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MWU Pharmacology II > Antihypertensives I and II > Flashcards

Antihypertensives I and II Flashcards

1
Q

What are the 4 major determinants of hypertension

A

1) Arterial Pressure
2) Autonomic Control
3) Renin Angiotensin Aldosterone System (RAAS)
4) Vascular Mechanisms

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2
Q

What are short and long term factors contributing to autonomic blood pressure control?

A

Short term - Adrenergic reflexes

Long Term - Adrenergic + hormonal + volume assoc. factors

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3
Q

What are the adrenergic receptors and effects on the vascular smooth muscle, kidneys, myocardium and CNS-neurons?

A
  • Vascular Smooth Muscles
    α1- stimulation causes vasoconstriction (smaller distribution and reduced expression of α2 in comparison to α1)
    β2- stimulation causes vasodilation (smaller distribution)
  • Kidneys
    α1 - tubular reabsorption of Sodium
    β1 - stimulation leads to renin release
  • Myocardium
    β1 - causes an increase in myocardial contraction
  • CNS – neurons
    α2 - act as negative feed back/ inhibitor for NE release
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4
Q

Name the two major vasoactive compounds contributing to blood pressure control, and their functions.

A

Nitric Oxide - major endogenous vasodilator

Endothelin - major endogenous vasoconstrictor

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5
Q

What are the 7 classes of antihypertensive drugs?

A
  1. Diuretics
  2. Sympatholytic Drugs
  3. Ca2+ Channel blockers
  4. ACE inhibitors
  5. Angiotensin II receptor (AT1R) antagonists
  6. Direct Renin Inhibitor
  7. Vasodilators
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6
Q

Name the 3 classes of diuretics.

A
  1. Thiazides and related agents
  2. Loop diuretics
  3. K+ sparing diuretics
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7
Q

Name the 2 thiazides, 3 loop and 4 K+ sparing diuretics

A

Thiazides: Hydrochlorthiazide, Chlorthiazide

Loop diuretics: Furosemide, Torsemide, Ethacrynic Acid

K + sparing diurectics: Amiloride, Triamterene, Spironolactone, Eplerenone

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8
Q

5 different groups of sympatholytic drugs

A
  1. B - receptor antagonists
  2. a - receptor antagonists
  3. a / B receptor antagonists
  4. Centrally acting adrenergic agents
  5. Adrenergic neuron blocking agents
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9
Q

Name 3 B, 3 a and 2 a / B receptor antagonists

A

B - receptor: Propranolol, Atenolol, Metaprolol

a - receptor: Prazosin, Terazosin, phentolamine

a / B - receptor: Labetalol, Carvedilol

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10
Q

Name 4 centrally acting adrenergic agents and 2 adrenergic neuron blocking agents

A

Centrally acting adrenergic agents: Methyldopa, Clonidine, Guanabenz, Guanfacine

Adrenergic neuron blocking agents: Guanadrel, Reserpine

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11
Q

Name 6 Ca 2+ Channel blockers

What’s the common ending

A

Verapamil, diltiazem, nifedipine, nicardipine, clevidipine,
amlodipine

remember dipine ending

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12
Q

Name 5 ACE Inhibitors

What’s the common ending?

A

Captopril, Lisinopril, Enalapril, Ramipril, Benazepril

remember pril ending

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13
Q

Name 5 AT II (AT1R) antagonists

Common ending

A

Losartan,
Candesartan, Valsartan, Telmisartan, Olmesatran

artan ending

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14
Q

Name the direct renin inhibitor

A

Aliskiren

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15
Q

Name the 3 vasodilators

A

Arterial: Hydralazine, Minoxidil

Arterial and Venous: Nitroprusside

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16
Q

Name the 3 loop diuretics, their MOA and location of MOA.

A

Furosemide, Torsemide, Ethacrynic acid

MOA:

Location is thick ascending limb

Reabsorption of sodium, potassium, and chloride are performed by a Na+/K+/2Cl– carrier (NKCC2), where the loop diuretics act.

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17
Q

Name the 2 Thiazide diuretics their location of action and MOA.

A

Hydrochlorthiazide and Chlorthiazide

MOA:
➢The distal convoluted segment actively pumps sodium and chloride out of the lumen of the nephron via the Na+/Cl– Carrier (NCC)

➢Na+/Cl– carrier is the target of the thiazide diuretics.

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18
Q

Name 3 adverse effects of Thiazide and Loop diuretics

effects on electrolytes, who should avoid them, Serious AE (what to do if this occurs?)

