Drugs Flashcards
1
Q
Acetazolamide
MOA
Uses (3)
Side Effects
A
Weak Diuretic inhibiting Carbonic anhydrase. This inhibits the exchange of Na+/H+ at the proximal tubule.
Used for:
- HTN
- Mountain sickness; mountain sickness induces alkalosis and acetazolaminde induces hyperchloremic* metabolic acidosis
- Glaucoma
Side Effects:
Hyperchloremic metabolic acidosis
- (a decrease in plasma bicarbonate concentration, and an increase in plasma chloride concentration)
2
Q
Loop Diuretics (4)
MOA
Location of action
Uses (3)
Side Effects (3)
A
•Inhibit Na/K/2Cl co-transport at the Thick Ascending Loop of Henle
- STONGEST Diuretics (BET Fu!)
- Bumetinide
- Ethacrynic acid
- Torsemide
- Furosemide
Uses:
HTN
Pulmonary Edema- helps with shortness of breath
Hypercalcemia (Blood)
Side Effects:
Hypercalciuria (urine)
Ototoxicity (Like with aminoglycosides)
Hyperchloremic metabolic alkalosis
3
Q
Thiazide Diuretics (3)
MOA and site of action
Uses (3)
Side Effects (4)
A
•Block Na/Cl cotransport on the Luminal side of DCT
- Hydrochlorothiazide
- Metolazone
- Indapamide
Uses
HTN, Hypercalciuria, Nephrogenic Diabetes Insipidus
Effects
Hyper GLUCH
Glycemia, Lipidemia, Uricemia*, Calcemia, Hypocholoremic metabolic alkalosis
- contraindicated for patients with gout
4
Q
Discuss K+ Sparing Diuretics (2)
A
- only diuretic that does not lose K+ in the urine. Increases K+ in the blood
- Aldosterone Blockade*
•Acts as an Antagonist on Receptor
•Prevents the formation of mediator proteins that stimulate the Na/K pump
Example: Spironolactone “Aldactone” - Principal Cell Blockade
•Does not require Aldosterone
Examples: Triamterene, Amiloride
- Great for SECONDARY HTN - HYPERaldosteronism
5
Q
Aldactone
MOA
Uses (4)
Side Effects (2)
A
AKA Spironolactone
Uses: HTN, Heart Failure, Primary Hyperaldosteronism, End Stage Liver disease
Side Effects: Hyperkalemia, Gynecomastia
6
Q
Inotropy
Chronotropy
Sites of (2) and the effects of B-1 receptors (4)
A
Contractility
Rate
Heart- increased inotropy and chronotropy, and increased AV NODE conduction velocity.
Renal Juxtaglomerular cells- increased RENIN release
7
Q
Beta-1 Selective Antagonists (6)
A
BABE NM
- Betaxolol
- Atenolol
- Bisoprolol
- Esmolol
- Nebivolol
- Metoprolol
8
Q
Locations of Beta-2 and effects (2)
Who may non-selective beta blockers be contraindicated for?
A
Bronchial smooth muscle- bronchodilation
Uterine muscle- uterine relaxation (tocolysis)
•Contraindicated to give a non-selective blocker to an acute asthmatic exacerbation
9
Q
Non-Selective (Blocks Both -1 & -2) - (4)
A
- Nadolol
- Propranolol
- Sotalol
- Timolol
10
Q
Other -Blockers
Non-Selective + alpha (2)
+ Sympathomimetic (Agonism + Antagonism)
- Beta-1 (1)
- Non-selective (2)
A
Non-Selective + alpha
•Carvedilol
•Labetalol
+ Sympathomimetic (Agonism + Antagonism)
- Beta-1
- Acebutolol - Non-Selective
–Penbutolol
–Pindolol
11
Q
Beta-Blocker Adverse Effects
Common (4)
Severe (3)
A
Common: •Sedation •Fatigue •Exercise Intolerance •Impotence
Severe
•Bradycardia and/or AV nodal Block
•Worsen heart failure
•Bronchoconstriction
Note: are used for Emergency situations of heart failure
12
Q
Beta blockers end in -_____
A
- lol
13
Q
Calcium Channel Blockers
Nondyhydropyridines
MOA and Effects (2)
A
-Work at the level of the heart
- Bind to L type Ca channels
- Negative Inotropic Effect
- ↓ Contractility (Stroke Volume)
- Bind to L type Ca channels
- Negative Chronotropic Effect
- ↓ Heart Rate (decrease the slope 4 of SA/AV node AP)
14
Q
Ca Channel Blockers Adverse Effects (3)
A
- Heart Block
- Worsen Heart Failure
- Constipation
Note: Not used for Emergency situations of heart failure
15
Q
Renin Angiotensin Aldosterone System
Receptors of kidney measure what (3).
