Lectures 12, 13, 14, and 15 Flashcards
1
Q
What are the functions of beta 1 receptors?
A
Stimulate renin release in kidney and increase heart rate and contractile force of heart
2
Q
What are the functions of beta 2 receptors?
A
Stimulate vasodilation of skeletal muscle and bronchodilation of lungs
3
Q
What conformation do noradrenaline and adrenaline bind to an adrenergic receptor?
A
Trans conformation (w/ respect to nitrogen and beta OH)
4
Q
Which absolute configuration is preferred in the adrenergic receptor?
A
R absolute configuration
5
Q
What must be done to make a beta antagonist?
A
- Retain high affinity for beta receptor
- Eliminate intrinsic activity
- Have higher affinity for beta vs. alpha receptors
6
Q
What effect do isopropyl and t-butyl have on alpha and on beta receptors?
A
- Alpha receptors – decrease potency
- Beta receptors – increase potency
7
Q
What does an isopropyl N-substitution do?
A
Confers beta selectivity
8
Q
What does addition of a sulfonamide to the meta position do?
A
Makes the molecule resistant to COMT, but still only a partial agonist
9
Q
What does a para sulfonamide plus an isopropyl group do?
A
Makes the compound a weak antagonist
10
Q
Is pronethalol or propranolol used more often and why?
A
Propranolol b/c pronethalol is toxic and possibly carcinogenic
11
Q
What is the difference btwn arylethanolamine and aryloxypropanolamine?
A
Position of attachment of ethanolamine or oxypropanolamine w/ respect to ring substituents
12
Q
Are arylethanolamines or aryloxypropanolamines more potent?
A
Aryloxypropanolamine
13
Q
What are aryloxypropanolamines used for?
A
Binding to beta receptors
14
Q
Does a t-butyl group produce beta 2 antagonist selectivity?
A
No, only beta 2 agonist selectivity
15
Q
What effect do para substitutions of aryloxypropanolamines have?
A
- Confer beta 1 vs beta 2 selectivity, so can produce cardioselective beta 1 antagonists
- Must be single para substitutions
16
Q
For arylethanolamine, the active isomer is ___
A
R and D
17
Q
For aryloxypropanolamine, the active isomer is ___
A
S and D
18
Q
How can effects of competitive antagonists of beta 1 (and sometimes beta 2) receptors be overcome?
A
Increased noradrenaline or adrenaline
19
Q
What are some effects of beta antagonists?
A
- Decrease heart rate, stroke volume, and force of contraction => decrease blood pressure
- Decrease renin release in kidney (may be secondary mechanism to decrease BP)
- Decrease intraocular pressure by decreased production of aqueous humor (used to treat glaucoma)
20
Q
What effect do non-selective beta antagonists have on the lungs?
A
Can cause bronchoconstriction and precipitate an asthmatic attack in those w/ asthma
21
Q
What makes the beta antagonists classified as class 2 antiarrythmic agents?
A
MSA (membrane stabilizing activity) or local anesthetic effect
22
Q
In which beta antagonists is MSA higher?
A
Those w/ high LogP
23
Q
When are MSA effects seen w/ beta antagonists?
A
At doses higher than what is needed for beta antagonist activity
24
Q
What is the MSA of propranolol?
A
Potent MSA b/c can penetrate BBB and cause CNS effects
25
Nadolol is like the ___ version of propranolol
Hydrophilic
26
What is timolol mostly used for?
Glaucoma tx as eye drops
27
What is bunolol mostly used for and what is significant about it?
- Glaucoma tx as eye drops
| - One of the few beta antagonists that come as S isomer only
28
Which beta antagonists are arylethanolamines?
Sotalol and labetalol
29
What is pindolol used for? Does it have MSA?
- Hypertension tx and as an adjuvant for depression tx
| - Has MSA
30
What is a common characteristic of the structure of selective beta 1 antagonists?
Single para substituent that is typically an aliphatic straight chain and hydrophobic
31
Which beta 1 antagonists have MSA?
