
|
Definition
excretion of waste products (urea, uric acid, creatinine)
regulation of NaCl, electrolyte content, volume of extracellular fluid
acid-base balance through bicarbonate buffering system
releasing hormones (erythropoietin, renin, cacitriol) |
|
|
Term
|
Definition
| stimulates the bone marrow to make RBCs produced by peritubular capillary endothelial cells in the kidney |
|
|
Term
|
Definition
maintain calcium for bones and for normal chemical balance in the body
active form of vitamin D |
|
|
Term
|
Definition
| vessels of the renal circulation |
|
|
Term
|
Definition
series of straight capillaries in the medulla
lie parallel to the loop of henle
branch off the efferent arterioles of juxtamedullary nephrons |
|
|
Term
1) participate in counter current exchange to concentrate urine
2) blood supply to the medulla |
|
Definition
| two functions of the vasa recta |
|
|
Term
| arcuate artery -> afferent arteriole -> passes through glomerulus -> 20% of blood enters Bowman's capsule -> 80% of blood enters efferent arteriole -> peritubular capillaries -> vasa recta -> venules -> vein |
|
Definition
|
|
Term
| Bowman's capsule -> proximal tubule -> descending loop of Henle -> ascending loop of Henle -> distal tubule -> collecting duct -> pelvis -> ureter -> bladder |
|
Definition
| path of urine formation in nephrons |
|
|
Term
| function of peritubular capillaries |
|
Definition
major function is to carry away in the renal veins water and solutes reabsorbed by the tubular epithelium.
also, deliver blood to tubular secretory sites where certain substances are secreted from the plasma into tubular fluid. |
|
|
Term
|
Definition
short loop of Henle
efferent arteriole gives rise to peritubular capillaries which envelope the entire nephron |
|
|
Term
| juxtamedullary glomerulus |
|
Definition
long loop of Henle that extend deep into the medulla
efferent arterioles give rise to 2 different capillary beds: peritubular capillaries which envelop the proximal and distal convoluted tubules and the vasa recta
the glomeruli are located at the junction of the medulla and cortical regions of the kidney |
|
|
Term
|
Definition
responsible for the formation of glomerular filtrate
afferent arteriole is larger in diameter than the efferent arteriole |
|
|
Term
endothelial cells: inner layer with pores
basement membrane: thick, contains negatively charged glycoproteins, pores
foot process: negatively charged with slit pores |
|
Definition
| 3 layers of the glomerular barrier |
|
|
Term
1) high hydrostatic pressures
2) large pores in the capillary endothelium
3) large pores in the basement membrane
4) filtration slits between pedicels |
|
Definition
| The glomerular capillaries are 100-400 times more permeable to ions than other capillaries in the body because of... |
|
|
Term
|
Definition
| side of membrane that faces the peritubular space |
|
|
Term
|
Definition
| side of the membrane that faces the luminal space |
|
|
Term
Driving force is NaKATPase which brings in K and takes out Na. A symporter brings in Na with aKG (from low concentration to high). An antiporter takes out aKG and brings in the acid. The acid then passes into the lumen by facilitated diffusion.
*location of antiporter and symporter is the basolateral side |
|
Definition
| mechanism of organic acid secretion in the proximal tubule |
|
|
Term
| Driving force is the NaKATPase which brings in K and takes out Na. Low concentration of Na in the cell allows an antiporter to bring in Na while taking out H (from a low concentration to high). Another antiporter brings in H and takes out the base into the lumen which entered the cell through facilitated diffusion. |
|
Definition
| mechanism of organic base secretion in the proximal tubule |
|
|
Term
| Proximal Convoluted Tubule |
|
Definition
60-70% of filtered Na reabsorbed
100% of glucose, AA, vitamins, proteins reabsorbed
80-90% filtered bicarbonate reabsorbed
site of active secretion of weakly acidic and weakly basic organic compounds |
|
|
Term
| Driving force is NaKATPase which brings in K and takes out Na. This drives the flow of Na inward while an antiporter takes H out to lumen. Bicarbonate in lumen will combine with H forming carbonic acid through carbonic anhydrase. Breaks down into CO2 and water which can freely diffuse into epithelial cells, turn into bicarbonate and be reabsorbed into the blood. |
|
Definition
| mechanism of reabsorbing bicarbonate in the proximal convoluted tubule |
|
|
Term
|
Definition
water moves out
concentrate urine (most important function) |
|
|
Term
|
Definition
20-25% of filtered Na reabsorbed
loop diuretics (furosemide) inhibit Na2ClK symport that is located in this area |
|
|
Term