A
Renal Arterial Pressure
[Na] in Renal Tubular Fluid
↑ Renal Sympathetic Nerve Activity
16
Q
Side effects of ACEi (2)
A
ACE converts vasoactive peptides to inactive fragments:
- Bradykinin
- Substance P
- Enkephalins
Side effects:
Blocks of ACE can lead to cough and angioedema
17
Q
Overall Effect of RAAS (4)
A
- Arterial Vasoconstriction*
- Increased sodium and water retention
- Left Ventricular Hypertrophy/Fibrosis
- Increased Sympathetic stimulation
- Increase in afterload, systemic vascular resistance
18
Q
RAAS sites for opportunistic Rx blocks
A
Renin- Aliskiren
ACE- ACEi
Angiotensin II receptor- Angiotensin II receptor blocker
Aldosterone receptor - Spironolactone
Note: All cause hyperkalemia.
19
Q
ACE-Inhibitors
Uses (2) Adverse Effects (4)
A
Uses:
•Hypertension
–Diabetics; especially for kidney failure
•Systolic Heart Failure
Adverse Effects
- Hyperkalemia- may be detrimental to cardiogenic arrhythmia
- Cough
- Angioedema
- Teratogenic
20
Q
Angiotensin Receptor Blockers
Uses (2) Adverse Effects (2)
A
Uses:
•Hypertension
–Diabetics
•Systolic Heart Failure
Adverse Effects
•Hyperkalemia
•Teratogenic
21
Q
ACEi end in -
Angiotensin II antagonists end in -
A
- il
- tan
22
Q
Discuss the relationship between alpha 1 and alpha 2 receptors
A
alpha 1- smooth muscle contraction
alpha 2- inhibits transmitter release, and inhibits smooth muscle contraction
23
Q
Alpha 1 blockers
Uses (2) Adverse Effects (2)
A
Uses
•Hypertension
•Benign Prostatic Hyperplasia
Adverse Effects
•Dizziness
•Orthostatic Hypotension
24
Q
Alpha 2 agonist
Methyldopa
Clonidine
A
Methyldopa
•Useful in pregnancy
•Can cause a hemolytic anemia
Clonidine- more common Rx
•Decreases heart rate
•Rebound hypertension after sudden withdrawal from a high dose; abrupt increase in HTN after missing a few doses
25
How is Orthostatic hypertension everted normally?
How do we prescirbe alpha 1 blocker to BPH patients?
Orthostatic hypertension is everted by the function of alpha stimulation because gravity takes over and we do not want blood to be taken away from our brain.
Benign Prostatic Hyperplasia patients prescribe the alpha 1 blocker at night so that they do not experience episodes of passing out.
26
Direct Vasodilators
One common side effect
One common side effect is peripheral edema: continue administration unless pt. definitely cannot tolerate the edema
27
Direct Vasodilators and discuss: Hydrazine (Uses-2 and side effect-1) and Minoxidil (MOA and Side effect-1)
```
Hydralazine
•Used for hypertension and heart failure
•Lupus Like syndrome
–Hydralazine
–Isoniazide
–Procainamide
```
Minoxidil
•Opens potassium channels, results in hyperpolarization and relaxation of the blood vessel membrane
•Hypertichosis
28
Direct Vasodilators
Sodium Nitroprusside discuss and route
IV
* Hypertensive Emergencies
* Cyanide Toxicity
* Sildenafil has similar mechanism
29
Ca Channel Blockers-Dihydropyridine
MOA/Effects
Side Effects (2)
Work in the periphery. The non-dyhydropyridines work on the heart
Dyhydropyridines
* Bind to L type Ca channels
* Peripheral Vasodilator
* ↓ Peripheral Vascular Resistance
Dihydropyridine: Adverse Effects
•Peripheral Edema
•Orthostatic Hypotension
30
Tx of chronic hypertension in Pregnancy
2 common Rx
Rx that are contraindicated
```
Labetalol
Calcium antagonists (CCB)
```
Teratogenic: ACEi, Angiotensin II receptor antagonist
31
Hypertensive Crisis
Define Hypertensive Urgency and Emergency
-Provide Systolic and Diastolic and whether there will be progression to end organ dysfunction or not.