- Metoprolol
- Acebutolol (some MSA)
- Betaxolol (some MSA)
- Bisoprolol
32
What effect does an sp2 hybridized NH in the meta position have?
Provides partial agonist activity but keeps competitive antagonist activity
33
What is labetalol used for?
Tx of high BP and heart rate
34
Is labetalol used often? Why or why not?
No b/c is a beta 1, beta 2, and alpha 1 antagonist
35
What is the main use of carvedilol?
Seen to decrease morbidity and mortality in heart failure and in post-acute MI patients
36
What are uses of beta blockers?
- High blood pressure (not first line, and use is decreasing)
- Arrhythmias (generally safe but not effective for prevention)
- Heart failure
- Angina*
- MI/heart attack (life saving drug both during MI and for tx after)
- Glaucoma*
- Migraines (rare)
- Tremors (rare b/c condition is rare)
37
What are some side effects of beta blockers?
- Fatigue
- Bronchospasm (only w/ asthmatics on non-selective beta blockers)
- Cold extremities
- Left ventricular insufficiency
- GI (nausea, vomiting, diarrhea, abdominal pain)
- CNS effects (hydrophobic beta blockers)
38
What are contraindications of beta blockers?
- Asthma (beta 1 selective are fine)
- Bradycardia
- Diabetics (sometimes)
39
What effect does LogP have on a beta antagonist?
Increased LogP = increased hepatic metabolism, decreased t1/2, decreased urinary excretion of unchanged drug, and decreased bioavailability
40
What type of metabolism can aryloxypropanolamines undergo?
- N-dealkylation (removal of isopropyl or t-butyl) => inactive metabolite, which can be oxidized by MAO
- Aromatic hydroxylation => active metabolite
41
What is significant about esmolol?
Beta 1 antagonist that is metabolized by esterases, which decreases t 1/2 and allows HCP's to have tight control over effect (rapid onset and quick elimination)
42
What is esmolol used for?
As continuous infusion for atrial fibrillation
43
Describe acebutolol metabolism?
Acebutolol (active) -- amidase --> inactive -- NAT --> diacetolol (active)
44
Acebutolol and diacetolol are ___ selective antagonists
Beta 1
45
What is different btwn diacetolol and acebutolol?
Diacetolol has longer t 1/2 and is found in higher concentration in plasma and has partial agonist activity
46
What should be given to a px that is having an MI or had an MI?
Beta blocker!!
47
Where and when is renin released?
Kidneys when BP sensing cells detect a decrease in BP
48
What is the function of angiotensin converting enzyme? How does it do this?
- Converts angiotensin 1 into angiotensin 2 and makes bradykinin inactive
- Cleaves histidine and leucine on C terminus to make angiotensin 2
49
What is the function of renin as an enzyme? How does it do this?
- Converts angiotensinogen into angiotensin 1
| - Cleaves valine and other aa's on the C terminus to make angiotensin 1
50
What are the effects of angiotensin 2?
- Vasoconstriction => increased BP
- Increase ADH => vasoconstriction => increased BP
- Increase ADH => increased H2O => increase blood volume, stroke volume, CO => increased BP
- Increase aldosterone => increased Na+ and H2O and decreased K+ => increased BP
51
What are the effects of bradykinin?
- Can increase prostaglandin synthesis => vasodilation
| - Vasodilation => decreased SVR => decreased BP
52
What is another name for ACE and where is it primarily found?
- Kininase 2
| - Mostly found in lungs
53
What receptors does angiotensin 2 bind to and what does this cause?
- Angiotensin 1 receptors (AT1)
| - Causes vasoconstriction, increased release of aldosterone from adrenal cortex, and increased ADH
54
Angiotensin 1 receptors is G alpha __
q
55
What effects does the angiotensin 1 receptor have around the body?
- Arterioles -- vasoconstriction and increased BP
- CNS -- increase ADH
- Adrenal cortex -- increase aldosterone
- Kidney - decrease renin through negative feedback
- Cellular effects -- increase phospholipase C, IP3, DAG, and intracellular calcium, and decrease K+ outflow
56
What are the ligands of angiotensin 1 receptor?