| a counter current multiplier mechanism involving tubules a source of energy, which is supplied by the Na pump and the active transport of NaCl in the ascending loop of Henle differences in permeability between tubules carrying fluid in opposite directions diffusion of NaCl into vessels taking blood down into the medulla and out of vessels passing back up to the cortex, maintaining hypertonicity in the medulla |
|
Definition
| Main factors of the counter current mechanism |
|
|
Term
|
Definition
5-10% filtered Na reabsorbed
thiazide diuretics inhibit Na/Cl symport found on the apical membrane |
|
|
Term
| late distal tubule and collecting duct |
|
Definition
2-3% of Na reabsorbed
aldosterone controls Na reabsorption
amiloride and triamterene block Na reabsorption
antidiuretic hormone controls water reabsorption |
|
|
Term
afferent arteriole
efferent arteriiole
distal tubule/loop of Henle
mesangial cells |
|
Definition
| juxtaglomerular apparatus consists of... |
|
|
Term
|
Definition
cells found in the afferent arteriole
release renin |
|
|
Term
|
Definition
localized in the distal tubule/loop of Henle
sense Na concentration |
|
|
Term
|
Definition
| As more NaCl is delivered to the DCT, GFR ( ) |
|
|
Term
uptake of Na, K, and 2Cl
generation of adenosine
activation of adenosine A1 receptor
increase in Ca in the mesangial cells
propagation of Ca signal through gap junction
vasoconstriction and inhibition of renin secretion |
|
Definition
| molecular mechanisms of tubuloglomerular feedback. |
|
|
Term
|
Definition
causes pathological changes in the vasculature and hypertrophy of the left ventricle
the principle cause of stroke
a major risk factor for coronary artery disease, myocardial infarction, sudden cardiac death
a major contributor to heart failure, kidney failure, dissecting aneurysm of the aorta |
|
|
Term
|
Definition
inhibit myocardial contractility
decrease ventricular filling pressure
decrease venous tone
decrease blood volume |
|
|
Term
| reduce sympathetic vascular resistance |
|
Definition
cause relaxation of muscles
inhibit vasoconstriction of vessels |
|
|
Term
|
Definition
|
|
Term
| HR (increased by SNS and catecholamines and decreased by PSNS) and stroke volume |
|
Definition
|
|
Term
| contractility (increased by SNS and catecholamines) and preload |
|
Definition
| stroke volume is determined by |
|
|
Term
| venous tone (increased by SNS and catecholamines) and intravascular volume (increased by thirst and Na/water retention) |
|
Definition
| preload is determined by... |
|
|
Term
| direct innervation (increased by a1 receptors), circulating regulators (increased by catecholamines and ATII), and local regulators (decreased by NO, H, adenosine and prostacylins and increased by endothelin, ATII, O2) |
|
Definition
|
|
Term
| atria and pulmonary vasculature |
|
Definition
low pressure sensors
volume barorecptors that stimulate the release of ADH |
|
|
Term
| the aortic arch, carotid sinus, and juxtaglomerular apparatus |
|
Definition
|
|
Term
| hydrocholorthiazide, chlorthalidone, indapamide, metolazone |
|
Definition
thiazide diuretics
has a benzene ring and a sulfonamide |
|
|
Term
inhibit Na/Cl transporter at the lumenal surface of the distal convoluted tubule
short term: decrease CO
long term: decrease peripheral vascular resistance (decrease Na in smooth muscle and decrease muscle sensitivity to vasopressors)
natriuresis of about 5-8% of filtered Na
shallow dose response curve
onset is slow (2-4 weeks)
less effective in renal failure |
|
Definition
| mechanism of action of thiazide diuretics |
|
|
Term
| hypokalemia hyponatremia hyperuricemia (gout): increase reabsorption in PCT due to volume depletion and decreased excretion in PCT due to competition with diuretics increase glucose levels (due to decreased K levels which leads to less insulin release) hyperlipidemia (increased LDL) erectile dysfunction nocturia |
|
Definition
| adverse effects of thiazide diuretics |
|
|
Term
increased delivery of Na to the collecting duct activates Na/K exchanger resulting in K loss
activation of renin-angiotensin-aldosterone system as a compensatory mechanism (aldosterone increases Na and decreases K and H) |
|
Definition
| mechanisms of hypokalemia by thiazide diuretics |
|
|
Term
| thiazides -> decreased distal tubule reabsorption of Na -> increased urine -> decreased EC volume -> increased proximal Na and water reabsorption -> decreased distal delivery of Na and water -> decreased urination |
|
Definition
| mechanism of action of the paradoxical effect of thiazide diuretics on NDI |
|
|
Term
furosemide, bumetanide, torsemide, ethacrynic acid
bet f |
|
Definition
|
|
Term
inhibit Na2ClK cotransporter in the thick ascending limb of the loop of Henle
inhibit 20-25% of Na reabsorption
direct vascular effects: increase venous capacitance and thereby decreasing left ventricular filling pressure
blocks tubular-glomerular feedback by inhibiting salt transport into macula densa cells (causes renin release)
short duration of action, rebound Na retention offsets the effectiveness of natriuresis |
|
Definition
