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Systemic Pharmacology > Anti-Hypertensives > Flashcards

Anti-Hypertensives Flashcards

1
Q

What are the first-line drugs used for Hypertension?

A

ABCD
1. ACE inhibitors/AT1 Blockers
2. Beta Blockers
3. Calcium Channel Blockers (Dihydropyridines)
4. Diuretics (Thiazide)

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2
Q

What are the second-line drugs used for Hypertension?

A
  1. Hydralazine
  2. Mineralocorticoid Receptor Antagonists
  3. Alpha Blockers
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3
Q

What are some Angiotensin Converting Enzyme Inhibitors?

A
  • Captopril
  • Lisinopril
  • Enalapril
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4
Q

What is the MOA of Angiotensin Converting Enzyme Inhibitors?

A
  1. prevents conversion of Angiotensin I to Angiotensin II so there will be no Angiotensin II effects :
    - sympathetic activation causing vasoconstriction and increased peripheral vascular resistance
    - aldosterone secretion which would cause sodium and water retention
  2. Blocks the normal physiological inactivation of Bradykinin leading to increased Bradykinin levels which stimulate Nitric Oxide and Prostaglandin synthesis. Nitric Oxide activated Guanylyl cyclase which forms cGMP from GTP. cGMP deactivates active myosin leading to myosin and actin uncoupling so there will be muscle relaxation.
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5
Q

What can Angiotensin Converting Enzyme Inhibitors be used for?

A
  • Hypertension
  • Cardiac Failure (because ACE-I reduced preload and afterload)
  • Prevents subsequent Myocardial Infarction (protective effect)
  • Chronic Renal Failure (hypertension is a cause of chronic renal failure because it can cause hypertensive nephropathy where nephrosclerosis occurs so since ACE-I can reduce systemic BP, there will be decreased damage to glomerulus and hence slows down progression to CRF)
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6
Q

What are the side effects of Angiotensin Converting Enzyme Inhibitors?

A
  • hypotension due to excessive reduction in BP
  • acute renal failure bcs ACE-I inhibit angiotensin II-mediated vasoconstriction of the efferent arterioles, reducing intraglomerular hydrostatic pressure and thereby decreasing GFR
  • hyperkalemia due to blocked aldosterone secretion
  • Angioedema (Bradykinin and Substance P induce inflammatory like vasodilation so there will be plasma extravasation)
  • Dry cough (increased sensitivity of bradykinin-dependent airway sensory nerve fibres)
    CONTRAINDICATED IN PREGNANCY BECAUSE TERATOGENIC
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7
Q

What are some AT1 Blockers?

A
  • Losartan
  • Valsartan
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8
Q

What is the MOA of AT1 Blockers?

A

Block Angiotensin II from binding to its AT1 receptor so there will be no effects of Angiotensin II :
- no sympathetic vasoconstriction
- decreased aldosterone secretion
- decreased inactivation of bradykinin so there will be nitric oxide and prostaglandin synthesis causing vasodilation

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9
Q

What are the side effects of AT1 Blockers?

A
  • same side effects as ACE inhibitors (acute renal failure, hyperkalemia, angioedema but NO/LITTLE DRY COUGH)
  • also CONTRAINDICATED IN PREGNANCY BECAUSE CAUSES RENAL FAILURE IN FETUS
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10
Q

Are AT1 Blockers and ACE Inhibitors given together?

A

No
1. they both work on the same pathway so there is no additive mechanism of action
2. but there is addition of the side effects which worsens the situation

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11
Q

What are some Beta Blockers given for hypertension?

A

Non selective :
- Propranolol
- Carvedilol

Selective Beta-1 antagonist :
- Atenolol
- Bisoprolol
- Metoprolol

Mixed :
- Nebivolol
(beta-1 selective at low doses but non selective at high doses. also has vasodilatory effects through increased NO release)

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12
Q

What is the MOA of Beta Blockers?

A
  1. Beta Blockers prevent adenylate cyclase activation so there will be lesser cAMP synthesised from ATP
  2. lesser cAMP available to activate PKA so PKA cannot open up plasma membrane calcium channel and this prevents calcium induced calcium release mechanism where extracytoplasmic calcium activates intracellular calcium release from sarcoplasmic reticulum
  3. lesser calcium-calmodulin complexes so MLCK won’t be dephosphorylated into its active form
  4. decreased MLCK phosphorylation of myosin light chain which is required for activation and myosin-actin complex formation so there will be reduced Heart Rate and cardiac contractility
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13
Q

What are the side effects of Beta Blockers?

