I.Adverse Effects of Diuretics
September 22, 2000Staci & Jeremy
Pharm, 9 a.m.
Dr. Tenner
Antihypertensives II
Dr. Tenner started by correcting a statement made at the end of the first hour. He said that diuretics cause hyperkalemia due to the decrease in intracellular sodium, however, he meant that this causes hypercalcemia.
I.Adverse Effects of Diuretics
- Sexual Dysfunction – most common side effect. This become a large problem with patient compliance.
1.He told us to think about a 40 year old, asymptomatic man being asked to take this drug that will decrease he sexual life, so that he can hang around longer. Since hypertension does not hurt, he will stop taking the drug to save his sex life. The take home lesson is: educate your patients on the drugs they are taking and explain possible side effects.
- Hypovolemia – especially a problem with elderly patients. Elderly patients tend to be 10-
20% volume restricted already. Therefore, giving a diuretic can exacerbate this problem leading to orthostatic hypotension.
- He related a story to us about his Grandmother who was on a diuretic for 10 years and then began passing out. She was taken to doctor, taken off the drug and the blood pressure never went back up. She was misdiagnosed from ONE BP reading in an office.
- Hypokalemia – Thiazide and Loop Diuretics, dose dependent
- plasma volume, plasma renin activity (PRA), K loss.
- Caution number < 3.5 meq/L
- predispose to arrhythmias , especially when patients have other CV problems
- May need to supplement K. Natural sources are not enough unless you eat a 6-foot banana a day, therefore use pill form or add K-sparing diuretics.
- Hypomagnesemia – Mg is the main stabilizer of the cardiac membrane.
- Story: When Coronary Bypasses were first started, the heart was slowed by a cold cardiplegic solution. After this solution was removed 50% of the patient recovered, the other experienced arrythmias and would never re-establish a regular heartbeat. When Mg was added to the solution the success rate increase to 90-95%.
- Hypercalcemia – thiazide and thiazide-like drugs
- may lead to arrhythmias
- Hyperuricemia
- Hyperlipidemia
- Allgeric responses
- Glucose intolerance
- Renal Insufficiency
II.Adverse Effects of Loop Diuretics
- It is important to recall that these drugs have a shorter half life but that they are very potent.
- They have the same general effects as list above.
- EXCEPTIONS: hearing loss and hypocalcemia
III.Adverse effects of K sparing diuretics
- Protect K and Mg
- Estrogenic side effects – gynecomastia – spironolactone is a competitive antagonist of steroid receptor.
IV.Drug Interactions
- Quinidine: Torsades de Pointes (in English that’s Ploymorphic Ventricular Tachycardia)
- Digoxin: K, Ca, Mg, = digoxin toxicity. Can push patients into arrhythmias.
- Corticosteroids: Na retention
- Warfarin: Lots of interactions, loses effectiveness when plasma volume decreases clotting factors increase.
- NSAIDS: Alter prostaglandin formation by blocking cyclooxygenase pathway. This is important in kidney function. Patients who take a lot of NSAIDS diuretic will NOT work.
- Hyperkalemic effects of K sparing drugs, enhanced by NSAIDS, -blockers, and ACE inhibitors because they all reduce aldosterone levels.
- ACE inhibitors
- Mechanism
1. Block angiotensin I angiotensin II by inhibiting angiotensin converting enzyme found in the endothelial cells (highest in the lung).
2. TPR by removal of AII, aldosterone, Na excretion, and plasma volume autocoids like bradykinin and substance P by inhibiting its destruction
3. prostaglandin production secondary to bradykinin
B. Captopril
1. First ACE inhibitor
2. t1/2 = 2-3 hours
3. can cause blood dyscrasias
C. Enalapril et al.
- PRODRUGS (except for Captopril and Lisinopril) – orally absorbed and then activated in the liver or small intestine
2. t1/2 = 11 hours – main advantage, can take once or twice a day
D. Lisinopril
1. Lysine derivative of Enalaprilate – therefore not metabolized
- t1/2 = 12 hours
- Pharmacology of ACE inhibitors
1. African-American populations are the least sensitive to ACE inhibitors due to low renin
activity
2. can decrease mortality with MI (heart failure or left ventricular dysfunction)
- preserve renal fxn in diabetes
- Little effect on lipids or sexual functioning
- Adverse Effects of ACE inhibitors
1. Hypotension and Na depletion – most common. Especially a problem with elderly,
who may already be volume depleted.