Hypertensive Urgency
•Systolic > 160 mmHG
•Diastolic > 100 mmHg
•* No progression to end organ dysfunction
Hypertensive Emergency*
•Systolic > 180 mmHg
•Diastolic > 120 mmHg
•* Evidence of impending or progressive target organ dysfunction
* Go IV (parenteral) and then when managed can move to Oral
32
List the IV Rx for nitro (2), CCB(2), ACEi (1), Direct vasodilator (1), alpha and beta blocker (1), beta blocker (1), alpha blocker (1)
Nitro: Sodium nitroprusside, Nitroglycerine
CCB: Nicardipine hydrochloride, fenoldopam mesylate
ACEi: Enaliprilat
Direct vasodilator: Hydralazine Hydrochloride
alpha and beta blocker: Labetalol HCl
beta blocker: Esmolol Hal
alpha blocker: Phentolamine
33
1. subcutaneous injection that reduces LDL
2. Lomitapide MOA and use
3. Mipomersem MOA and use
- Alirocumab (PCKSK9)
- microsomal triglyceride transfer protein- high refractory hypertriglyceremia
- It is an antisense therapeutic that targets the messenger RNA for apolipoprotein B. It reduces LDL-C, non HDL-C, and apolipoprotein B
34
Major players of reducing morbidity and mortality.
– Statins (reductase inhibitors)
– Bile acid sequestrants
Informational
35
Sites of action:
Statin
Resin
Niacin
Ezetmibe
- Inhibit HMG-CoA Reductase
- Inhibit Bile acid reuptake from intestines
- Inhibit uptake of cholesterol by VLDL-B-100
- Inhibit cholesterol uptake from intestines
36
STATINS
* Derived from Penicillium or Aspergillus fungi: (3), which has the best SI and what population is it used most for?
* Synthetic (3)
– Lovastatin (Menacer®)- first one made
– Pravastatin (Pravachol®)- best SI and often used for the elderly- compensates potency for safety
– Simvastatin (Zocor®)
– Atorvastatin (Lipitor®)
– Fluvastatin (Lescol®)
– Rosuvastatin (Crestor®)
37
3-hydroxy-3- methylglutaryl coenzyme A (HMG CoA) reductase. The statins ________ inhibit the first committed step in the synthesis of cholesterol
-competitively
IC50s for statin in the nM range.
The half maximal inhibitory concentration (IC50) is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function.
38
Mechanism of statin lipid lowering action
Increased clearance of two things.
• Inhibition of HMG CoA reductase results in the
decrease in a critical intracellular pool of cholesterol
resulting in an increased expression of LDL RECEPTORS.
This increases the clearance of LDL. Most effective
class for lowering LDL levels – 25–45%.
• Inhibit the hepatic formation of lipoproteins.
• Composition of VLDL is altered so that VLDL clearance
is also increased
39
Pharmacokinetics of Statins
```
Route
Metabolism
Substrates for
Which two have >12 hr half lives?
bound to what in plasma
Excretion
Time of dose administration
```
• Variable oral absorption
• Extensive (>60%) first-pass hepatic clearance;
effects on cholesterol occur primarily in the liver
• Substrates for CYP3A4/2C9 except for pravastatin
(sulfation)
• Atorvastatin & rosuvastatin have long half-lives (>12
hrs)
• Highly bound to plasma proteins (>95%)
• Primarily biliary excretion;
40
Comparison of Statins
Ability to lowe LDL cholesterol, serum TGs, and increase HDL Cholesterol.
Which statin has the longest effect on HMG CoA reductase?