A

➢ The Thiazide and Loop diuretics are K+ depleting
(Hypokalemia) diuretics.

➢ Thiazides appear in breast milk so should be avoided by nursing mothers

➢ Serious AE is Ischemic Ventricular Fibrillation and sudden death in patients. It is mostly due to joined effects of hypokalemia, hyponatremia and calcium imbalance. Careful monitoring is required and should be switched to K+ sparing diuretic medications.

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19
Q

What are the 4 K+ sparing diuretics, their MOA, location and adverse effects?

A

Amiloride, Triamterene, Spironolactone, Eplerenone

➢ MOA- By targeting ENaC (Epithelial Sodium Channels), these agents prevent Sodium re-absorption fromcollecting duct.

➢This class also spare K+ ions (also referred to as K+ sparing diuretics)

➢ AE- Hyperkalemia

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20
Q

What receptors do Atenolol and Metoprolol block?

A

Cardioselective B1 blockers

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21
Q

What receptors does propranolol block?

A

B1 and B2

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22
Q

What receptors do Labetolol and Carvedilol block?

A

a and B (B1 and B2)

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23
Q

What is the MOA of beta blockers in the myocardial tissue, and kidneys? Effect on peripheral resistance?

A

β1 receptors are widely present in myocardial tissue and blocking of this receptor causes a reduction in myocardial contractility, heart rate, and cardiac output.

β1 receptors are also present in the kidneys, and following blockade of β1 receptors of the juxtaglomerular cells, renin secretion is reduced thus
decreasing Angiontensin II levels

It also cause a decrease in peripheral resistance resulting in the reduction in arterial pressure (Renin-AngII-AT1R effect)

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24
Q

What is a major adverse effect associated with beta blockers, and what causes it?

A

Rebound hypertension.

Sudden discontinuaiton of B1 adrenergic blockers can produce a withdrawal syndrome.

This is likely due to upregulation of beta receptors (adaptive response of body)

This leads to enhanced sensitivity to endogenous catecholamines

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25
Q

Identify 2 contraindications of beta blockers.

A

1) It should be avoided in patients with reactive airway disease (asthmanonspecific beta 2 receptor blockade)

2) It should not be administered to patients with myocardial conduction defects like SA or AV nodal dysfunction (careful monitoring required)

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26
Q

Identify some drug-drug interactions of beta blockers.

A

A nonselective beta blocker in combination with Epinephrine causes hypertension - result of α adrenergic receptors stimulation (Epinephrine effect).

Should not be administered with drugs that inhibit SA/AV conduction, such as Verapamil/Diltiazem (Calcium channel blockers) leading to conduction block.

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27
Q

Name 3 a1 adrenergic receptor antagonists, and their MOA

A

Prazosin, Terazosin and Doxazosin

MOA :- α1 adrenergic receptor antagonists reduce arteriolar resistance and increase venous capacitance (action on vascular smooth muscle).

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28
Q

What are some adverse effects of a1 blockers.

A

➢ The α1 adrenergic blockers cause a variable amount of postural hypotension.

➢ Retention of salt and water occurs following chronic use, and this compensates the postural hypotension but accompanied by peripheral edema

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29
Q

Describe the structure of Labetolol.

A

Mixture of four stereoisomers. One isomer is an α1 antagonist, another nonselective beta antagonist with slight partial agonist activity, and the other two isomers are inactive.

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30
Q

Which drug can reduce blood pressure in cases of hypertensive emergencies or crisis?

A

Labetolol - ➢Due to its ability to block α1 adrenergic receptors, labetalol i.v can reduce blood pressure sufficiently in case of hypertensive emergencies or crisis.

31
Q

Describe alpha / beta activity of Carvedilol.

A

Carvedilol is a beta receptor antagonist with also α1 receptor antagonist activity. The ratio of α1 to beta receptor antagonist potency for carvedilol is approximately 1:10.

32
Q

How is Carvedilol metabolized? What can it be given with as an adjunct therapy? What are some contraindications?

A

Carvedilol metabolism :- Oxidation and glucuronidation in the liver; the oxidation occurs via CYP2D6.

It can be used as an adjunctive therapy with diuretics and ACE inhibitors.

Contraindications: It should not be given to patients with decompensated heart failure who are dependent on sympathetic stimulation.

33
Q

What are the 4 centrally acting adrenergic agents

A

methyldopa,
clonidine, guanabenz, guanfacine

34
Q

Explain metabolism of methyldopa, the MOA and result?

A

Methyldopa (prodrug) is metabolized by the L-aromatic amino acid decarboxylase in adrenergic neurons
* α-methyldopamine – > α-methylnorepinephrine.