2. Dry, irritation cough – most common reason why patient quit taking the medicine. It
is thought to be associated with increased levels of bradykinin (giving sodium
cromolyn will take care of this).
3. Hyperkalemia – No AII release no aldosterone release no Na resorbtion (not losing K)
4. Angioedema – This is where the lips, throat, mouth and mucous membrane swell and can lead to
suffocation.
5. Renal failure – This becomes a problem in patients that have renal artery stenosis
6. Protienuria, rash, pancytopenia, fever and bone marrow depression
VI. Angiotensin Receptior Antagonist
A. Losartan – may prove to be as effective but without the cough or angioedema. It is thought to be less effective
In African-Americans.
VII. Spironolactone
A. Competitive antagonist of aldosterone – blocks aldosterone receptors in the kidneys – can cause gynecomastia. VIII. Sympatholytic Agents
A. HR, CF, VR, TPR are all controlled by sympathetics.
- 2 agonist
1. Mechanism
a. Brain – decrease SAS tone
b. blunts release of catecholamines and reflexes
c. in systolic and diastolic BP w/ little effect on HR
2. Methyldopa
a. almost obsolete, causes sexual dysfunction
b. “false transmitter”
3. Clonidine
a. little orthostatic hypotension
b. dry mouth, drowsiness, depression, and sexual dysfunction
c. Withdrawl sensitivity – can lead to hypertensive crisis
4. Guanabenz
5. Guanfacine
IX. Ganglionic Blockers – Trimethapham Camsylate
- Horrible drug to take – patients feel bad
- Mechanism of action
1. HR, VR, TPR, and CF completely
2. block both sympathetic and parasympathetic outflow – used in surgery.
3. Advantage: vasodilation w/out reflexes
C. Adverse Effects
1. Orthostatic Hypotension
2. Sexual Dyfunction
- Paralytic ileus
4. Urinary retention
X. Depletors of Neurotransmitters at Nerve Terminals
A. Mechanism of action
1. VR, TPR, HR, CF
2. depletion of adrenergic neurotransmitter
B. Reserpine
1. Depletes catecholamines in the brain and peripherally
2. Causes severe depression and suicidal tendencies (esp. type A personalities), sex drive lowered
3. Least desirable of the antihypertensives but doctors still use it because it is dirt cheap
C.Guanethidine
1. No CNS effects therefore NO Depression
2. Enters nerve terminals through amine transport system, so drugs that block this system (cocaine,
amphetamines, tricyclic antidepressants) will prevent Guanethidine from working properly
3. Can cause retrograde ejaculation, not good for your sex drive
D. Adverse Effects
1. Orthostatic hypotension (Dr. Tenner lost his softball game and his old professor)
2. Fluid retention- reflexes decrease VR, TPR, CO, & HR – Kidney incr. RAAS & reabs. more Na & water
3. Sexual dysfunction
4. Parasympathetic predominance
a. nasal stuffiness
b. incr. gastric acid secretion, diahrrea, indigestion
c. bradycardia
5. Supersensitivity- due to increase in the number of receptors, use caution with OTC decongestants
XI. Alpha-antagonists
A. Mechanism of action
1. decreases TPR and VR
2. increased reflex HR (tacycardia), CF, and RAAS
B. Phentolamine
1. nonselective and antagonist
2. reversible
- Phenoxybenzamine
1. nonselective 1 and 2 antagonist
2. irreversible
C. Prazosin (drugs ending with –sin are selective 1 adrenergic antagonists)
1. well absorbed orally
2. less reflex tachycardia because no 2 blockade
3. first dose syncope- give first dose at night
D. Adverse Effects
1. orthostatic hypotension
2. nasal stuffiness
3. ulcers
4. impotence
5. no lipid effects
XII. - Adrenergic Receptor Blockers (very important, end in –olol)
A. Nonselective
1. Propranolol- gets into CNS
2. Timolol and Nadolol- do not get into CNS
B. Cardioselective (1 selective)
1. Metoprolol