A2 and A3
57
What is the function of AT receptor blockers?
Prevent A2 from binding to AT 1 receptor
58
What are renin inhibitors used for?
Treating hypertension
59
What is the only approved renin inhibitor and what does it do?
- Aliskiren
- Mimics angiotensinogen, so blocks conversion of angiotensinogen into A1 => lower levels of A2 => decreased vasoconstriction, blood volume, and BP
- Reversible competitive inhibitor
60
What is significant about teprotide?
- First residue is a pyroglutamate (cyclic glutamate)
- Has many proline residues that decreases proteolytic degradation
- ACE inhibitor
61
What is a disadvantage to teprotide?
No oral bioavailability
62
What peptide can become the lead compound for developing a new drug from teprotide?
Ac-FAP (phenylalanine and proline)
63
What is an advantage and a disadvantage to Ac-FAP?
Binds to active site, but can be hydrolyzed by ACE
64
What effect does zinc have on Ac-FAP?
Polarizes the C=O bond, making it a better electrophile
65
What are S1, S1', and S2'?
Binding pockets of ACE
66
What are disadvantages to captopril?
- Causes taste disturbances and rashes
- Can oxidize to form disulfide bonds
- Very short t 1/2
- Most problems attributed to high affinity zinc binding group SH (solution = dicarboxylate ACE inhibitors which replace SH w/ COOH)
67
What is significant about enalapril?
Pro-drug (catalyzed by esterases)
68
What is significant about lisinopril? (*common exam question)
Only ACE inhibitor that doesn't need to be a pro-drug b/c di-zwitterion is electrically neutral
69
What are the dicarboxylate ACE inhibitors used for?
- Heart failure
- Hypertension
- Acute and post-MI
70
Which drugs are dicarboxylate ACE inhibitors?
- Enalapril
- Ramipril
- Lisinopril
- Quinapril
- Perindopril
- Trandolapril
71
Phosphonate ACE inhibitors are metabolized by _____
Esterases
72
What are the uses of ACE inhibitors?
- Hypertension (decrease SVR, dilate arteries, and BP decrease over long term)
- Congestive heart failure (over time increase SV and CO, decrease remodeling of heart, and decrease sudden death and MI)
- MI
- Diabetes and renal failure
73
What are some ACE inhibitor side effects?
- Hypotension (esp. w/ first dose and captopril)
- Cough
- Hyperkalemia (not a problem w/ normal kidney function)
- Acute renal failure
- Fetopathic potential
- Skin rash (more common w/ captopril)
74
What usually causes the cough seen from ACE inhibitor use?
Increased bradykinin and/or prostaglandins in lungs
75
How can the coughing side effect of ACE inhibitors be decreased?
- Aspirin or iron supplementation
| - Decrease dose or switch to ARB
76
Can ACE inhibitors be taken during pregnancy?
No
77
What do angiotensin 2 receptors blockers bind to?
AT1 receptors located at both vascular and adrenal sites
78
When are angiotensin 2 receptors blockers used?
Px who need ACE inhibitor tx but can't tolerate it
79
____ was the first ARB
Losartan
80
What is important about losartan?
The carboxylate metabolite is 10-40x more potent than losartan itself
81
What is losartan a competitive antagonist of and what does this cause?
- Thromboxane A2 receptor
| - Causes decreased platelet aggregation
82
What is important about candesartan cilexetil?
- More potent than losartan
| - Pro-drug converted to candesartan by esterases
83
What is important about telmisartan?
Only benzoic acid bi-phenyl ARB
84
What is important about valsartan?
Only ARB w/ no imidazole or equivalent functionality
85
Generally having more carboxylates will ____ oral absorption of a drug
Decrease (can get around this by adding an ester)
86
What are some physicochemical properties of filtered components that should be considered?
- MW below 50 kDa
- Overall charge
- Degree of plasma protein binding
87
What are the 6 important regions of a nephron?
