Term
hydralazine
the only direct acting vasodilator
well absorbed from the GI tract
metabolized in the GI and liver
about 85% is bound to plasma proteins (high lipophilicity)
plasma half life is higher in slow acetylators |
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Definition
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Term
| metabolism of hydralazine |
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Definition
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Term
develops in patients with slow acetylator phenotypes
metabolism of hydralazine involves an acetylation step, which is catalyzed by human acetyl coenzyme A-dependent N-acetyl-transferase (NAT)
2 isoenzymes are known for both N and O acetylations (NAT2 acetylation polymorphism is important in clinical pharmacology b/c of its role in activation and/or deactivation of aromatic amines and hydrazines)
a reduction in the activity/stability of the NAT2 enzyme has been observed in slow acetylators
the incidence of the slow acetylator phenotype is 5-10% in asians, 50% in americans (both white and black), and 60-70% in northern europeans
mechanism not understood but thought to be an immunological |
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Definition
| hydralazine-induced lupus-erythematosus (LE) syndrome |
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Term
minoxidil
K channel opener approved for severe hypertension
no plasma protein binding
oral dosing -> hypotensive effect in 30 min -> effects can last 2-5 days (formation of an active metabolite) |
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Definition
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Term
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Definition
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Term
diazoxide
1,2,4 benzothiadiazine
K channel opener
non-diuretic hypotensive agent useful in the management of hypoglycemia
approximately 90% is bound to plasma proteins
being a sulfonamide, it can be solubilized in alkaline solutions (sodium salt) |
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Definition
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Term
metabolism of diazoxide
approximately 20-50% is eliminated unchanged along with its major metabolites |
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Definition
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Term
1) cardenolides (a,B unsaturated lactone)
[image]
2) bufadienolides (a-pyrone)
[image] |
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Definition
The R portion of a cardiac glycoside may be one of 2 things. The R group defines the class.
[image] |
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Term
| digitoxin (3-B-D-digitoxose sugar + digitoxigenin) |
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Definition
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Term
| digoxin (3-B-D-digitoxose sugars + digoxigenin) |
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Definition
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Term
[image]
unsaturated lactone at C17 is important for receptor binding. The unsaturated lactone analogue shows diminished activity.
Other a,B unsaturated open chain groups on C17 can replace lactone with no impact on activity (i.e. a,B unsaturated nitrile (CN))
Key interactions between the carbonyl oxygen (or nitrile oxygen) with the cardiac glycoside binding site on Na/K/ATPase.
Steroid ring system provides the lead structure for cardiac glycoside activity.
The C-D cis ring juncture is critical for actvity.
[image]
The 14B OH is not essential for activity (equatorial).
Although AB cis is not mandatory for cardiac glycoside activity, it is characteristic of all clinically useful cardiac glycosides. Conversion to trans will lead to a drop in activity.
The steroid nucleus is very lipophilic.