| mechanism of action of loop diuretics |
|
|
Term
excessive salt and water depletion
hypokalemia
hypomagnesemia (predisposes arrythmias)
hypocalcemia
hyperuricemia (reduced uric acid secretion in PCT)
ototoxicity with deafness (more common with furosemide) |
|
Definition
| adverse effects of loop diuretics |
|
|
Term
aminoglycosides (synergism of ototoxicity caused by both drugs)
anticoagulants (increased anticoagulant activity, displaces plasma protein binding)
digitalis glycosides (increased digitalis induced arrythmias)
lithium (increased plasma levels of lithium, reduced renal clearance)
propranolol (increased plasma levels of propranolol)
sulfonylureas (hyperglycemia due to decreased insulin release) |
|
Definition
| loop diuretic drug interactions |
|
|
Term
| amiloride, triamterene, spironolactone |
|
Definition
|
|
Term
K sparing diuretic
act at the collecting duct spironolactone and its active metabolite canrenone compete with aldosterone for its receptors. Results in less Na channels on the apical membrane, less NaKATPase channels on basolateral membrane, and less K channels on the apical membrane) natriuresis is 2-3% of filtered Na used together with thiazides and loop diuretics |
|
Definition
| mechanism of action of spironolactone |
|
|
Term
K sparing diuretic
act at the collecting duct block the Na channel at the apical surface of the renal tubule natriuresis is 2-3% of filtered Na used together with thiazides and loop diuretics |
|
Definition
| mechanism of action of amiloride and triamterene |
|
|
Term
hyperkalemia (more common with renal disease, elderly, or combination treatment of ACEi)
hyponatremia
spironolactone has a progestogenic and anti androgenic effect (impotence, menstrual irregularities)
nausea, vomiting, leg cramps |
|
Definition
| adverse effects of K sparing diuretics |
|
|
Term
| propranolol, timolol (glaucoma - inhibits the production of aqueous humor), nadolol |
|
Definition
|
|
Term
competitively block the effects of NE
have equal affinity for B1 and B2 receptors
do not have intrinsic sympathomimetic activity
decrease heart rate
reduce force of cardiac contraction
block release of renin (by blocking B1 receptors in the kidney)
peripheral resistance initially increases as a result of blocking B2 receptors in blood vessels
long term use of B blockers decrease peripheral resistance |
|
Definition
| mechanism of action of non selective B blockers |
|
|
Term
heart failure if there is pre existing poor left ventricular function
excessive bradycardia
bronchospasms in asthmatics
hypoglycemia in diabetics by blocking glucose release (B2 receptor mediated action)
increased triglycerides
CNS effects: sleep disturbance, vivid dreams, hallucinations
sudden withdrawal symptoms
additive effects when diltiazem or verapamil is coadministered |
|
Definition
| adverse effects of non selective B blockers |
|
|
Term
| metoprolol, atenolol, bisoprolol, betaxolol (glaucoma) |
|
Definition
selective B1 blockers
have a single benzene ring |
|
|
Term
have greater affinity for B1 than B2
cardioselective B blockers
produce less bronchoconstriction and other B2 mediated effects
their selectivity for B1 is not absolute
low or no intrinsic sympathomimetic activity
decrease heart rate
reduce force of cardiac contraction
block the release of renin |
|
Definition
| mechanism of action of selective B1 blockers |
|
|
Term
withdrawal symptoms with abrupt discontinuation
AV block
bradycardia
pulmonary edema |
|
Definition
| adverse effects of selective B1 blockers |
|
|
Term
| acebutolol, penbutolol, pindolol |
|
Definition
| B blockers with intrinsic sympathomimetic activity |
|
|
Term
B blockers with intrinsic sympathomimetic activity
penbutolol is nonselective with ISA and is highly lipid soluble. |
|
Definition
| mechanism of action of penbutolol |
|
|
Term
|
Definition
| combined a and B blockers |
|
|
Term
nonselective B blocker with partial agonist activity (B2) and a selective a1 blocker
decreases HR and CO as a result of B1 blockade and it decreases PVR as a result of a1 blockade |
|
Definition
| mechanism of action of labetalol |
|
|
Term
non selective B blocker and a selective a1 blocker (1:10, a1:B)
also has antioxidant and antiproliferative effects (beneficial effects for patients with congestive heart failure) |
|
Definition
| mechanism of action of carvedilol |
|
|
Term
pindolol non selective
partial agonist activity for pindolol is B2>B1
decrease in heart rate and contractility with pindolol are weakened by its ISA effect |
|
Definition
| mechanism of action of pindolol |
|
|
Term
B blocker with intrinsic sympathomimetic activity
acebutolol is cardioselective
ISA is selective for B1
less likely to cause bradycardia and cold extremities |
|
Definition
| mechanism of action of acebutolol |
|
|
Term
|
Definition
| B blocker with nitric oxide potentiating vasodialatory effect |
|
|
Term