1) Proximal convoluted tubule
2) Descending loop of Henle
3) Thick ascending limb of loop of Henle
4) Distal convoluted tubule
5) Late distal tubule and collecting duct
6) Distal collecting duct
88
Where are the major sites of water reabsorption?
- Proximal convoluted tubule
| - Distal collecting duct
89
Where do carbonic anhydrase inhibitors work and what do they do?
- Proximal convoluted tubule
| - Convert H2CO3 -> CO2 and H2O in luminal membrane; does the opposite inside the proximal tubule cell
90
What occurs in the proximal convoluted tubule?
- Antiport sends Na+ from luminal membrane into proximal tubule cell and H+ in the opposite direction
- Symport sends Na+ and HCO3- from proximal tubule cell out to basolateral membrane
- ATPase brings K+ into cell and Na+ out to basolateral membrane
91
What occurs in the descending loop of Henle?
- Surrounding medullary interstitium has high [Na+] compared to luminal fluid entering the loop of Henle
- 15% of water from luminal fluid is drawn out by osmosis into interstitium and subsequently reabsorbed into bloodstream
92
Luminal fluid is _____ as it flows through descending loop of Henle
Concentrated
93
What occurs in the thick ascending limb of loop of Henle?
- Na+/K+/2Cl- symporter
- Passive channel transports K+ out to basolateral membrane and luminal membrane
- ATPase pumps Na+ out to basolateral membrane and K+ inside loop of Henle
- Passive transporter of Cl- to basolateral membrane
94
What inhibits the Na+/K+/2Cl- symporter in the ascending limb of the loop of Henle?
Loop or high-ceiling diuretics
95
What is the major site of Na+ reabsorption?
Ascending limb of loop of Henle
96
Why are the ascending limb of the loop of Henle and the distal convoluted tubule thick?
To be a barrier to H2O
97
What occurs in the distal convoluted tubule?
- Na+/Cl- symporter
- Passive transporters of Cl- and K+ to interstitium
- ATPase
98
What inhibits the Na+/Cl- symporter in the distal convoluted tubule?
Thiazide and thiazide-like diuretics
99
What occurs in the late distal tubule and collecting duct?
- Passive Na+ transporter into cell
| - Passive K+ transporters into luminal fluid and interstitium
100
Where does luminal fluid lead to?
Urine
101
Where does interstitium lead to?
Blood
102
What inhibits the passive Na+ transporter in the late distal tubule and collecting duct?
K+ sparing diuretics
103
What does the late distal tubule and collecting duct dictate?
Final acidity and K+ content of urine
104
What is the net water flow in the distal collecting duct?
From lumen -> interstitium
105
What is aquaporin-2 and where is it found?
- Found in distal collecting duct
| - A water channel that passively reabsorbs water
106
What occurs in the distal collecting duct?
- Aquaporin-2
- ADH binds to V2 (G alpha s), secreting adenylate cyclase, which releases cAMP to PKA and binding causes increased synthesis of aquaporin 2 channel
107
What is the general function of diuretics?
Increase excretion of water from kidneys
108
What are diuretics used for?
- Edema (accumulation of fluid in interstitial spaces)
| - Hypertension** (decrease blood volume, venous return, CO, and BP)
109
What are present in almost all diuretics?
Sulfonamides, so px w/ sulfa allergies can't take diuretics
110
What is the most common thiazide diuretic?
Hydrochlorothiazide
111
Are thiazide diuretics used as monotherapy?
Rarely
112
Describe the thiazide paradox
- One acute effect of thiazides is decrease in blood volume
- Blood volume returns to normal w/in 4-6 weeks of thiazide initiation, but lowered BP is still maintained
- Mechanism unknown (thought to mediate blood vessel relaxation => decreased SVR)
113
What is the difference btwn thiazide and thiazide-like drugs?
Thiazide-like drugs have an amide instead of a sulfonamide
114
What are some thiazide-like drugs?
- Metolazone
- Indapamide
- Chlorthalidone
115
What extends the duration of metolazone?