```
• Ability to lower LDL cholesterol:
Very good (24-60%)
• Ability to lower serum triglycerides:
Modest (10-29%)
Ability to increase HDL cholesterol:
Poor (6-12%)
```
• Atorvastatin has longest effect on HMG CoA reductase ~
20 hrs from a single dose
41
Adverse Effects of Statins
• Remarkably free of dose-limiting side effects
• Mild gastrointestinal upset is the most common adverse
reaction
• Headache, loss of concentration
Rarely:
• Hepatotoxicity—mild increases in hepatic transaminases
which usually resolves
- Routinely monitor serum enzymes such as
aminotransferase
- Over 3 x normal discontinue treatment
- Underlying liver disease or alcohol abuse increases risk
• Myopathy—mild elevations of CPK may occur in 5–
10% of patients;
Myositis is rare (
42
Drug Interactions- Statins
• The risk of myopathy is increased when statins are
given with fibrates or nicotinic acid
• Drugs which inhibit statin metabolism*: (Memorize)
Macrolides; cyclosporine**, azole antifungals,
fluoxetine, metronidazole, ritonavir, zafirlukast
• Drugs which increase statin metabolism:
Barbiturates, carbamazepine, rifampin, phenytoin
* May increase the side effects of statins! e.g. increases risk of myopathy
** immunosuppressant Rx
43
Bile acid sequestrates (3)
Developed originally for what?
MOA and chemical property. Why does it work?
* Cholestyramine
* Colestipol
* Colesevelam
Originally developed to alleviate the symptoms of
cholestasis
- These drugs (sit in the intestinal wall) are positively charged binding
RESINS which ionically bind bile acids.
with the decrease of reuptake of bile acids from enterocytes to hepatocytes the liver begins to recruit more LDL do break them down and make bile acids. So then the bile acids never come back from the intestine when they get there. They are excreted out.
44
Adverse Effects of the Sequestrants
• Palatability—resins have a consistency of sand
• Bloating, flatulence, constipation; dietary fiber may
relieve
• Steatorrhea may occur in pre-existing bowel disease
or cholestasis
• Increases in serum triglycerides
• Rarely: malabsorption of vitamin K or folic acid
• Dry, flaking skin
45
Drug Interactions of Sequestrates
When should other drugs be taken (time) before or after resin?
Which anti-lipid Rx is not interfered with Resin?
```
• Resins can bind drugs, particularly those that are anions
but cations and neutral drugs are also affected.
Cardiac glycosides Thiazides
Warfarin Gemfibrozil
Furosemide Tetracycline
Vancomycin Thyroxine
Iron salts Statins
Folic acid Phenylbutazone
Aspirin Ascorbic acid
Glipizide Raloxifene
```
• Drugs should be given either 1-2 hours before or 4 hours
after the resin
• Niacin absorption is not interfered with
46
Nicotinic acid or niacin
| -Water soluble vitamin which is converted into an amide and incorporated into NAD
Informational
47
Mechanism of niacin hypolipidemic action (4) and causes (2).
1. Inhibition of VLDL secretion
2. Interference with apolipoprotein synthesis
3. Increased clearance of VLDL via lipoprotein lipase
4. Inhibition of intracellular lipase*
In addition, nicotinic acid also:
1. Decreases the clearance of HDL
2. Decreases the levels of Lp(a) – only agent that does
this
*contributes to the breakdown of triglycerides into free fatty acids.
48
Effects of niacin on lipids
Give rough changes in VLDL, LDL, HDL, Lp(a) levels
Lipoprotein(a) [Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a) [apo(a)], which is covalently bound to the apoB of the LDL like particle.
• 20–80% decrease in VLDL in 1 to 4 days
• 10–20% decrease in LDL in 3 to 5 weeks
• Variable increase in HDL:
– HDL
49
```
Niacin Pharmacokinetics
Route
Time for peak levels
Half life, how many doses per day?
metabolism/excretion
```
* Well absorbed orally; peak levels in 30–60 minutes
* Short half-life requiring 3 times a day dosing
* Primarily excreted unchanged in the urine
50
Niacin adverse effects (4)
| Advice for consumption.
Adverse effects* significantly limit the usefulness of niacin.
• Majority of patients have intense flushing (take at bedtime) and pruritis of face and upper body.
An aspirin prior to dose alleviates symptoms
• GI: dyspepsia, vomiting, diarrhea; incidence reduced if
taken with a meal or a non-Al++ containing antacids- take tums. May precipitate peptic ulcer
• Dry skin
• Increased plasma glucose and decreased glucose
tolerance occur frequently; should not be given to
diabetics
• Increased uric acid levels that may cause gout (20%)
*Tolerance to the increased doses does increase so more successful in getting patients to be on Niacin compared to the bile sequestrates.