Sugars increase water solubility, thus improving absorption and penetration through lipid bilayers. |
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Definition
| SAR of cardiac glycosides |
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Term
not patentable
cost of sample collection
lack of reproducibility and difficulty in isolating active compounds
not water soluble (problematic oral bioavailability)
unstable in vivo (not always efficacious in man)
problems with large scale supply and synthesis, if a drug should emerge. |
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Definition
| challenges with natural products |
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Term
privileged structures (scaffolds that are active at a lot of different targets)
sometimes minimal modifications are needed
often multiple mechanisms of action; they can inhibit cell growth through different pathways |
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Definition
| advantages of natural products |
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Term
Na/K/ATPase
bind to the digitalis receptor site of the pump
they lie across the surface of the pump's alpha subunit with the sugar away from the surface and free to move into contact with one or more aromatic residues
[image] |
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Definition
| probable receptor for cardiac glycosides |
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Term
1) kidneys
2) liver
only difference is OH group on C12. |
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Definition
digoxin is excreted by the ( )
digitoxin is excreted by the ( ) |
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Term
extensive protein binding (90% vs 30% with digoxin)
half life of 5-7 days (vs 1-2 days with digoxin)
extensive metabolism (cleavage of the 3 deoxy sugars attached at C3, hydroxylation at C12, glucuronidation of metabolites) |
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Definition
| digitoxin has been discontinued because of: |
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Term
metabolism of digoxin
antibiotics are sometimes administered to reduce gut flora (a minority of patients have gut flora that metabolize digoxin to dihydrodigoxin) |
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Definition
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Term
the gradient
molecule's lipid solubility
size
degree of ionization
the area of absorption surface |
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Definition
| diffusion rate is proportional to: |
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Term
1) stimulation of synthesis of cAMP (adrenergic, dopaminergic agonists)
2) inhibition of hydrolysis of cAMP (phosphodiesterase 3 inhibitors) |
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Definition
| 2 types of positively inotropic non-glycosides |
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Term
inamrinone (or amrinone)
PDE3 inhibitor
lactate salt used IV for short term use in congestive heart failure
half life: 3-4 hours
elimination: 63% unchanged
protein binding: 10-49%
metabolism: N-acetate, N-glycolyl, O-glucuronide |
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Definition
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Term
milrinone
PDE3 inhibitor
preferred over inamrinone (or amrinone)
half life: 2-3 hours
elimination: 83% unchanged
protein binding: 70%
metabolism: O-glucuronide |
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Definition
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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
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Definition
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Term
dobutamine
B1 adrenergic agonist (S isomer is a B1 agonist and an a1 agonist, R isomer is a a1 antagonist, when racemate is used the alpha effects cancel each other out, so mainly B1 agonist)
dopamine analogue with a chiral center
stereochemistry impacts ability of the molecule to activate the receptor (R and S is important for intrinsic activity - maximal activity that the complex, drug and receptor, displays. not as important for affinity - how the drug binds to the receptor)
know how to draw R and S |
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Definition
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Term
metabolism of dobutamine
oxidation of dobutamine (third structure) to o-quinone results in change of color of solution to pink. |
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Definition
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Term
amyl nitrite
antianginal organic nitrite |
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Definition
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Term
glyceryl trinitrate (nitroglycerin)
antianginal organic nitrate |
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Definition
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Term
isosorbide dinitrate
antianginal organic nitrate |
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Definition
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Term
pentaerythritol tetranitrate
antiangianl organic nitrate |
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Definition
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Term
tenitramine
antianginal organic nitrate |
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Definition
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Term
hydrolysis of organic nitrates that takes place in the presence of moisture (degredation)
volatile (can escape from the dosage form)
small esters (lipophilic)
know how to draw this mechanism |
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Definition
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Term
metabolism of nitrates
the half life of dinitrate metabolites is about 40 minutes (approximately more than 20 times that of glyceryl trinitrate) |
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Definition
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Term
nitroglycerin activation
nitroglycerin binds to one of the two cysteines to form a thionitrile complex, as an intermediate. Then NO2- is released from the complex and reduced to NO. |
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Definition
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Term
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Definition
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Term
triglyceride
triesters of glycerol with 3 long chain carboxylic acids |
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Definition
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Term
phospholipid
major lipid component of cell membranes
glycerol backbone linked by ester bonds to 2 fatty acids and one phosphoric acid |
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Definition
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Term
sphingosine
sphingolipids have this as their backbone
sphingolipids are a major lipid constituent of neuronal axons in the brain (mylein) |
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Definition
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Term
biosynthesis of cholesterol
stage one: synthesis of isopentenyl pyrophosphate, a building block
synthesis of mevalonate from acetoacetyl CoA and acetyl CoA
conversion of mevalonate, by phosphorylation and decarboxylation, into isopentenyl pyrophosphate. The step catalyzed by 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase is the primary control for cholesterol biosynthesis
stage two: 6 isopentenyl pyrophosphate molecules are coupled to form squalene
stage three: cyclization of squalene and conversion into cholesterol
first cyclization via squalene epoxide to lanosterol
lanosterol is converted to cholesterol (complex series of reactions) |
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Definition
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Term
formation of bile acids
the most abundant bile acids are chenodeoxycholic acid (45%) and cholic acid (31%). These are the primary bile acids.