A
  • Bradycardia and Hypotension from too much decrease in heart rate and contractility
  • Reduced exercise contractility because of the reduced heart contractility and cardiac output
  • AV nodal block which is a wanted effect in atrial arrhythmias but AV node cannot be blocked for too long as well
  • Bronchoconstriction especially due to non-selective beta blockers because beta 2 agonists normally cause cAMP synthesis which then goes on to phosphorylate MLCK into its inactive form such that myosin light chain cannot be phosphorylated and activated to form a complex with actin for bronchodilation. but beta 2 antagonists would prevent this bronchodilation. so CAUTION IN ASTHMATICS
  • can also cause vivid dreams and clinical depression
  • CANNOT USE IN DIABETICS BECAUSE BETA BLOCKERS MASK HYPOGLYCEMIC SYMPTOMS LIKE INCREASED HR, SWEATING AND TREMORS
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14
Q

What are Beta Blockers used for?

A
  • Hypertension
  • Cardiac Failure
  • Following myocardial infarction
  • Abnormal heart rhythms
  • Anxiety disorders
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15
Q

What are some calcium channel blockers used in Hypertension?

A

Dihydropyridines:
- Nifedipine
- Amlodipine

Non-dihydropyridines like Verapamil and Diltiazem can also be used. They have equal efficacy to Nifedipine

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16
Q

What are calcium channel blockers used for?

A
  • Hypertension
  • Anti-angina
  • Anti-arrhythmia (Non-dihydropyridines) because calcium ion channels involved in heart muscle depolarisation
  • Amlodipine can also be used to prevent myocardial infarction and stroke

*not used in heart failure because decrease heart contractility TOO MUCH

17
Q

What is the MOA of dihydropyridine calcium channel blockers?

A
  • Blocks ligand type calcium channels from opening so less extracellular calcium ions enter the cells and induce calcium release from sarcoplasmic reticulum. so decreased calcium-calmodulin complex to activate MLCK which will phosphorylate myosin to form complex with actin for muscle contraction
  • DHPs have higher affinity for arterial blood vessels than cardiac muscle. decreased vascular contraction means decreased peripheral resistance and afterload so BP drops (non-DHPs have higher affinity for cardiac muscles than blood vessels)
18
Q

What are the side effects of dihydropyridine calcium channel blockers?

A
  • Flushing, dizziness, nausea, constipation which occur due to excessive drop in blood pressure from vasodilation
  • Peripheral edema because vasodilation leads to increased vascular permeability
    SHOULD NOT BE USED IN CONGESTIVE HEART FAILURE AS CALCIUM CHANNEL BLOCKERS CAUSE DECREASED MYOCYTE CONTRACTILITY.
19
Q

Can beta-blockers and calcium channel blockers be used together?

A

Yes because these two drugs work on different pathways. Beta blockers cause indirect inhibition of calcium channels but calcium channel blockers cause direct inhibition of extracellular calcium influx.

20
Q

What are some diuretics used for Hypertension?

A

Thiazides :
- Hydrochlorothiazide
- Indapamide

21
Q

What is the MOA of thiazides?

A
  1. they block the Na/Cl transporter on the apical membrane of distal convoluted tubule. so these ions remain in lumen and cause hypertonicity so at the collecting ducts, water will remain in the lumen and not get reabsorbed passively so there will be increased urination volume
  2. Thiazides inhibit NaCl reabsorption by blocking the Na+/Cl- transporter on the apical surface. The resulting decrease of Na+ concentration in the tubular cells enhances the activity of the Na+/Ca2+ exchanger on the basal surface, creating an increased drive for Ca 2+ reabsorption through the epithelial Ca2+ channels on apical surface. Net result of thiazide enhances Ca2+ reabsorption, thus reducing hypercalciuria

(thiazide MOA is dependent on renal prostaglandins so NSAIDS can interfere with thiazide MOA by reducing prostaglandin synthesis)

*look at lecture slides for diagram

22
Q

What are thiazides used for?