51
Niacin adverse effects (continued)
* Conjunctivitis
* Nasal stuffiness
* Cardiac arrhythmias
* Hepatotoxicity
Usually occurs at doses of 2 g/day or more
– Elevated AST and ALT
– Stop drug if elevated 3x upper normal level
– Jaundice
• Birth defects
• May increase the risk of myositis when used with a
statin
52
Major therapeutic uses of niacin (3)- for hypercholesterolemia and familial combined hyperlipoproteinemia.
Niacin is an effective therapy for conditions in which
there is increased VLDL. In order to enhance
acceptance niacin is often used in combination since
this permits the use of lower doses.
• Adjunctive therapy to lower LDL in familial
hypercholesterolemia. In combination with a resin
• Familial combined hyperlipoproteinemia to lower
triglycerides and to raise HDL
53
Fibric acid derivatives (2)
* FENOFIBRATE- MORE COMMON IN USA
| * Gemfibrozil
54
Mechanism of vibrate action (3 IMPORTANT)
IMPORTANT ACTIONS
• Fibrates up-regulate lipoprotein lipase; increases the
clearance of VLDL
• Increased oxidation of fatty acids in liver and muscle
• Decreased platelet reactivity and aggregation (not
mediated by PPAR
OTHER ACTIONS
• Up-regulate Apo AI genes
• Decrease expression of Apo C-III (LPL inhibitor)
Effects are mediated by fibrate activation of the
nuclear transcription factor peroxisome proliferatoractivated
receptor (PPAR)
55
Fibrate effects on lipids; VLDL, HDL
EFFECTIVE TX FOR (2)
• Decrease in VLDL (40–55%)
• Increased HDL* (10–15%) because there is less
exchange of cholesteryl esters for triglycerides
• Effective in the treatment of:
Familial hypertriglyceridemia
Familial dysbetalipoproteinemia
* would try Niacin first before using Fibrate for this reason
56
Pharmacokinetics of fenofibrate
```
Route
Bound to what?
Enters what circulation?
Half life
Excretion
```
- oral w/ meal
- protein
- enterohepatic
- 20 hrs
- Renal elimination of glucuronide conjugates
57
Adverse Effects of fenofibrate
* Muscular pain*
* Elevated aminotransferases*
• Gastrointestinal upset (5%)
• Skin rashes
• Myopathy particularly when given with statins
• Cholelithiasis: women, obese patients & Native
Americans are at greatest risk
• Potentiation of warfarin anticoagulant action
• Do not use in pregnancy or in children
* Be aware when patient is also on statin
58
Ezetimibe
```
MOA
Metabolism
Excretion
Additive with ____.
Toleration?
Interactions (3)
```
Inhibitor of luminal cholesterol uptake by enterocytes by inhibiting the transport protein NPC1L1
- Gluconronidated in intestinal epithelium
- 70 % excreted in feces, 10 % urine
* Limited clinical data, additive with statins
* Well tolerated
• Interactions
– Gall bladder disease
– Resins bind ezetimibe
– Cyclosporine raises plasma levels
59
Use 10 year risk for calculator to asses for risk of atherosclerosis (calculator)- used to understand what patients to treat or not.
In general effects of hypolipidemic agents in
combination on LDL-cholesterol and HDL-cholesterol is greater than lone Tx.
Informational
60
Shoulder & upper limb, and heart share the same pathway thus the primary sensory cortex cannot discern if the pain is coming from heart, shoulder, or upper limb.
Pseudounipolar - one branch goes to periphery as a nociceptor and the other branch goes into the dorsal root of spinal cord.
The secondary neuron at the dorsal horn crosses the spinal cord and rises as a _________ tract and passes through the __________ and eventually synapses with the _______. Then the synapsed axon goes to the PRIMARY __________.
neospinothalmic
lower, upper medulla, pons, midbrain
tertiary neuron of the ventral posterolateral nucleus of thalamus.
sensory cortex
61
Ischemic heart pain- What is the mediator and how is pain noticed?
Ischemic heart releases lactic acid that activate acid sensing ion channels on the sensory terminal.
This creates currents through the sensing ion channels activating the afferent neurons to carry the pain signal to the spinal cord and up to the brain.
62
Markers for myocardial tissue injury (2)
• Serum troponin T is a highly specific marker
• CK‐MB is an isoenzyme of CK that exists
cardiac muscle This is an important marker
for myocardial damage.