MOA :- The α-methylnorepinephrine (MNE) acts on the presynaptic adrenergic neurons (α 2) in the CNS by preventing further release of NE (negative feedback loop)

As a result, the vasoconstrictor adrenergic signals are reduced

35
Q

Describe MOA of clonidine, guanabenz and guanfacine

A

MOA:- They stimulate the α2A subtype receptors in the brainstem as a result there is reduced NE release and plasma NE

36
Q

Identify some adverse effects of the centrally acting adrenergic agents

HR / liver / why is close monitoring required?

A

severe bradycardia and sinus arrest and hepatotoxicity.

1-5% of these patients develop a hemolytic anemia, so close monitoring and immediate discontinuation
of drug is required.

37
Q

What are the 2 adrenergic neuron blocking agents?

A

Guanadrel, Reserpine

38
Q

How does guanadrel work, and its MOA?

A

➢Inhibits the peripheral postganglionic adrenergic
neuronal activation.

➢MOA:- Acts as exogenous false neurotransmitter that is accumulated, stored, and released like NE but is inactive at adrenergic receptors. (Replacement for NE)

39
Q

Guanadrel: Adverse effects, drug-drug interactions and contraindications.

A

Adverse Effects: Intermittent Hypotension and Sexual dysfunction due to loss of sympathetic function

DDI for Guanadrel:
Drugs that compete for the catecholamine transporter on the presynaptic region will reduce the effects of guanadrel.

Eg:- tricyclic antidepressants, cocaine, chlorpromazine, ephedrine, phenylpropanolamine and amphetamine

Contraindicated
Guanadrel can promote NE release from pheochromocytomas, so not used in the patients.

40
Q

What is the MOA of Reserpine? What type of transporter does it affect?

A

They remain tightly bound to vesicles in both CNS and Peripheral neurons.

It has both central and peripheral effect.

It causes irreversible binding followed by loss of function of Vesicular Monoamino Transporter, (VMAT2), known to store and accumulate
catecholamines.

41
Q

Reserpine: Adverse effects and contraindications

A

Adverse Effects:
Psychotic depression which eventually leads to suicide.

Drug must be immediately discontinued following signs of depression, effects lasts for many months even after discontinuation of the drug

Contraindications :
Never should be administered to patients with depressive illness

42
Q

What is the mechanism of action of Calcium Channel Blockers

A

The CCBs block the L-type calcium channel

They decrease the intracellular calcium pool and calcium mediated calcium increase

The effects are on cardiac muscle and vascular smooth muscle

They slow down the heart rate and decrease peripheral vascular resistance

43
Q

Name 4 calcium channel blockers most important for exam

A

Nifedipine - 1st Gen dihydropyridine group
Verapamil - phenylalkylamine group
Diltiazem - benzothiazepine group
Clevidipine - ultra short acting 3rd gen dyhydropyridine

44
Q

How is clevidipine administered and metabolized?

A

Clevidipine (administered as i.v inj) – is the ultra short acting (3rd gen) dihydropyridine class with high specificity to vasculature. Metabolism of clevidipine is hepatic and renal independent and is by plasma and tissue esterases.

45
Q

What is a major adverse effect associated with calcium channel blockers?

A

As a result of decrease in peripheral vascular resistance caused by the Ca2+ channel blockers, could indirectly evokes a baroreceptor mediated sympathetic discharge. As a result, tachycardia pursues due to SA node activation.

46
Q

Drug-drug interactions and contraindications of calcium channel blockers

A

**DDI- **In combination with β receptor antagonist, it aggravates the negative chronotropic effect.

Contraindication-In patients with a history of SA nodal block, MI, angina or severe cardiovascular events, the combination with β receptor antagonist can lead to heart block. Should be avoided.

47
Q

Identify the direct renin inhibitor, its MOA, adverse effects and contraindications

A

Aliskiren

  • MOA :- It directly and competitively inhibits renin, as a result, renin mediated cleavage of angiotensinogen to angiotensin I (Ang I) is completely blocked.

AE- Angioedema has been reported in clinical trial.

Contraindicated in pregnant women
due to fetal damage

48
Q

What are the 5 ACE Inhibitors and their MOA?

A

Captopril, Lisinopril, Enalapril, Ramipril, Benazepril

MOA :- Involves the inhibition of ACE thus preventing Ang II generation

49
Q

What are the primary and secondary benefits to using ACE inhibitors?