B blocker with nitric oxide potentiating vasodilatory effects
B1 selective at 5 mg but loses its selectivity at >10mg
less B blocker related side effects such as fatigue, bradycardia, and impotence |
|
Definition
| mechanism of action of nebivolol |
|
|
Term
|
Definition
| sulfhydryl containing ACE inhibitor |
|
|
Term
|
Definition
| phosphonate containing ACE inhibitor |
|
|
Term
enalapril, benazepril, lisinopril, quinapril
qbel |
|
Definition
| dicarboxylate containing ACE inhibitors |
|
|
Term
block the formation of angiotensin II and inhibit the breakdown of brandykinin, a vasodilator
antihypertensive action is mainly due to decreasing PVR
decrease both venous and arterial pressure
reduce angiotensin-induced aldosterone secretion which prevents the compensatory increase in Na retention and plasma volume
renal Na retention is decreased and renal K retention is increased. |
|
Definition
| mechanism of action of ACE inhibitors |
|
|
Term
cause fetal morbidity and mortality
cause renal failure in patients with bilateral renal artery stenosis
dry cough
rash (captopril b/c of SH group)
angioedema
abnormal taste sensation (SH group) |
|
Definition
| adverse effects of ACE inhibitors |
|
|
Term
antihypertensive action of ACEi is augmented by diuretics
interact with K sparing diuretics and K supplements causing hyperkalemia
increase serum levels of lithium
NSAIDs reduce the effects of ACEi by blocking synthesis of vasodilatory prostaglandins |
|
Definition
| ACE inhibitor drug interactions |
|
|
Term
| angiotensin II receptor type 1 |
|
Definition
located in vascular and myocardial tissue, brain, kidney, and adrenal cortex
mediates feedback inhibition of renin release
mediates aldosterone release |
|
|
Term
| angiotensin II receptor type 2 |
|
Definition
located in the adrenal medulla, kidney, brain, fetal vascular smooth muscle
mediates vascular development |
|
|
Term
losartan, candesartan, irbesartan, valsartan, telmisartan, eprosartan
(LIVE CT) |
|
Definition
| angiotensin II receptor antagonists |
|
|
Term
selective for AT1 receptor subtypes (10,000 fold selective)
blocks binding of angiotensin II to AT1 receptor
by preventing the effects of angiotensin II they relax smooth muscle and promote vasodilation, increase renal salt and water excretion (by blocking the release of aldosterone), reduce plasma volume
cough is not an adverse effect |
|
Definition
| mechanism of action of angiotensin II receptor antagonists |
|
|
Term
hypotension
hyperkalemia
reduced renal function
should not be administered to patients who are pregnant or breast feeding |
|
Definition
| adverse effects of angiotensin II receptor antagonists |
|
|
Term
|
Definition
| angiotensin II has a ( ) effect on renin release |
|
|
Term
|
Definition
|
|
Term
renin inhibitor
blocks the first and rate limiting step of the renin-angiotensin-aldosterone system
does not effect kinin metabolism |
|
Definition
| mechanism of action of aliskiren |
|
|
Term
may cause fetal and neonatal morbidity and morality
head and neck angioedema
hypotension
hyperkalemia
renal dysfunction
cough |
|
Definition
| adverse effects of aliskiren |
|
|
Term
| reduces blood concentration of furosemide |
|
Definition
| drug interactions of aliskiren |
|
|
Term
angiotensin I
angiotensin II
angiotensin I and II |
|
Definition
ACE inhibitors increase levels of ( )
ARBs increase levels of ( )
renin inhibitors block both ( ) and ( ) |
|
|
Term
|
Definition
| Ca channel blockers, non-dihydropyridines |
|
|
Term
nifedipine, amlodipine, felodipine
(FAN) |
|
Definition
| Ca channel blockers, dihydropyridines |
|
|
Term
block L-type Ca channels of blood vessels and the heart
arterial dilation (dihydropyridines are more potent)
coronary artery dilation: prevention or relief of coronary vasospasm improves coronary blood flow
negative chronotropic effect: verapamil and diltiazem slow the rate of firing of the SA node and slow conduction of impulse through the AV node
reduced cardiac contractility: particularly verapamil has a negative inotropic effect
have little effect on venous beds |
|
Definition
| mechanism of action of non-dihydropyridines Ca channel blockers |
|
|
Term
block L-type Ca channels of blood vessels
arterial dilation: more potent vasodilators
short acting dihydropyridines produce a rapid drop in blood pressure and reflex SNS activation leads to tachycardia
coronary artery dilation; prevention or relief of coronary vasospasms improves myocardial flow
have little effect on venous beds |
|
Definition
| mechanism of action of dihydropyridine Ca Channel blockers |
|
|
Term
reduced cardiac contractility: can precipitate heart failure in patients with pre-existing poor left ventricular function
bradycardia and heart block
altered gut motility; constipation |
|
Definition
| adverse effects of non-dihydropyridine Ca channel blockers |
|
|
Term
arterial dilation: headache, flushing, dizziness, ankle edema.