• CK‐MM is an isoenzyme of CK that exists in
skeletal muscle
• Troponin T and I in the cardiac and skeletal muscles
have different amino acid sequences. This difference
allows the development of specific antibodies to
cardiac troponin T or I which can be measured in
blood samples by immunoassay
• Creatine kinase (CK), also called creatine
phosphokinase (CPK), is an enzyme found in
the muscle and brain tissue.
63
Short acting Nitros (less than an hour effects are gone) and route- (2)
Amyl nitr-ITE (Inhalation)
Nitroglycerin (sublingual and IV)
64
Long acting Nitros (more than an hour to work effects are still present)
Nitroglycerin:
Buccal (Transmucosal)
Oral
Transdermal
Isosorbide dinitrate:
Oral
Sublingual
Isosorbide mononitrate:
Oral
Erithrityl tetranitrate:
Oral
Sublingual
```
Pentaerythritol tetranitrate (PETN):
Oral
```
65
Transdermal nitroglycerine
popular route because patients with nocturnal angina their sleep cycle is disrupted. Thus put this on chest at night and becomes slowly absorbed throughout the night.
Informational
66
Increase in systolic wall stress will increase MVO2
Increase in _________ will
increase ventricular pressure, ventricular wall
tension and MVO2
Myocardial oxygen demand.
ventricular end‐diastolic volume
67
Increase in the fraction of time during which
| wall stress is exerted will increase MVO2
Informational.
E.g. HR and Ejection Time.
68
smoking releases catecholamines from different places ex.s adrenal medulla, chemoreceptors
Increases the MVO2 because the catecholamines increase myocardial muscle contractility.
69
Preload
After load
Role of Nitros
The pressure in ventricle at the end of diastole
The pressure the ventricle must exert upon contraction of systole to eject blood.
Decrease preload and after load
70
NTG is denitrated in tissues and liver, by (enzyme), and NO is liberated.
Vasodilator Veins>large arteries> arterioles
Vasodilation of veins---> decreased Venous return--> decrease preload
mitochondrial aldehyde dehydrogenase
Liver by glutathione‐S‐transferase and nitrite ion
is liberated. Nitrite ion is reduced to nitric oxide
(NO) by enzymes (e.g., xanthine oxidoreductase).
71
• Dilation of arterioles by nitrates decreases
systemic blood pressure causing decrease in the
after‐load on the heart
• Decreases in pre‐load (due to venous pooling of
blood) and after‐load (due to arteriolar
vasodilation and fall in BP) result in decrease in
myocardial oxygen demand.
• Decrease in myocardial oxygen demand is the
most important mechanism by which nitrates
relieve anginal pain
72
Ischemia is a very strong stimuli to dilate arterioles
Fluid travels the path of least resistance.
Informational
73
Discuss coronary steal phenomenon with a specific Rx compared to NTG.
Dipyridamole or Hydralazine vasodilator the arterioles over the coronary arteries. The ischemic affected arteriole is already dilated but now the dilates the unaffected arteriole side. While the normal coronary artery and collateral artery remain normal size.
More blood will travel to the newly dilated unaffected arteriole side.
74
NO---- cGMP mechanism for dilation
cGMP dephosphorylates MLC-P.
75
sodium nitroprusside is NOT used to treat angina.
Discuss the use and preparation of nitroprusside. Why the precautions?
Used for treatment of hypertensive emergencies and heart failure when short term reduction of cardiac pre-load and after load is needed.
•Liberates CN ion; mitochondrial enzyme, RHODANASE, in presence of a sulfur donor, converts CN to less toxic thiocyanate.
•To prevent excessive CN formation, the drug
must be prepared just before use and placed
in an opaque container.
76
Side effects of nitrates
• Because of venous pooling of blood, nitrites and
nitrates produce postural hypotension and associated
dizziness and weakness
• Dilation of meningeal blood vessels may cause
pulsating headache. With prolonged use, tolerance
develops to this side effect
• Dilation of cutaneous vessels may cause flushing of
skin
• Nitrite ion generated may oxidize hemoglobin to
methemoglobin causing methemoglobinemia which
results in anemic hypoxia. This is not a common side
effect
INFORMATIONAL
77
Emergencies: fast onset dosage forms of nitrates
used
• Maintenance therapy: long acting dosage forms
used
INFORMATIONAL
78
Nitrites may cause vasodilation of cerebral
blood vessels along with warm sensations
and facial flushing.