A

➢Primary benefit includes prevention of vasoconstriction due to Ang II binding to its receptor

➢Secondary benefit includes inhibition of the rise in aldosterone levels and aldosterone mediated increased Na+ uptake, partially mediated by AT1 receptor activation

50
Q

Identify an adverse effect of ACE inhibitors

A

Angioedema- swelling of the mucosal, dermal and subcutaneous tissue due to vascular leakage. It is life threatening and ACE Inhitors should be immediately discontinued when the signs appear.

Cough is a common adverse effect due to bradykinin accumulation

51
Q

Indentify some contraindications of ACE inhibitors and a drug-drug interaction.

A

ACE Inhibitors are contraindicated during pregnancy due to heavy risk to fetal health.

It is also contraindicated in patients with compromised renal function or renal failure.

DDI: - Hyperkalemia results from moderate to high doses in combination with K+ sparing diuretics, so monitoring is required

52
Q

What are the 7 AT1 receptor antagonists and their MOA?

Just remember the ending

A

Losartan, Valsartan, Telmisartan, Azilsartan , Candesartan, Eprosartan Irbesartan
-Sartan ending

MOA: By antagonizing the effects of AngII on the AT1 receptors, these agents relax smooth muscle and thereby promoting vasodilation. By preventing aldosterone synthesis these agents promote renal salt and water excretion, reduction in plasma volume.

They act specifically on AT1 receptors, present in vascular tissue, heart, kidneys, brain and zona glomerulosa (site of aldosterone synthesis in adrenal glands).

53
Q

Explain relationship between long term AT1 receptor blocker use and renin / angiotensin II levels.

A

AT1 also is involved with negative feedback inhibition of renin release. Due to AT1 R inhibition there is enhanced Renin and Angiotensin II levels in the circulation, because the AT1 R are not able to activate negative feedback loop.

54
Q

What are some adverse effects of AT1 Receptor Antagonists.

A

Hypotension, hyperkalemia and reduced renal function

55
Q

What type of drug is hydralazine, and its MOA?

A

Vasodilator

Hydralazine- One of the most orally active drug.

MOA:- Hydralazine causes a decrease in intracellular calcium, mostly by preventing an Inositol TriPhosphate 3 (IP3) mediated release of Ca2+ from intracellular pools (from SR).

56
Q

What kind of drug is Minoxidil, and its mechanism of action?

A

K+ ATP Channel opener

MOA :- Minoxidil (parent drug) is inactive, and it
needs to be converted to an active metabolite
minoxidil N-O Sulfate (Minoxidil Sulfate) by hepatic
sulfotransferase.

Minoxidil Sulfate activates ATP modulated K+ channel, opening the K+ channel and promoting efflux of K+ in smooth muscle cells causing hyperpolarization and relaxation

57
Q

What are some adverse effects of Minoxidil?

A

Adverse effects – Hirsuitism (excess hair growth) , Pseudoacromegaly (No major influence of Growth Hormones)

Serious Adverse Events with warning
- Pericardial effusion is a rare but dreadful effect. Minoxidil should be discontinued

58
Q

What is the nitro-vasodilator and its MOA

A

Arterial and Venous (Nitroprusside)

MOA:- It immediately releases NO-> which then activates guanylyl cyclase –cGMP-PKG leading to vasodilation.

59
Q

What can nitroprusside do that other vasodilators cant, and what are some contranindications?

A

Nitroprusside has the ability to dilate both arterioles and venules to the same extent.

Contraindictaions: In renal and hepatic failures and compromised functions not recommended

60
Q

Explain the drug metabolism of nitroprusside

A

Ideally one molecule of sodium nitroprusside reacts with hemoglobin in blood to form —–→ cyan-methemoglobin + free Cyanide (CN) ions + NO

Thiosulfate in the system reacts with cyanide to form thiocyanate (water soluble and less toxic than cyanide), which is eliminated in the urine

The remaining cyanide binds with mitochondrial cytochrome enzymes and prevent oxidative phosphorylation inside the cells causing cellular toxicity

61
Q

What are some adverse effects and toxicities of nitroprusside?

A

The short term effects are due to excessive vasodilation and hypotension so close monitoring is required.

A rare phenomenon of cyanide toxicity, due to conversion of nitroprusside to cyanide and thiocyanate. Accumulation of cyanide causes lactic acidosis and it can result in anorexia, nausea, fatigue, disorientation and toxic psychosis.

62
Q

What is a preventative measure for cyanide toxicity with nitroprusside?

What is the preferred treatment method?

A

Preventive measure for cyanide toxicity: Administration of thiosulfate as prolonged infusion based on the dose of sodium nitroprusside administered.