tachycardia and palpitations
nausea and heartburn (nifedipine) |
|
Definition
| adverse effects of dihydropyridine Ca channel blockers |
|
|
Term
| hydralazine, minoxidil, nitroprusside |
|
Definition
|
|
Term
vasodilator
causes direct vasodilation of arterial smooth muscle
does not dilate epicardial coronary arteries or relax venous smooth muscle
vasodilation of hydralazine is a powerful stimulator of the SNS
postural hypotension is not a problem |
|
Definition
| mechanism of action of hydralazine |
|
|
Term
vasodilator
parent drug is inactive and has to be metabolized to minoxidil sulfate which activates the K/ATP channels
allows K into smooth muscles causing hyperpolarization and relaxation of smooth muscle
produces arterial vasodilation but has essentially no effect on venous side
is associated with reflex increase in myocardial contractility and CO
salt and water retention due to increased proximal renal tubular reabsorption, which is secondary to reduced renal profusion pressure
should never be given alone; should be given with a diuretic to avoid fluid retention or a B blocker to avoid reflex tachycardia |
|
Definition
| mechanism of action of minoxidil |
|
|
Term
a nitrovasodilator that releases NO
NO activates guanylyl cyclase
mimics the production of NO by vascular endothelial cells
tolerance develops to nitroglycerin but not nitroprusside
dilates both arteries and veins
must be given by continuous IV infusion to be effective
primarily used to treat hypertensive emergencies |
|
Definition
| mechanism of action of nitroprusside |
|
|
Term
headache, dizziness, flushing
tachycardia
fluid retention
a systemic lupus erythematosis-like syndrome (hydralazine)
thiocyanate accumulation: causes tachycardia, sweating, hyperventalation, metabolic acidosis (nitroprusside) |
|
Definition
| adverse effects of vasodilators |
|
|
Term
| prazosin, terazosin, doxazosin |
|
Definition
|
|
Term
binds to postsynaptic a1 receptor (competative)
inhibits vasoconstriction induced by endogenous catecholamines
lowers blood pressure by: reducing tone in arteries and dilating veins which reduces venous return and therefore cardiac output |
|
Definition
| mechanism of action of a1 blockers |
|
|
Term
postural hypotension, especially with the first dose
lethargy, headache dizziness
palpitation from reflex cardiac stimulation
nausea
impotence
diarrhea |
|
Definition
| adverse effects of a1 blockers |
|
|
Term
alcohol: additive hypotension effect
sildenafil: can lead to sympathomimetic hypotension
sympathomimetics: can decrease hypotensive activity |
|
Definition
| a1 blocker drug interactions |
|
|
Term
| phenoxybenzamine, phentolamine |
|
Definition
| non selective alpha blockers |
|
|
Term
phenoxybenzamine is a long acting noncompetitive (irreversible) antagonist at bock a1 and a2 receptors
phentolamine is a short acting competitive antagonist at both a1 and a2 receptors
decrease PVR and blood pressure
venodilation is prominent
cardiac stimulation: cardiovascular reflexes and enhanced NE release due to a2 antagonism
mainly used to treat hypertension in patients due to pheochromocytoma |
|
Definition
| mechanism of action of non selective alpha blockers |
|
|
Term
postural hypotension
reflex tachycardia
arrhythmia
fatigue, headache, dizziness
nasal congestion
ejaculation dysfunction |
|
Definition
| adverse effects of non selective alpha blockers |
|
|
Term
| methyldopa, clonidine, guanabenz, guanfacine |
|
Definition
| centrally acting a2 agonists |
|
|
Term
act at presynaptic autoreceptors (a2) in the CNS
reduce central sympathetic nervous outflow
increase vagal outflow from the vasomotor center
reduces both arterial and venous tone
methyldopa is a prodrug that is metabolized to an active molecule a-methylnorepinephrine
clonidine also binds to peripheral post synaptic a2 receptors which causes vasoconstriction
guanabenz and guanfacine are similar to clonidine
methyldopa is the drug of choice for pregnant woment |
|
Definition
| mechanism of action of centrally acting a2 agonists |
|
|
Term
sympathetic blockade: failure of ejaculation, postural hypotension (less with clonidine due to its direct peripheral action)
unopposed parasympathetic action: diarrhea
dry mouth (xerostomia)
CNS effects: sedation, drowsiness, depression
fluid retention
sudden withdrawal of clonidine or guanabenz can cause severe rebound hypertension with tachycardia, sweating, and anxiety
methyldopa induces autoimmune hemolytic anemia, hepatitis, and lupus like syndrome |
|
Definition
| adverse effects of centrally acting a2 agonists |
|
|
Term
|
Definition
adrenergic neuron blockers
site of action is post ganglionic presynaptic nerve terminals |
|
|
Term
specifically inhibit the function of peripheral postganglionic adrenergic neurons
taken up into the neuron by uptake 1 that is responsible for the reuptake of NE
replace NE in the secretory vesicles
deplete NE in the secretory vesicles
released by stimuli but inactive
when given IV, these agents initially can replace NE in an amount sufficient to increase arterial blood pressure |
|
Definition
| mechanism of action of adrenergic neuron blockers |
|
|
Term
hypotension during standing, exercising, ingestion of alcohol, hot weather; results from lack of sympathetic compensation
fatigue, weakness
congestive heart failure due to drug induced fluid retention
impotence
diarrhea |
|
Definition
| adverse effects of adrenergic neuron blockers |
|
|
Term
levodopa and alcohol: additive hypotensive activity
MAO inhibitors: contraindicated for combinations with these agents
oral contraceptives and sympathomimetics: can decrease hypotensive activity
tricyclic antidepressants: block the uptake of these agents into nerve endings and prevent their actions |
|
Definition
| adrenergic neuron blockers drug interactions |
|
|
Term
|
Definition
| drug that inhibits synthesis of NE |
|
|
Term
inhibits tyrosine hydroxylase, the enzyme that catalyzes the conversion of tyrosine to DOPA, the rate limiting step of catecholamine synthesis
used in patients with pheochromocytoma along with phenoxybenzamine and other alpha blockers
side effects: orthostatic hypotension, sedation, diarrhea, anxiety |
|
Definition
| mechanism of action of metyrosine |
|
|
Term
|
Definition
| drug that prevents storage of NE |
|
|
Term
binds tightly to storage vesicles and prevents storage of NE, dopamine, serotonin
catecholamines leak into cytoplasm and are destroyed by MAO
recovery of sympathetic function requires synthesis of new storage vesicles which takes days to weeks after discontinuation of the drug |