within the liver, the carboxy group of these primary acids is conjugated via an amide bond to either glycine or taurine before they are re-secreted into bile. |
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Definition
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Term
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Definition
bind bile acids in the intestines, impeding their absorption. With the bile acid pool being depleted, 7-a-hydroxylase is upregulated, which in turn increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in increased activity of the biosynthetic enzyme HMG CoA reductase and an increase in the number of hepatic LDL receptors
They are anion-exchanging resins, thus they are able to selectively bind and exchange negatively charged atoms or molecules with one another (selectivity arises from the fact that these positively charged resins do not bind equally to all anions)
binding is irreversible |
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Term
cholestryramine
bile acid sequestrant
consists of polystyrene primarily, with a small amount of divinylbenzene as the cross-linking agent. It also contains fixed amounts of quaternary ammonium per gram of dry resin
the positively charge groups function as the binding sites for the bile acids |
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Definition
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Term
| mechanism of bile acid sequestrants |
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Definition
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Term
colestipol
bile acid sequestrant
consists of tetraethylenepentamine with epichlorhydrin as the cross linker.
it is marketed as a hydrochloride salt
the functional groups are the secondary and tertiary amines |
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Definition
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Term
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Definition
[image]
primary amine
[image]
secondary amine
[image]
alkylated amine
[image]
decylated amine |
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Term
natural: lovastatin, mevastatin
synthetic: pravastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin |
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Definition
| two classes of HMG-CoA reductase inhibitors |
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Term
| mevastatin and lovastatin are prodrugs and activated form mimic the endogenous enzyme |
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Definition
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Term
lovastatin
natural HMG CoA reductase inhibitor |
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Definition
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Term
pitavastatin
synthetic HMG CoA reductase inhibitor |
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Definition
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Term
simvastatin
synthetic HMG CoA reductase inhibitor |
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Definition
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Term
pravastatin
synthetic HMG CoA reductase inhibitor |
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Definition
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Term
fluvastatin
synthetic HMG CoA reductase inhibitor |
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Definition
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Term
atorvastatin
synthetic HMG CoA reductase inhibitor |
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Definition
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Term
rosuvastatin
synthetic HMG CoA reductase inhibitor |
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Definition
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Term
[image]
lactones need to by hydrolyzed to be active
the original bicyclic ring can be replaced by other rings
statins consist of 2 components, a 3,5-dihydroxyheptanoic acid and a ring with lipophilic substituents
the 3,5-dihydroxy acid is essential
statins with a lactone ring are cyclic esters (prodrugs)
stereochemistry at 3 and 5 OH groups must be the same with that found in lovastatin and mevastatin
the distance between C5 and the ring system has to be 2 carbon atoms otherwise activity will be reduced or eliminated
a double bond at C6 and C7 increases or decreases activity depending on ring system (for ring A ethyl is optimal)
ring can be a pyrrole (atorvastatin), indole (fluvastatin), pyrimidine (rosuvastatin), partially reduced naphthalene (pravastatin, lovastatin)
Ring A:
bicyclic is essential. replacement by a cyclohexane resulted in 10,000 fold decrease in activity
ester is needed (replacement to an ether decreased activity)
stereochemistry of the ester side chain is not important for activity
methyl group at R2 increases activity (simvastatin > lovastatin)
R1 = OH enhances hydrophilicity and perhaps some cellular specificity (higher hepatic selectivity) |
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Definition
SAR of HMG CoA reductase inhibitors: Ring A
[image] |
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Term
[image]
lactones need to by hydrolyzed to be active
the original bicyclic ring can be replaced by other rings
statins consist of 2 components, a 3,5-dihydroxyheptanoic acid and a ring with lipophilic substituents
the 3,5-dihydroxy acid is essential
statins with a lactone ring are cyclic esters (prodrugs)