It binds to carbonic anhydrase in erythrocytes, which acts as a reservoir of drug, extending duration
116
What are some side effects of thiazide and thiazide-like drugs?
- Loss of Na+, Cl-, K+, and water
- Hypokalemia (dose dependent)
- Hyperuricemia could precipitate gout
- Hyperglycemia (dose dependent)
117
What is the function of loop or high-ceiling diuretics?
Inhibit Na+/K+/2 Cl- symporter in thick ascending limg of loop of Henle => massive loss of Na+, K+, Cl-, and water
118
What are loop or high-ceiling diuretics mostly used to treat?
Edema (especially w/ heart failure)
119
What are 2 loop or high ceiling drugs?
- Furosemide
| - Bumetanide
120
Are loop or high ceiling drugs used for hypertension?
No
121
What are some side effects of loop or high ceiling drugs?
- Hypokalemia
- Hyponaturemia
- Hypochloremia
- Dehydration
- Hyperuricemia could precipitate gout
- Ototoxicity (rare and usually reversible)
122
What is the function of potassium sparing diuretics?
Inhibit passive Na+ transporter in late distal tubule and collecting duct => modest diuresis
123
What are 2 examples of potassium sparing diuretics?
Amiloride and triamterene
124
What are potassiums sparing diuretics mostly used for?
To counteract hypokalemia from thiazide and loop diuretics (triamterene supplied in combination products w/ HCTZ)
125
What is the function of aldosterone in the late distal tubule?
Increases expression of passive Na+ transporter and Na/K ATPase => increased Na+ and decreased K+ reabsorption
126
What is used for aldosterone insufficiency?
Fludrocortisone
127
What is spironolactone?
Mineralocorticoid receptor antagonist (K+ sparing diuretic)
128
When is spironolactone given?
W/ thiazide or loop diuretics to decrease risk of hypokalemia
129
What is hemostasis?
Natural process to prevent blood loss from a damaged blood vessel
130
What is an embolism?
Thrombus migration (in brain = stroke; in heart = MI)
131
What is the general process of hemostasis?
Tissue injury -> vasoconstriction -> primary hemostasis, platelet aggregation -> secondary hemostasis, coagulation
132
What occurs in primary hemostasis?
- Platelets adhere to injured blood vessel
- Platelets aggregate primary hemostatic plug
- Platelets stimulate coagulation factors
133
What occurs in secondary hemostasis?
- Coagulation cascade starts
- Fibrin clot forms
- Reinforces primary hemostatic platelet plug
134
What causes platelet adhesion?
GP1a/2a and GP1b are receptors that bind to collagen and von Willebrand factor (respectively), causing platelets to adhere to sub-endothelium of a damaged blood vessel and become activated
135
What do adherent platelets release?
Substances that activate nearby platelets and recruit them to the site of injury
136
What forms the primary hemostatic plug?
Activated platelets
137
What initiates the coagulation system?
Tissue factor, which is in the subendothelium, via the extrinsic coagulation pathway
138
What is the coagulation cascade?
- Series of steps that ultimately lead to fibrous reinforcement of the primary hemostatic plug
- Series of clotting factors in a cascading activation
139
What are clotting factors?
Serine proteases that recognize a very specific sequence, often 4-5 aa's long
140
What do clotting factors begin as?
Inactive form cleaved by another clotting factor to become active (this is indicated w/ an "a" after the factor)
141
Does one protease activate only one clotting factor?
No, can activate many
142
____ augment the activation of clotting factos
Phospholipids and Ca2+
143
What does thrombin do?
Stimulates platelet activation and aggregation
144
What are differences btwn the intrinsic and extrinsic pathways?
- Intrinsic is slow (takes seconds to produce fibrin) and stays active longer
- Extrinsic is rapid (takes milliseconds to produce fibrin) and stays active for less time
145
How is the coagulation process stopped?
Endogenous inhibitors of coagulation factors
146
What is the function of antithrombin?