|
Definition
| mechanism of action of reserpine |
|
|
Term
catecholamine
B receptor agonist |
|
Definition
|
|
Term
propranolol
non selective B receptor antagonist
aryloxypropanolamine
unsubstituted on the 4 position |
|
Definition
|
|
Term
Pindolol
non selective B receptor antagonist with partial agonist activity (has an H bond donor group)
aryloxypropanolamine
unsubstituted position 4 |
|
Definition
|
|
Term
penbutolol
non selective B receptor antagonist with partial agonist activity (has an H bond donor group)
aryloxypropanolamine
unsubstituted 4 position |
|
Definition
|
|
Term
carteolol
non selective B receptor antagonist with partial agonist activity (has an H bond donor group)
aryloxypropanolamine
unsubstituted position 4 |
|
Definition
|
|
Term
nadolol
non selective B receptor antagonist
aryloxypropanolamine
unsubstituted position 4 |
|
Definition
|
|
Term
sotalol
non selective B receptor antagonist
EXCEPTION: not aryloxypropanolamine
unsubstituted position 4 |
|
Definition
|
|
Term
metipranolol
non selective B receptor antagonist
aryloxypropranolamine
EXCEPTION: has a substitution on position 4 |
|
Definition
|
|
Term
acebutolol
selective B1 blocker with partial agonist activity (has an H bond donor group)
aryloxypropanolamine
substituted position 4 |
|
Definition
|
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Term
atenolol
selective B1 blocker
aryloxypropranolamine
substituted position 4 |
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Definition
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Term
metoprolol
selective B1 blocker
aryloxypropanolamine
substituted position 4 |
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Definition
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Term
betaxolol
selective B1 blocker
aryloxypropanolamine
substituted position 4 |
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Definition
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Term
esmolol
selective B1 blocker
aryloxypropanolamine
substituted position 4 |
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Definition
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Term
bisoprolol
selective B1 blocker
aryloxypropanolamine
substituted position 4 |
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Definition
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Term
labetalol
non selective B blocker and alpha blocker
racemic mixture of four stereoisomers
2 are inactive, one responds to alpha receptor and one to B receptor |
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Definition
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Term
carvedilol
non selective B blocker and alpha blocker |
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Definition
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Term
antagonists: the side chain must be a secondary amine
catechol ring can be replaced (phenylether, sulfonamides, amides, indoles, naphthalene)
side chain is isopropyl-aminoethanol or an aryloxyaminopropanol
the side chain hydroxyls are essential
4 substituted are selective B1 blockers
side chain nitrogen is basic and these compounds are formulated as salts to improve solubility
bulky N-substituents are needed with the isopropyl being the smallest effective substituent (this eliminates alpha receptor activity) |
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Definition
| structure activity relationship of B blockers |
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Term
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Definition
Substrate: alcohol, phenol, primary/secondary amine, carboxylic acid
What phase 2 metabolism occurs? |
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Term
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Definition
Substrate: alcohol, phenol, primary/secondary amine
What phase 2 metabolism occurs? |
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Term
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Definition
Substrate: arylamine, primary alkylamine
What phase 2 metabolism occurs? |
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Term
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Definition
Substrate: alcohol, phenol, thiol
What phase 2 metabolism occurs? |
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Term
carbonic anhydrase in an enzyme that converts CO2 and water into carbonic acid and to protons and bicarbonate
carbonic acid formation decreases, sodium cannot be exchanged, sodium and large amounts of water are excreted. |
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Definition
| mechanism of action of carbonic anhydrase inhibitors |
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Term
acetazolamide
sulfonamide
a thiadiazole derivative
carbonic anhydrase inhibitor |
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Definition
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Term
methazolamide
a thiadiazole derivative
carbonic anhydrase inhibitor |
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Definition
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Term
an electron withdrawing group at C6 is necessary for activity (trifluoro-methyl groups at C6 are better than Cl in terms of solubility, duration of action)
sulfonamide at C7 is needed for activity
saturation of the double bond at C3/C4 makes it more active
lipophilic substituents at C3 enhances activity
alkyl substitution at N2 decreases polarity, thus increasing the duration of action
not extensively metabolized, excreted unchanged. |
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Definition
| structure activity relationship for thiazide diruetics |
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Term
chlorothiazide
thiazide diuretic |
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Definition
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Term
quinethazone
thiazide diuretic
18-24 hours duration vs chlorothiazide 6-12 |
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Definition
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Term
metolazone
thiazide diuretic
8-12 hours |
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Definition
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Term
furosemide
loop diuretic
derivative of anthranilic acid
free acid, thus stronger than thiazides
mainly excreted unchanged (some metabolism on the furan ring) |
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Definition
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Term
bumetanide
