Pharmacology of Cardiovascular Disease

1. Captapril

Nota:

• Used in hypertension, congenitive heart failure, oedema (swelling in extremities => used to get rid of fluid that is causing this swelling)
• Not entirely certain how they work => know that they do increase Sodium (Na+) and some Chloride (Cl-) excretion => the water follows by osmosis => this leads to a decrease in blood volume => lowered BP => this effect occurs within 6 weeks => then start to normalize => but still get anti-hypertensive effect => conversely some diuretics that are better than thiazide diuretics which profoundly affect blood volume and sodium plasma levels => but do not have antihypertensive effect => so possibly more than just volume reduction that is having the effect

1. Loop
2. Thiazide

   Nota:

   • Work in the distal tubule in the kidney => blocks the NA+/Cl- cotransporter => leads to sodium being left in the kidney tubule => water stays in the kidney tubule => is excreted as urine => however, because there is at that point more sodium than normal => when it passes through the collecting duct => there is more sodium to activate the sodium channels there => potassium gets pumped out as a result (because it is a sodium/potassium pump) => thus pt's are predisposed to hypokalaemia when on these drugs => solution is to give potassium supplements or to use a potassium sparing diuretic instead
   • When we start using a thiazide diuretic => the body is going to respond => will detect the level of sodium in the plasma is lowered => kidney will start pumping out renin => stimulates production of angiotensin which leads to production of aldosterone => aldosterone will promote sodium retention (and thus potassium loss) => can get around this by using an ACEi => by blocking ACE, we block Angiotensin I from being converted to Angiotensin II => thus block aldosterone production => so get double whammy effect => quite good to use together => start with one or the other => if not enough, add them together
   1. Bendroflumethiazide
   2. Side Effects

      Nota:

      • Get potassium (K+) loss in plasma => hypokalaemia => this can be a major issue if pt also has other CVD => can be predisposed to arrhythmia's => do have strategies to circumvent this => e.g.can give potassium supplements or can give potassium sparing diuretic instead NOTE: do not give alongside ACEi => will get opposite => hyperkalaemia
      • the ATP sensitive potassium channels are also found on the pancreas => can impair insulin secretion => can cause hypoglycaemia => problem in diabetic patients
      • Impotence was a problem in male pt's in clinical trials => possibly due to vasodilation in the erectile tissue  => could possibly lead to impotence
3. Potassium Sparing

   Nota:

   • Diuretic that specifically targets the sodium/potassium pumps in the collecting duct => less likely to get hypokalaemia
   • Spironolactone works by inhibiting aldosterone => which promotes the action of the sodium/potassium pump => so by blocking the action of aldosterone => reduce the action of sodium/potassium pumps
   1. Amiloride

1. Losartan

1. Spironolactone
   1. Link to potassium sparing diuretics

Nota:

• One side effect is raynaud's syndrome => get cold extermities => due to blocking beta receptors in the very small blood vessels in the extremities => can also get bradycardia (slow heartbeat) some beta blockers are less likely to get these => e.g. pindolol (non-selective), metoprolol (cardioselective)
• Used in heart failure => seems paradoxical => would think you wouldn't want to slow heart down => however, initially pt's feel worse => but by slowly titrating up the dose => after the initial period, pt's feel better => have better outcomes, live longer
• Also used in angina => is reducing the work the heart is doing => reduces the oxygen demands Used in arrhythmia's => the sympathetic ns is pro-arrhythmagenic => beta-blockers block the increasing sino-atrial node activity Also used in glaucoma and myocardial infarctions
• They can be useful in hypertension but are being used less and less => are getting lower down in the NICE guidelines => however, there are certain situations where they can be useful => e.g. if the pt can't tolerate the other drugs that would usually be prescribed first or if the hypertension isn't getting better on the other drugs or if there is evidence of significant sympathetic drive, driving the hypertension
• Beta blockers are generally used to slow the heart beat => thus the blood pressure is lowered => because the flow of blood isn't being pushed as hard by the heart

1. Cardioselective

   Nota:

   • More selective for beta1 than beta2 => more watersoluble => don't cross BBB
   1. Atenolol
2. Non-selective

   Nota:

   • Don't distinguish between beta1 and beta2 => very lipophilic => cross BBB very easily => can cause very vivid, strange dreams => if so, can switch to a more watersoluble drug => won't cross BBB => won't affect dreams
   1. propranolol
3. Mixed pharmacology

   Nota:

   • Not only do not distinguish between beta1 and beta2 but also block alpha1 receptors => this can be very beneficial as this means get double whammy effect  => by blocking alpha1 receptors in the vasculator => get vasodilation => so can get affect on heart as well as in the periphery
   1. Labetalol

      Nota:

      • Labetalol (and carvedilol) are good because they have both alpha and beta blocking activity => get double effect => both on heart and vasculator => however, are associated with postural hypotension (from alpha blocking effect
4. Side Effects

   Nota:

   • Beta blockers have a long list of side effects => has led to them being used less and less => because we now have better drugs
   • => can cause bronchospasm => mainly a problem in asthmatics => Raynaud's syndrome => the beta blockers block receptors in the fine vasculator of the extremities => leads to vasoconstriction => pt get's cold extremities => if the drugs are stopped suddenly, can get rebound hypertension => need to make sure pt is aware of this => pt can get vivid, bizarre dreams => mainly a problem with the lipophilic ones (cross the BBB) => solve by switching to more water-soluble beta blocker => can mask the sympathetic response to hypoclycaemia (tremor/feeling faint when pt hasn't eaten) => problem for diabetics => body responds to low glucose levels by stimulating the sympathetic ns => is a warning sign => beta blockers will mask that mechanism => avoid in severe diabetes => can cause fatigue or lethargy => because the sympathetic ns is being blocked => have to be careful in pt's with heart failure => can cause heart block in certain situations => particularly if used in combination with rate-limiting calcium channel blockers

Nota:

• Also called sympatholytics => cause vasodilation by blocking alpha receptors in the blood vessels => sympathetic nerves innervate the blood vessels (i.e. arterioles) => noradrenaline causes them to constrict => by blocking that mechanism => causes vessels to relax => i.e. vasodilation => get a lowering of total peripheral resistance => so BP is lowered

1. Alpha1 selective
   1. Terazosin

      Nota:

      • Used to treat both hypertension and benign prostatic hyperplasia => useful if pt has both diseases
   2. Link to Labetalol
2. Alpha2 selective

   Nota:

   • Not particularly useful in CVD
   1. Yohimbine
3. Non-selective
   1. Phenoxybenzamine

      Nota:

      • Is not specific for alpha receptors => also antagonises the action of acetylcholine, histamine and 5HT Is irreversible => is not used very much => is still sometimes used in preparation for surgery to decrease bleeding, in phaeochromocytoma
   2. Phentolamine

      Nota:

      • More selective than phenoxybenzamine => but still not selective between alpha 1 and 2 => because it also blocks alpha 2 => blocks negative feedback mechanism in pre-synaptic neuron => get more NA release => not much of a problem in vasculator but is problem in heart => heart will start beating faster => opposite of what we want to be doing
4. Side effects

   Nota:

   • Can get postural hypotension => effectively inhibiting sympathetic drive to the blood vessels => normally when you change the position of your body => e.g. from horizontal to vertical => blood will fall in body due to gravity => body will respond to this by activating the sympathetic ns => get contraction of muscles in blood vessels to prevent blood from falling too far => BP will be restored => circulation to the brain will be maintained => with alpha blockers, lose this reaction => so pt may faint if they stand up too quick etc => consequently often advised to take these drugs at night

Nota:

• Don't really use them (in hypertension at least) because they don't distinguish between sympathetic and parasympathetic ns => get wide range of side effects => cause profound falls in blood pressure => get postural hypotension, flushing => have short duration of action

1. Link to Amiloride

1. Alpha 2 receptor Agonist
   1. Clonidine, Moxonidine

      Nota:

      • These are both direct alpha 2 receptor agonists => they switch off NA release from the neuron  => this can act as a sort of breaking mechanism => if you activate these receptors in the region of the brain that controls sympathetic flow => will reduce sympathetic drive to periphery => this will have an antihypertensive effect
   2. Side effects

      Nota:

      • Classic side effects for reduction in sympathetic activity  => sedation => can use as a sedative => used in veterinary medicine  => issue of rebound hypertension on withdrawal => have to ween pt's off the drug => also can get dry mouth and impotence => a positive side effect is increased HDL and decreased LDL 
   3. Alpha-methyldopa

      Nota:

      • Alpha methyldopa is a pro-drug that is almost identical in structure to L-DOPA (a precursor to NA) => has an additional methyl group => the enzymes that would usually convert L-DOPA to NA now convert the pro-drug to alpha-methyl-NA
      • Alpha-methyl-NA has affinity for alpha 2 receptors => whereas NA adrenaline has an affinity for alpha 1 and beta receptors => so will have double effect => activates alpha 2 receptors, which prevent more NA from being released from the presynaptic neuron => also preventing more NA from being made, thus preventing it's activation of alpha 1 and beta receptors post-synaptically 

Nota:

• Alpha Blockers aren't grouped with these as vasodilators because they are indirect vasodilators => are blocking vasoconstriction => thus have a vasodilatory effect
• These drugs act directly to relax smooth muscle => if we have vasodilation => gives rise to a decrease in total peripheral resistance => which leads to a fall in blood pressure