• These effects of nitrites may contribute to
the users' perception of a rush or high.
INFORMATIONAL
79
Erectile function is due to _______ stimulation.
Parasympathetic
80
Nitric oxide (NO) is released from noncholinergic,
non‐adrenergic nerve terminals
• NO increases cGMP in non‐vascular smooth
muscle of the corpora cavernosa in the male
sexual organ
• Blood flow into the sinuses of the corpora
cavernosa increases causing erection
Informational
81
Both nitrates and viagra increase cGMP. Therefore,
potentiation of cGMP induced hypotension may be
dangerous in these patients.
Informational
82
1. Naldolol
| 2. Propranolol
Non-selective beta blockers
1. long acting
2. membrane stabilizer
Both used for TYPICAL angina and MI
83
1. Atenolol
| 2. Metoprolol
β1-selective adrenergic receptor blockers
1. No comment
2. Membrane Stabilizer
β1-selective adrenergic receptor of HEART!
84
beta blockers decrease heart rate, myocardial
contractility and blood pressure; MVO2 is
decreased.
Informational
85
Activation of beta‐1 adrenergic receptors: effect on
| myocardial contractility
NE--> beta-1---> Goes through Gs, cAMP, PK-A, calcium channel phosphorylated and opens, Ca2+ to SR to release Ca2+
86
Activation of beta‐adrenergic receptors in the
cardiac ____ node tissue increases the
automaticity of these cells resulting in increase in
heart rate.
SA
87
Effect of sympathetic nerve stimulation on
coronary artery smooth muscle
alpha-1
beta-2
NE---> alpha-1 R---> Gq---> PLC---> IP3---> SR---> Ca2+ released.
NE---> beta-2 R---> Gs---> cAMP---> phosphorylate MLCK---> relaxation because now MLCK is inactivated
88
Non‐selective β‐adrenergic receptor blockers (e.g.
Propranolol) may cause coronary artery
vasoconstriction
Informational
89
Non‐selective β‐adrenergic receptor blockers:
clinical uses
• These drugs are NOT useful in the treatment
of Prinzmetal’s angina because of the
possible constriction of coronary arteries due
to un‐opposed effect of alpha‐1 adrenergic
receptor activation.
• β1‐selective adrenergic blockers may not
have this side effect
Informational
90
Used in combined therapy (beta blocker) with nitrates because:
Nitrates may cause a decrease in systemic blood
pressure and baroreceptor reflex increase in heart rate and
contractility. These effects are undesirable in
angina.
Beta‐adrenergic receptor blockers prevent
nitrate‐induced reflex increase in heart rate and
myocardial contractility.
• Doses have to be carefully titrated.
91
Dihydropyridines (2)
Effective for?
CCB
Nifedipine
Amlodipine
Effective for: Coronary vasodilation
92
Benzothizepines (1)
Effective for
CCB
Diltiazem
Effective for:
1. Decrease in automaticity (SA node effect; decrease in HR)
2. Decrease in AV node conduction
Less effective for Coronary vasodilation and Decrease in cardiac contractility
93
Papaverine (1)
Effective for
CCB
Verapamil
Effective for all: Coronary vasodilation
Decrease in cardiac contractility
Decrease in automaticity (SA node effect; decrease in HR)
Decrease in AV node conduction
94
```
Amlodipine
Nicardipine
Nifedipine
Diltiazem
Verapamil
```
CCB for both kinds of anginal pain
95
Calcium channel blocker alone is not effective in
| the treatment of ______.
unstable angina
Therapeutic effects of calcium channel blockers
These drugs:
• Prolong the time to onset of angina during
exercise
• Decrease frequency of anginal attacks
• Decrease the need to administer nitroglycerin
• Combined treatment with a calcium channel
blocker and a nitrate or a beta‐blocker has an
additive effect
96
Calcium channel blockers: therapeutic effects
• They reduce the amount of calcium entering the
smooth muscle cells
1. Relaxation of coronary arteries and therefore
increase in blood supply to the myocardium
2. Relaxation of systemic arterioles and therefore
decrease in systemic blood pressure, decrease
in after‐load on the heart and decrease in
myocardial oxygen demand (MVO2).