loop diuretic
more potent than furosemide
replacement of phenoxy with Ar-S also results in a potent compound |
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Definition
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Term
torsemide
loop diuretic
contains a sulfonylurea, instead of the sulfonamide group in other loop diuretics
sulfonylurea is more acidic than sulfonamide (plasma binding 99%) |
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Definition
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Term
ethacrynic acid
loop diuretic |
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Definition
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Term
ethyl-ester (prodrug) is hydrolyzed
2,3 dichloro is necessary
instead of alpha,beta unsaturated ketone, an aromatic ring with m-OH and a p-methyl-amine group (position blocked for aromatic hydroxylation)
an ether (-O) or sulfide (-SH) can replace the carboxyl with no impact on activity
sulfhydryl enzymes cannot add to double bond, mechanism of action unknown
[image] |
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Definition
| structure activity relationship of loop diuretics |
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Term
spironolactone
K sparing diuretic
competitive antagonist to mineralocorticoids, like aldosterone
promiscuous binder to other steroid receptors |
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Definition
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Term
| activation of spironolactone to carnenone |
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Definition
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Term
not much flexibility for SAR
lower alkylamine group instead of amine reduces the activity by half
****para hydroxylation or a para-methyl group are detrimental to activity****
it possesses basic nitrogens
metabolism: mostly aromatic hydroxylatio, followed by sulfation
[image]
triamterene |
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Definition
| structure activity relationship of K sparing diuretics (triamterene and amiloride) |
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Term
triamterene
K sparing diuretic |
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Definition
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Term
amiloride
K sparing diuretic
similar to triamterene but open chain
extensively metabolized, 50% excreted unchanged |
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Definition
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Term
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Definition
| aspartyl protease that cleaves the Leu-Val bond in angiotensinogen |
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Term
1) terminal COOH with an amino acid (Arg) on ACE (salt bridge)
2) H bond between H bond donor on ACE and the terminal amino acid of substrate
3) R1 and R2 hydrophobic interactions with ACE
4) Zn coordinates and stabilizes the transition state of the labile bond at the penultimate amino acid of the substrate
[image] |
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Definition
| key interactions for substrate binding to the active site of ACE |
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Term
captopril
ACE inhibitor
sulfhydryl containing inhibitor |
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Definition
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Term
enalapril
ACE inhibitor
dicarboxylate containing inhibitor
enalapril is a prodrug, enalaprilat is the active form of enalapril
be able to recognize the transition state and the binding interactions |
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Definition
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Term
lisinopril
dicarboxylate ACE inhibitor |
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Definition
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Term
moexipil
dicarboxylate ACE inhibitor |
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Definition
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Term
perindopril
dicarboxylate ACE inhibitor |
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Definition
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Term
ramipril
dicarboxylate ACE inhibitor |
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Definition
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Term
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Definition
| ACE is a stereoselective target |
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Term
fosinopril
phosphonate containing ACE inhibitor |
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Definition
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Term
substituent coordinating with Zn must correlate with L amino acid stereochemistry
the N ring must contain a carboxylate, resulting in an ionic bond
large rings are needed to fill the hydrophobic pocket
coordination with the Zn occurs via a sulfhydryl, carboxylate, or a phosphinic group
esterification produces prodrugs, thus increasing bioavailibility |
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Definition
| structure activity relationship of ACE inhibitors |
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Term
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Definition
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Term
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Definition
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Term
losartan
ARB
acidic (tetrazole ring has a pKa of 6 and is ionized at physiological pH)
low but adequate bioavailability |
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Definition
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Term
irbesartan
ARB
acidic (tetrazole ring has a pKa of 6 and is ionized at physiological pH) |
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Definition
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Term
valsartan
ARB
acidic (tetrazole ring has a pKa of 6 and is ionized at physiological pH)
carboxyl group that is ionized at physiological pH
low but adequate bioavailability |
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Definition
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Term
telmesartan
ARB
acidic (tetrazole ring has a pKa of 6 and is ionized at physiological pH) |
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Definition
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Term
candesartan
ARB
acidic (tetrazole ring has a pKa of 6 and is ionized at physiological pH)