stereochemistry at 3 and 5 OH groups must be the same with that found in lovastatin and mevastatin
the distance between C5 and the ring system has to be 2 carbon atoms otherwise activity will be reduced or eliminated
a double bond at C6 and C7 increases or decreases activity depending on ring system (for ring B ethenyl is optimal)
ring can be a pyrrole (atorvastatin), indole (fluvastatin), pyrimidine (rosuvastatin), partially reduced naphthalene (pravastatin, lovastatin)
Ring B:
W, X, Y can be C or N
p-fluorophenyl cannot be coplanar with the central aromatic ring (co-planarity results in loss of activity)
R substituent can be an aryl group, a hydrocarbon chain, an amide or a sulfonamide
may contain a C6-C7 double bond
n=0 (five membered ring) or n=1 (six membered ring) |
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Definition
| SAR or HMG CoA reductase inhibitors: Ring B [image] |
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Term
lovastatin binding to HMG CoA Reductase
1) the C5-OH H bonds to lysine and glu
2) H bond between asn and the hydroxyl
3) carboxylate H bonds with arginine
4) reduced naphthalene ring is positioned in a hydrophobic pocket defined by leucine, alanine, serine, alanine, and isoleucine |
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Definition
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Term
4 of the 6 statins are lipophilic (lovastatin, simvastatin, atorvastatin, and fluvastatin) and 2 are more hydrophilic (pravastatin and rosuvastatin)
all contain a carboxylic acid
indole and pyrrole nitrogens are not ionizable (aromaticity)
[image]
rosuvastatin's pyrimidine ring is weakly basic, not ionized either
[image]
hydrophilic statins may stay in the liver longer since they are too hydrophilic to distribute out; lipophilic statins have a lower hepatoselectivity (hydrophilic statins are more hepatotoxic)
lipophilic bind more extensively to serum proteins |
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Definition
| physicochemical properties of HMG CoA reductase inhibitors |
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Term
metabolism of atorvastatin (Ring B statin)
both are active metabolites
CYP3A4 and CYP2C9 are both involved in the oxidative metabolism of statins |
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Definition
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Term
metabolism of lovastatin and simvastatin
hydroxylation at 3 and 6 positions (CYP3A4) |
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Definition
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Term
| hydroxylation at the indole ring at C5 and C6, and also dealkylation of indole nitrogen and hydroxylation of the isopropyl group on the indole ring (CYP2C9) |
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Definition
[image]
what is the metabolism of fluvastatin? |
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Term
| metabolism of rosuvastatin |
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Definition
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Term
ezetimibe
inhibits cholesterol absorption in the intestine by binding to specific transport proteins (located in the wall of the small intestine)
hydroxyphenyl helps localize the compound in the intestine
phenol's (acid) pKa is 9.72, thus the compound is unionized at physiological pH
glucuronidation (phenol), oxidation (benzylic hydroxyl). Both glucuronide and ezetimibe are extensively bound to plasma proteins
oral absorption 35-60%, cLogP=3.5 |
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Definition
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Term
metabolism of ezetimibe
both parent and metabolite are >90% protein bound |
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Definition
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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
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Definition
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Term
ciprofibrate
fibrate
not approved in the US |
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Definition
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Term
benzafibrate
fibrate
not approved in the US |
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Definition
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Term
[image]
[image]
derivatives of phenoxy-isobutyric acid; isobutyric acid essential
esters: require activation by esterases
para aromatic substitution on the ring or a chloro containing isopropyl ring results in compounds with a longer half life
gemfibrozil has an n-propyl spacer (vs the phenoxyisobutyric acid of the rest) and is active
[image]
gemfibrozil
[image]
ciprofibrate |
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Definition
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Term
all acidic, ionized at physiological pH
clofibrate and fenofibrate are prodrugs
[image]
clofibrate
[image]
fenofibrate |
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Definition
| PK and physicochemical properties of fibrates |
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Term
| metabolism of gemfibrozil |
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Definition
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Term
niacin
inhibits lipolysis in adipose tissue
decrease triglyceride synthesis and VLDL
well absorbed from the GI tract
pKa=4.76 |
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Definition
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