- Inhibits thrombin (2a), Xa, IXa
| - Acts like a substrate for clotting factor, trapping it in an acyl-intermediate
147
What does antithrombin require for activity?
Naturally produced heparins
148
What is needed on heparin to bind to antithrombin?
In the A domain, a penta-saccharide minimum sequence
149
What is the pharmacological use of heparin?
Stop blood coagulation
150
What differentiates one heparin from another?
Number of monosaccharides, types of monosaccharides, and presence of charges on them
151
What is the significance of the neutral region of heparin?
- Not critical to interaction w/ antithrombin or thrombin
- Suppressing charges in this region don't affect anticoagulant activity, but can decrease undesired interactions (esp. w/ platelet proteins)
- 2-3 disaccharide units
152
What is the minimum chain length of heparin that is required for substantial thrombin inhibition?
16 saccharide units
153
What is the function of the T-domain of heparin?
- Binds to exosite 2 of thrombin, but only if total length of molecule is 16 saccharide units or more
- Must be charged for binding to thrombin
154
What are the various types of heparin?
- Unfractionated heparin
- Low molecular weight heparin
- Synthetic heparin
- Differ in mechanism of action, MW, pharmacokinetics, and side effects
155
What is the size of unfractionated heparin?
18 or more mono-saccharides
156
What is the function of unfractionated heparin on thrombin (IIa)?
- Inhibits thrombin (IIa) by binding to antithrombin and an exosite 2 on IIa via negative charges at the end of the extended heparin chain
- Called the bridging mechanism and increases the rate of reaction btwn IIa and antithrombin
- Also induces a conformational change in RCL of antithrombin that increases rate of reaction btwn antithrombin and thrombin (conformational change mechanism)
157
What is the function of unfractionated heparin on Xa?
Inhibits Xa by inducing conformational change in RCL of antithrombin that increases rate of reaction btwn antithrombin and Xa; requires binding by penta-saccharide to antithrombin
158
What is the size of low molecular weight heparin?
Less than 18 mono-saccharides
159
What is the function of low molecular weight heparin and synthetic heparin?
Inhibits Xa by inducing conformational change in RCL of antithrombin that increases rate of reaction btwn antithrombin and Xa (same as unfractionated heparin); requires binding by penta-saccharide to antithrombin
160
What is the size of synthetic heparin?
- 5 mono-saccharides (fondaparinux)
| - Almost exactly the same as the Heparain penta-saccharide, except fondaparinux has an additional methy-group
161
What is the ratio of anti-Xa:IIa for the various types of heparin?
- Unfractionated -- 1:1
- Low molecular weight -- 2-4:1 (inhibits Xa more)
- Fondaparinux -- >100:1
162
What are the mechanisms of the various types of heparin?
- Unfractionated= bridging and conformation
| - Low molecular weight and fondaparinux = antithrombin conformation
163
How is unfractionated heparin administered?
Continuous IV administration
164
How is low molecular weight heparin administered?
Subcutaneous injection
165
Can heparin be used in pregnancy?
Yes
166
What drugs does heparin interact w/?
- ASA, NSAIDs, dextran, dipyridamole, ticlopidine
| - IV nitroglycerin decreases heparins anti-coagulation effect, so may need to use higher doses
167
What are some side effects of heparin?
- Bleeding
- Heparin induced thrombocytopenia (more common in unfractionated)
- Osteoporosis (very very rare)
- Allergy
168
What are the uses of heparin?
- Prevent venous thromboembolism
- Treat deep vein thrombosis
- Prevent thrombosis during surgery, dialysis
- LMWH SC injection where oral anticoagulants are contraindicated
- MI (typically unfractionated via continuous IV)
- May be used in pregnant px prone to miscarriages to prevent miscarriages (only LMWH or UFH w/o benzyl alcohol as a preservative)
169
Which heparin has dose-dependent kinetics?
Unfractionated
170
What is unique about the structure of carvedilol?
- Has meta sp2 hybridized NH, but doesn’t produce partial agonist activity
- No isopropyl or t-butyl substitution on N