1. Calcium Channel Blockers

   Nota:

   • In order to induce contraction in the cell => part of the mechanism is the opening of voltage operated calcium channels => calcium goes on to activate other things that ultimately lead to the contraction of the cell
   • In order to prevent the contraction of the cell is to block these calcium channels => cell will be unable to contract  => this results in vasodilation
   • Looking at different calcium channel blockers => some are more selective for the vascular smooth muscle cells => while others are more selective for the cardiac cells => the reason for this selectivity is unclear => could be that the calcium channels in the heart are opening more often than in the vascular smooth muscle => could be that affinity for verapamil is greater in that state
   1. Nifedipine - Amlodipine

      Nota:

      • Used in hypertension and angina => in angina, are trying to reduce cardiac work => can reduce preload => can do this by causing a decrease in TPR
      • Have much less of an affect on the heart => can get effect in large enough doses => because causing vasodilation => get side effects like flushing, palpitations etc => can give alongside beta blocker => because effectively not touching heart
      1. Side effects

         Nota:

         • Because causing vasodilation => get flushing, headacher & postural hypotension
   2. Verapamil

      Nota:

      • Selectively blocks the voltage-gated calcium channels in the heart => have got to be careful if someone's got heart failure => don't want to give a drug that stops the excitability of the heart
      • Verapamil selectively targets the heart => it is negatively chronotropic (effect on the heartrate) and ionotropic (effect on the ion channels)  => useful in arrhythmia's => verapamil is very poor at arterial dilation => therefore poor at causing flushing and palpitations  => this is a good thing => if you are treating arrhythmia's => don't want these side effects
      • Don't want to give with a beta blocker => would then have two drugs slowing the heart => can also aggravate HF
      1. Do Not give in Heart Failure
   3. Diltiazem

      Nota:

      • Sits in middle between verapamil and nifedipine/amplodipine => does touch the heart, but not as much as verapamil  => can use with beta blockers but needs to be monitored
      1. Do Not Give in Heart Failure
2. Potassium Channel Activators

   Nota:

   • Open potassium channels to cause vasodilation => during a normal contraction => sodium channels will open and sodium will flow in the cell => they will then close and potassium channels will open => this will gradually repolarize the cell => this is called the refractory period => eventually the potassium channels close => but slightly overshoot the voltage => cell will be hyperpolarized and unable to commence another action potential => by keeping the potassium channels open with a drug => cell can be kept hyperpolarized => can't contract => causes vasodilation => because voltage-operated calcium channels will close and won't open again until the next action potential, which is being prevented from happening by keeping the potassium channels open
   1. Side effects

      Nota:

      • Headaches => vasodilation in the head used to promote hair growth for this reason => increased blood flow to the hair follicle stimulates hair growth
   2. Minoxidil

      Nota:

      • A potent and long-acting vasodilator => used as a drug of last resort in severe hypertension => when pt has shown to be unresponsive to other treatments => has marked salt and water retention => prescribed alongside a loop diuretic => also causes reflex tachycardia => prescribe a betablocker alongside to combat
   3. Hydralazine

      Nota:

      • Rarely used as mechanism of action is unknown => works mainly on arteries and arterioles => causes a fall in blood pressure => get reflex tachycardia and thus increased cardiac output => originally used in hypertension => but alternative agents generally preferred => has some use in short-term treatment in severe hypertension during pregnancy => but can cause a disorder resembling SLE (lupus) => also some place in treating HF pt's of African origin (in combination with a long-acting organic nitrate)
   4. Sodium Nitroprusside

      Nota:

      • Is what is known as a NO donor => NO is donated into the blood => it activates guanylyl cyclase => causes conversion of GTP to cGMP => this causes vasodilation => mainly used for hypertensive crisis => can give iv injection => get profound reduction in BP => can't really give chronically => body builds up tolerance => not clear why tolerance develops => one thought is that within the cell there are proteins with sulfyl hydryl groups that are necessary for the release of NO => could be that you use up these sulfyl hydryl groups=> also thought that there could be an increase in oxygen radicals => which is inactivating the NO=> can somewhat combat tolerance => by having pt only take dose during day => skip night => tolerance is slower to develop
   5. Bosentan
3. Side effects

   Nota:

   • Can get reflex tachychardia => because there is a fall in BP => body will sense this => will increase heart rate in an attempt to restore the BP => this can be a problem if there are comorbidities => i.e. cardiac problems => can give beta blockers to combat this
   • Can also get oedema => because of the vasodilation => can get fluid retention in the extremities => will get swelling in the extremities => combat this by giving a diuretic alongside