97
Calcium channel blockers: therapeutic effects
• They reduce the amount of calcium entering the
cardiac muscle cells.
This effect results in
negative inotropic effect and decrease in
myocardial oxygen demand (MVO2).
• They reduce automaticity of sinoatrial node cells
in the heart and decrease heart rate. Decrease in
heart rate (negative chronotropic effect) is likely
to decrease MVO2.
98
Slop changes of 4 for SA/AV node AP determines ...
HR
Phase 4 = Diastolic Depolarization
99
```
Calcium channel blockers: clinical uses
Long‐term treatment of:
• Typical angina
• Prinzmetal’s angina
• Hypertension
• Cardiac arrhythmias
```
Informational
100
Fatty acid oxidation inhibitors:
| mechanism of action
Inhibit Long-chain 3-ketoacyl-coenzyme Athiolase because it mediates fatty acid oxidation
shift myocardial metabolism toward greater use of
glucose as a substrate resulting in reduced oxygen demand which is helpful in patients with angina pectoris.
• Trimetazidine (a fatty acid oxidation inhibitor) is not available in USA.
101
Ranolazine was believed to act only as an inhibitor of fatty acid oxidation.
• However, high concentrations of the
drug are needed to serve as an
inhibitor of fatty acid oxidation.
Instead its believed to inhibit late sodium current.
102
0- Na+ channels open, Na+ enters the cell
1- Na+ channels close
2- Ca2+ channels open, Ca2+ enters the cell
3- K+ channel open, K+ leaves cell
4- Normal resting potential is reestablished
Note: During phase 1 Na+ channels close, BUT NOT ALL. Thus we get a late sodium current which will continue throughout the length of the action potential.
Late sodium current which propagates with opening/closing of Na+ channels all throughout the length of the AP.
103
In an ischemic heart the late sodium current is increased.
With the increased influx of late sodium current inside the cell it will reverse ______.
Ca2+/Na+ exchanger.
Most of the time Na+‐Ca++ exchanger is in Na+
influx‐Ca++ efflux mode.
But with the ischemic heart the late sodium current is increased.
Now we have Ca2+ influx at the Na/Ca exchanger.
At the end of diastole there will be an observed increased myocardial tension compared to normal conditions with no ischemia.
104
At the end of diastole there will be an observed increased myocardial tension compared to normal conditions with no ischemia.
Na+ - Ca++ exchanger is reverted back to Na+
| influx-Ca++ efflux mode
105
• Typical angina: for maintenance
therapy calcium channel blockers,
beta-adrenergic receptor blockers and
LONG acting nitrates
```
• Prinzmetal’s angina: Nitrates and
calcium channel blockers are used;
non-selective beta-adrenergic receptor
blockers should not be used because
of potential constriction of coronary
arteries elicited by them
```
Informational
106
Thrombi formed from ulcerated or ruptured atherosclerotic plaques in unstable angina will cause what?
These thrombi may cause recurrent ischemic episodes.
107
Unstable angina: therapy‐1
HERPARIN
```
• Intravenous heparin is administered
to prevent blood clotting:
• Normally plasma antithrombin
inhibits clotting factor proteases,
especially thrombin, to prevent
clotting. This action is accelerated
by heparin.
```
108
Unstable angina: therapy‐2
ASPIRIN
• Aspirin reduces ischemic episodes in these patients:
• Normally, arachidonic acid is released from
membrane phospholipids by phospholipases.
• Oxygenation of arachidonic acid by cyclooxygenases
(COX I & II) results in liberation of
thromboxane A2.
• Thromboxane A2, liberated from platelets, INDUCES
platelet aggregation.
• Aspirin irreversibly inhibits COX I & II. Thromboxane
A2 formation is decreased and platelet aggregation
is decreased.
109
Unstable angina: therapy‐3
Rx. is administered to reduce
platelet aggregation by blocking the
adenosine diphosphate (ADP) receptor on
platelets
Rx Inhibitors of platelet glycoprotein IIb/IIIa
receptor complex
• Clopidogrel (Plavix)
• (e.g., Abciximab [ReoPro],
tirofiban [Aggrastat]) to prevent platelet
aggregation
• In addition, standard therapy with
combination of nitrates, beta‐adrenergic
blockers and calcium channel blockers is used