2. Atenolol
- Blockers with Intrinsic Sympathomimetric Activity (ISA) – Dr. Tenner says ISA is no big deal
1. Pindolol
D. Mechanism of Action
1. decrease CO by decreasing HR and CF
2. decrease RAAS, no compensatory fluid volume expansion
3. increase TPR and VR through reflex (resembles diuretics)
4. CNS- don’t worry about it, only concerns the lipid soluble drugs
E. Adverse Effects
1. Bronchospasms via 2 blockade- bad for asthmatics, COPD, and smokers
2. Heart Failure- usually during first dose- causes decompensation and patients go back into heart failure
3. Bradycardia and AV block
- Peripheral vascular disease and Raynaud’s disease- in winter the 2 blockade causes exaggerated 1 vasoconstriction leading to vasospasms and limb ischemia causing an intense burning sensation
- Depression
- Strange dreams with the lipid soluble drugs
- Sexual dysfunction
F. Labetalol- a great drug
1. antagonist activity
2. no reflex tachycardia
3. Best and Worst of both worlds: Adverse Effects
a. orthostatic hypotension
b. bradycardia
c. heart block
d. decreased cardiac force, bad in asthmatics
XIII. Vasodilators- second or third line drugs, causes a lot of reflex activity and tolerance
A. Decrease TPR- direct vasodilator on arteries, K+ channel agonists
1. Hydralazine
a. causes SLE at high doses
b. rapid drop in TPR leads to angina pectoris because lose driving force (diastolic pressure)
c. not used anymore unless used in combo with or blockers or ACE inhibitors
2. Minoxidil (Rogaine)
a. everybody got hairy
XIV. Solubility of Beta Blockers- Lipid soluble and water soluble
A. Lipid soluble- Propranolol, Tenolol, and Metoprolol
1. metabolized by liver into water soluble metabolite and excretes it
2. short half life- must be given 2-3 times a day
3. get into brain and cause depression and dreams
4. contraindicated in person with chirrotic liver
B. Water soluble- Nadolol and Atenolol
1. don’t get into the brain, not metabolized by liver, just excreted unchanged
2. long half-life- give 1-2 times a day
XV. Calcium Channel Blockers- very low half lives so must be given many times a day when used as antihypertensives
A. Phenylalkylamine: Verapamil- 1st one used
- Benzothiazipine: Diltiazem- 3rd one, Best one (Japanese made)
1. Verapamil and Diltiazem are equally potent at arteries and heart at decreasing HR and CF
C. Dihydropyridines: Nifedipine, et al.- 2nd one used
1. potent on arteries, decrease TPR, short half life
D. Pharmacology of Calcium Channel blockers
1. blockade of L-type, voltage-operated, calcium channels
E. Positive Indications for Drugs Used in the Treatment of Hypertension (when need to decrease TPR and CO)
1. Edema, Dsypnea – use diuretic
2. Hypokalemia- use spironolactone
3. Sinus tachycardia, arrythmias, angina, and dissecting aneurysm- use Beta blockers
4. Renal impairment- use Furosemide over thiazides
5. If African American- salt sensitive HTN so diuretics best, followed by antagonists and then ACE inhib
6. If young Caucasian- use blockers and then as get older use ACE inhib., Ca channel blockers and
sympatholytics
7. If elderly- use Ca channel blockers
F. Contraindications for Various Antihypertension Drugs
1. Diabetes- Thiazides because can get hyperglycemia
2. Hypokalemia- Diuretics
3. Elderly living alone- All posturally acting drugs, makes them fall down
- Depression- Reserpine, maybe Beta blockers
5. Angina- Vasodilators- decrease TPR, take off driving force
6. Asthma- Beta blockers
7. Cardiac Failure- Verapamil, Beta blockers
8. Vascular Disease- Beta blockers
Scribe note: If scribe seems patchy at times it is because Dr. Tenner ran through many drugs saying we will talk about them in greater detail later on.