A
  • Hypertension
  • Congestive Heart Failure (decreases blood volume so decreased preload)
  • Nephrolithiasis due to hypercalciuria
  • Nephrogenic Diabetes Insipidus (nephrogenic DI caused by low or no response to ADH so there is no water reabsorption at the collecting ducts causing excess urination. However, thiazides cause sodium chloride excretion so there is decreased osmotic pressure in the body fluids and a decreased sense of thirst. This causes extracellular volume to decrease and GFR decreases as well leading to lower urine production and proximal reabsorption of water so there is lesser water delivered to collecting duct causing decreased urination)
23
Q

What are the side effects of thiazides?

A
  • hypokalemia metabolic alkalosis (thiazide causes large volume of urination so this causes decreased blood volume and hence RAAS activation causing aldosterone mediated K+ and H+ secretion at the collecting duct)
  • hyponatremia (MOA of thiazide is to block sodium reabsorption at DCT)
  • hyperuricaemia (thiazides directly increase urate reabsorption at PCT) so can cause gout
  • hyperglycemia (hypokalemia caused by thiazides means there is decreased K+ in the interstitium so K+ channels at pancreatic B cells are open for longer leading to hyperpolarization which does not allow voltage gated calcium channels to open so there is reduced exocytosis of insulin granules which is activated by calcium influx)
  • hyperlipidemia
  • hypercalcemia (from increased calcium reabsorption)
24
Q

What is the MOA of hydralazine?

A
  • inhibits IP3 induced release of calcium from the sarcoplasmic reticulum so calcium-calmodulin complexes cannot be formed to dephosphorylate MLCK and hence there will be decreased activated myosin forming actin-myosin complexes for vasoconstriction
  • decreased peripheral resistance can cause reflex compensatory epinehrine/norepinephrine release so there is increased venous return and cardiac output which helps heart failure with reduced EF
25
Q

What is hydralazine used for?

A
  • first line for heart failure with reduced EF and given tgt with Isosorbide dinitrate
  • second line for hypertension that is not responsive to first line drugs
  • first line for peripartum or postpartum haemorrhage
26
Q

What are the side effects of hydralazine?

A
  • Flushing, hypotension and tachycardia related to baroreflex associated sympathetic activation
  • hydralazine induced lupus syndrome causing athralgia, myalgia, serositis and fever but resolved when stop using hydralazine
    CONTRAINDICATED IN CORONARY ARTERY DISEASE BECAUSE HYDRALAZINE’s STIMULATION OF SYMPATHETIC SYSTEM CAUSES INCREASED CARDIAC OXYGEN DEMAND WHICH CAN LEAD TO MYOCARDIAL ISCHEMIA
27
Q

What are some mineralocorticoid receptor antagonists used in hypertension?

A
  • spironolactone
  • eplerenone
  • finerenone
28
Q

What are some alpha adrenergic antagonists?

A
  • Prazosin
  • Alfuzosin
  • Terazosin
29
Q

What is the MOA of alpha adrenergic antagonists?

A

Block a1 receptors on vascular smooth muscles in the periphery which cause vasoconstriction so by preventing this, alpha adrenergic antagonists reduce peripheral vascular resistance and stop BP from rising

  • also used for symptomatic relief of urine retention due to BPH as a1 agonists cause inhibition of urination at bladder by causing muscle contraction of the bladder neck and prostate
30
Q

What are side effects of alpha adrenergic antagonists?

A
  • safe to use in renal impaired patients because does not affect renal blood flow and GFR
  • no teratogenicity at clinical doses
  • but there may be reflex tachycardia, depression, urinary frequency and flushing
31
Q

What are the drug combinations that can be used for Hypertension?

A
  1. Calcium Channel blocker and ACE Inhibitor/AT1 Blocker
  2. Calcium Channel blocker and Diuretic
  3. Diuretic and ACE Inhibitor/AT1 Blocker
  4. Calcium Channel Blocker and Beta Blocker
    CANNOT COMBINE ACE INHIBITOR/AT1 BLOCKER + BETA BLOCKER

*Beta blocker and thiazide diuretics should not be used in diabetic patients

32
Q

What is sodium nitroprusside?

A
  • used for lowering of blood pressure immediately in adults and children with high blood pressure. can also be used for congestive cardiac failure
  • complexed with nitric oxide (NO) and five cyanide ions
  • SNP reacts with sulfhydryl groups on erythrocytes (as well as albumin and other proteins) to produce nitric oxide (NO)
  • can cause cyanide poisoning

Systemic Pharmacology (8 decks)

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