Pharmacological strategies to reduce cardiovascular risk

nitrates

Vasodilators (short lived but potent)

Induce release of nitric oxide (NO)

In Low dose

• relax venous smooth muscle

  • via cGMP mediated activation of PKG

In High dose

• relax arteriolar smooth muscle

  • via cGMP mediated activation of PKG

→ dilation of peripheral arteries & veins (reduces preload and afterload)

PKG

Protein Kinase G

• activated by nitrates via cGMP

• activates a variety of systems:

  1. Activates K+ efflux channels by phosphorylation → hyperpolarisation

  2. Activates pumps to sequester calcium

     • calcium inhibited from promoting muscle contraction

  3. Inhibits rho kinase (ROCK) → stimulates myosin phosphatase

     • myosin inhibited from binding to actin, contracting muscle

• Thereby promotes muscle relaxation

nitrate subgroups

1. Short acting

   • Glyceryl trinitrate (GTN)

   • Three Ns sourced per molecule (compared to one - this means faster and more intense onset)

   • Sublingual or IV (high first pass)

   • Acts in seconds to relieve pain of attack

2. Long acting

   • Isosorbide dinitrate, isosorbide mononitrate

   • One N sourced per molecule (mononitrate form)

   • Oral (sustained release) or transdermal patch

   • long term will cause problems

nitrate AEs

• Vasodilation → lowered BP → can evoke reflex tachycardia

  • HR will increase in response to try and increase BP

    → ↑ cardiac oxygen demand

  • response: beta-blocker (targets SA node)

• Headache (vasodilation of brain blood vessels ouch)

• Flushing (duh)

• Dizziness (postural hypotension)

• Tolerance

  • Ensure 8-10h nitrate free interval per 24h

explain nitrate tolerance

• Within 24 hours, vasodilation → BP drops → body compensates:

  1. RAAS activation: kidneys retain sodium + water → ↑ plasma volume

     (homeostasis: since venous return ↑ but heart isn’t able to pump faster, body holds onto water)

  2. ↑ catecholamines → vasoconstriction.

  3. ↑ vasopressin (ADH): more water retention → ↑ plasma volume

• True tolerance: After about 48–72 hours of continuous exposure, body decreases NO production

  1. aldehyde dehydrogenase inhibition (enzyme that converts nitrates to NO)

  2. increased chemical mechanisms which scavenge/inactivate nitric oxide (since NO is a reactive chemical species → body has mechanisms in place to rapidly inactivate it)

Aspirin mostly deactivates platelets in______

Aspirin mostly deactivates platelets in hepatic portal system (as aspirin is inactivated in the liver-> converted to salicylic acid)

Aspirin, when its bound to COX in a platelet, is active for_____

active for 7-10 days (platelet lifespan)

NSAID (ibuprofen) and aspirin drug interaction

Ibuprofen taken at the same time as aspirin-> ibuprofen blocks the access of aspirin (steric interference)

Shouldn't be taken at the same time

Adenosine Diphosphate (ADP) role in platelet formation

Released from platelet dense-granules & injured cells

binds to 2 platelet G-protein-coupled receptors:

• P2Y1

  • initiates ADP-induced platelet aggregation

• P2Y12

  • Mediates platelet activation:

    • inhibits adenylate cyclase-mediated signaling pathway

      &

    • decreases intracellular cAMP levels.

    → decreased rate of phosphorylation of vasodilator-stimulated phosphoprotein

    → decreased activation of GPIIb/IIIa receptor & platelet aggregation

clopidogrel MOA

Active metabolite of clopidogrel (since clopidogrel is a prodrug) irreversibly inactivates P2Y12 receptor

→ prevents ADP binding to this receptor and activating glycoprotein IIb/IIIa

→ inhibits ADP-induced platelet aggregation and reduces platelet dense-granule secretion (which includes ADP)

Clopidogrel vs Ticagrelor

Both are P2Y12 receptor blockers, but: 
Clopidogrel has to be metabolised to its active metabolite before it exerts its action on the receptor, whereas Ticagrelor can directly act on the receptor

→ certain drugs can prevent the metabolism of clopidogrel into its active state

Ticagrelor is also reversible whereas clopidogrel is irreversible

statins

HmG CoA reductase inhibitor

• Rate-limiting enzyme in cholesterol synthesis

By decreasing the cellular production of cholesterol, statins force the cell to import (through diet rather than making) more of it, using the LDL-receptor. This reduces cholesterol circulating in plasma.

Always ends in -statin e.g. Rosuvastatin (this is literally a random one, idek if we need an example)

statins AEs

• Myalgia/myopathy

  • Myalgia (aches & weakness) + increased creatine kinase (marker of muscle damage)

  • Super bads

• Diabetes mellitus T2

• Skin rashes

• GIT

• Drug interactions

  • warfarin (­ bleeding risk)

  • Myopathy incidence significantly higher when statins taken with CYP inhibitors

(might just need to know myalgia)

Fibrates

• usually a statin works better, except for hypertriglyceridemia (isolated)

• e.g. Gemfibrozil or Fenofibrate

Fibrates MOA

Activate PPAR (peroxisome proliferator-activated receptors), esp PPARα:

• Intracellular receptors modulate carbohydrate & fat metabolism

• Induce transcription of a number of genes that facilitate lipid metabolism

• increase ­activity of lipoprotein lipase & increase synthesis of apoC-III together enhance clearance of circulating TG-rich lipoproteins.

→ increased hepatic fatty acid oxidation → increased production of TG-rich lipoproteins

(might not need to know in detail)