carboxyl group that is ionized at physiological pH
low but adequate bioavailability |
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Definition
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Term
eprosartan
ARB
acidic (tetrazole ring has a pKa of 6 and is ionized at physiological pH)
carboxyl group that is ionized at physiological pH
low but adequate bioavailability |
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Definition
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Term
the acidic group mimics the Tyr-4OH or Asp1-COOH of ATII
[image]
tetrazole and COOH should be in ortho position in the biphenyl series
[image]
R2 is an n-butyl or can be replaced by an ethyl-ether
imidazole or an isosteric replacement are needed to mimic His6 of ATII
R1: carboxy-, hydroxymethyl, ketone, benzimidazole |
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Definition
| structure activity relationship of ARBs |
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Term
| L type calcium channels, alpha1 subunit |
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Definition
One of 6 subclasses of channels
high voltage channel (they require large depolarization)
long lasting channel and the site of calcium channel blockers
the subunit forms the ion conducting pore, while others have functions such as gating modulation
the subunit is a transmembrane spanning protein with four domains |
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Term
amlodipine
dihydropyridine Ca channel blocker
good lipophilicity
unionized |
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Definition
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Term
felodipine
dihydropyridine Ca channel blocker
good lipophilicity
unionized |
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Definition
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Term
nifedipine
dihydropyridine Ca channel blocker
good lipophilicity
unionized |
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Definition
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Term
a substituted phenyl ring at C4 is optimal for activity.
ortho or meta substituents (regardless of electron donating or accepting distribution) are preferred; lack of substitution or para- are detrimental to activity
perpendicular orientation of phenyl and dihydropyridine rings
esterification at C3 and C5 are essential for activity. electron withdrawing groups decrease agonistic activity. if non identical substituents on C3 and C5, stereoselectivity is observed
R1 substituent can be bigger than methyl, tolerance on the receptor site
[image] |
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Definition
| structure activity relationship of dihydropyridine Ca channel blockers |
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Term
diltiazem
benzodiazepine Ca channel blocker
more basic than dihydropyridines (has a teriary amine where as the dihydropyridines have a conjugated carbamate with resonance)
exists in the uncharged form
different binding site than the dihydropyridines |
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Definition
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Term
verapamil
phenylalkylamine Ca channel blocker
more basic than dihydropyridines (has a teriary amine where as the dihydropyridines have a conjugated carbamate with resonance)
exists in the uncharged form
different binding site than the dihydropyridines |
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Definition
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Term
prazosin
alpha 1 adrenergic blocker
shorter duration of action than terazosin |
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Definition
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Term
terazosin
alpha 1 andrenergic blocker
longer duration of action than prazosin |
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Definition
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Term
doxazosin
alpha 1 adrenergic blocker |
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Definition
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Term
tamsulosin
alpha 1 andrenergic blocker
exception to the rule |
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Definition
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Term
methyldopa and methylnorepinephrine
centrally acting sympatholytic drugs
to increase solubility, methyldopate ethyl ester hydrochloride (salt) is prepared
activity stems from its metabolism to methylnorepinephrine (decarboxylation and hyroxylation) thus it stimulates the central presynaptic a2 receptors and decreases NE release |
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Definition
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Term
moxonidine
a2 adrenergic agonist
binds to I1
bioavailability >90% |
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Definition
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Term
guanfacine
a2 adrenergic agonist
more selective than clonidine, but 5 to 20 fold less potent
at physiological pH, it is predominately unionized, thus lipid soluble |
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Definition
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Term
rilmenidine
a2 adrenergic agonist
binds to I1 |
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Definition
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Term
clonidine
a2 adrenergic agonist
binds to I1
presence of an amino-imidazoline group
bioavailability 90%
more selective for a2 adrenoreceptors |
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Definition
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Term
guanabenz
a2 adrenergic agonist
differs structurally to clonidine, amino-guanidinium
mostly unionized at physiological pH (lipid soluble)
oral bioavailability 80% |
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Definition
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Term
metyrosine
centrally acting agent
inhibits tyrosine hydroxylase |
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Definition
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Term
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Definition
| volume baroreceptors stimulate the release of ( ) |
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Term
| S stereoisomer is 100 times more potent than R. |
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Definition
| For beta blockers, which stereoisomer is more potent R or S? |
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