Preferred treatment: Administration of hydroxocobalamin (IV route) which combines with cyanide to form Cyanocobalamine (vitamin B12) when administered for longer duration.

63
Q

What is pulmonary hypertension (PH)?

A

A disorder of pulmonary vasculature which is normally accompanied by cardiopulmonary, vascular and inflammatory disorder

Pulmonary Hypertension accompanied by narrowing of vessels (arteries) and enlargement of ventricular muscles in the heart (hypertrophy)

64
Q

What are some classifications of pulmonary hypertension?

5 of them

A

Pulmonary Arterial Hypertension

Pulmonary Hypertension due to left heart disease

Pulmonary Hypertension due to respiratory diseases or hypoxia

Chronic thromboembolism mediated Pulmonary Hypertension

Pulmonary Hypertension due to multifactorial causes

65
Q

What are the 4 classes of drugs to treat PH

A
  1. Soluble Guanylyl Cyclase (sGC) Stimulators
  2. Phospho-diesterase 5 (PDE5) Inhibitors
  3. Prostacyclins and prostacyclin receptor agonists
  4. Endothelin receptor Antagonists
66
Q

Name 1 soluble guanylyl cyclase Stimulator and 2 Phospho-diesterase 5 Inhibitors

A

Soluble Guanylyl Cyclase (sGC)Stimulator: Riociguat

Phospho- Diesterase 5 (PDE5) Inhibitors: Sildenafil, Tadalafil

67
Q

Name 3 Prostacyclins and Prostacyclin Receptor Agonists

1 agonist and 2 analogs

A

Selexipag – prostacylin receptor (IPR) agonist

Iloprost and Treprostinil – Prostacyclin analogs

68
Q

Name 3 endothelin receptor antagonists

common ending?

A

Bosentan, Ambrisentan and Macitentan

common ending: entan

69
Q

Riociguat: Class, MOA and metabolism

A

Class: Soluble Guanylyl Cyclase (sGC)Stimulator

MOA: It is a direct activator of sGC and also sensitizes the
endogenous sGC to NO signaling

Metabolism: converted to active form by CYP1A1 (major), which then has to be converted to N-glucuronide form which
is inactive and excreted

70
Q

Adverse effects of Riociguat

A

Adverse Effects –Embryo-fetal toxicity is reported with
use. Should be avoided along with Nitrovasodilators or PDE5
inhibitors. Known to cause severe hypotension

71
Q

Sildenafil and Tadalafil: Class, MOA and Adverse Effects

A

Class: Phospho- Diesterase 5 (PDE5) Inhibitors

MOA – Competitive and selective inhibitor of PDE5. Prevents he breakdown of cGMP to 5’ –GMP, resulting in enhanced GMP and PKG signaling cause smooth muscle relaxation. Sildenafil is more selective towards PDE5.

Adverse effects – Incidence of hypotension and fatal hypotension

72
Q

Selexipag, Iloprost and Treprostinil: Classes, MOA and Adverse Effects

A

Selexipag: IPR agonist
Iloprost and Treprostinil: Prostacyclin analogs

MOA – Prostacyclins (endogenous), its analogs and receptor
agonists bind to the prostacyclin receptor- (IPR) on the membrane of pulmonary artery smooth muscle cells. IPR activation leads to activation of cAMP—> PKA signaling with resultant relaxation of pulmonary artery smooth muscles.

Adverse effects – Nausea, vomiting and flushing

73
Q

Bosentan, Ambrisentan and Macitentan: Class and MOA.

A

Endothelin receptor Antagonist

Endothelin is a natural endothelium derived constricting factor. Endothelin acts via ETA and ETB receptors. ET receptors are coupled to Gq-protein. Once activated ET receptors leads to activation of Inositol Triphosphate (IP3). IP3 causes the release of calcium from sarcoplasmic reticulum (SR) resulting in increased smooth muscle contraction.

MOA – The antagonists (Bosentan, Ambrisentan and Macitentan) by blocking ET receptors prevents the ET receptor mediated contraction, with resultant relaxation of smooth muscles.

74
Q

Endothelin Receptor Antagonist Metabolism and Adverse Effects

A

Metabolism: Mostly metabolized by CYP3A4 and CYP2C9

Bosentan is a strong CYP3A4 inducer too, so should be avoided with drugs that are mostly metabolized by CYP3A4

Adverse effects: Rarely pulmonary edema, testicular atrophy and infertility

Also know to increase liver transaminases

MWU Pharmacology II (8 decks)

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