Topic 4: CVS pharmacology

What are the effects of sympathetic stimulation on the heart? What receptors are involved?

NT: NA

receptor: beta-1 adrenoceptor

effect:

• increased heart rate (chonotropic)

• increased force of contraction (inotropic)

• increases impulse of formation and reduces time period between formation (dromotropic)

• enhanced electrical conductance/automaticity

• increased cardiac oxygen consumption

• reduced cardiac efficiency

adrenaline = major domain is beta receptors

What is the mechanism of action of sympathetic stimulation of the heart?

mechanism:

1. stimulation of beta-1 adrenoceptors activates cAMP

2. cAMP activates PKA

3. PKA phosphorylates alpha-1 subunit of Ca2+ channels

4. this increases probability of Ca2+ channels opening

5. this increases Ca2+ influx

6. Ca2+ sensitivity of contractile machinery increases by phosphorylation of troponin C

7. this faciliates Ca2+ capture by SR (increases amount stored by SR)

8. this increases the amount of Ca2+ available for release by action potential

What are the effects of parasympathetic stimulation on the heart? What receptors are involved?

NT: ACh

receptor: M2 receptors

effect:

• vagal nerve fibres

• slows HR (chronotropic)

• decreases force of contraction (inotropic)

• decreases automaticity/inhibits AV conduction (dromotropic)

what is the mechanism of action of parasympathetic stimulation of the heart?

mechanism:

1. M2 receptors are negatively coupled to adenylyl cyclase

2. stimulation of M2 receptors causes inhibition of adenlyl cyclase

3. this decreases cAMP levels

4. this inhibits/decreases Ca2+ current/levels

5. and opens K+ channels

6. so increased K+ and decreased Ca2+ causes hyperpolarisation of cells

7. this has a decreased capacity to activate action potentials

Describe the factors involved in regulating coronary blood flow.

1. physical factors

   • BF occurs during diastole

   • tachycarida shortens diastole time → decreases time available for myocardial perfusion

2. vascular control by metabolites

   • decrease in arterial pO2 and pH causes increase in vasodilator compounds:

   • PGE2, PGI2, adenosine

3. neural and humoral control

   • sympathetic innervation - NA

   • circulating catecholamnes - A

   • alpha-1 = vasoconstriction

   • beta-2 = vasodilation

About what percentage of cardiac output is used to perfuse the heart itself through the coronary circulation?

myocardium accounts for 11% total body oxygen and receives 4% cardiac output as coronary blood flow

What is angina pectoris? Describe the different types of angina.

is when the oxygen supply to myocardium is insufficient to meet its metabolic demands

• often caused by coronary artery disease = obstruction of at least 50% in at least 1 major coronary artery

• causes pain in chest, arm, neck that is brought on by exertion or excitement

1. classic/stable/exertional angina

   • atheromatous plaques narrow arteries

   • exercise increases O2 consumption → not enough O2 supply → ischaemic muscle pain from waste products

2. unstable angina

   • pain occurs with less and less exertion until pain at rest

   • due to ruptured atheromatous plaque causing platelet-fibrin thrombus

   • incomplete occlusion of coronary vessel

   • increased risk of infarction

3. variant/prinzmetal/vasospastic angina

   • vasospasm of coronary vessels

   • may or may not be assoc with atherosclerosis

What mediators are thought to be responsible for anginal pain?

waste products/metabolites stimulate nociceptors/pain fibres which cause pain

• K+

• H+

• adenosine

what are the four classes of drug used for the treatment of angina.

1. nitrates

2. beta blockers

3. Ca2+ antagonists

4. K+ channel activators

What is the mechanism of action of nitrates for angina?

glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate

effect: peripheral vasodilation (NO mechanism)

mechanism:

• nitrates converted to NO

• NO directly induces vascular SM to dilate = vasodilation

  1. liberation of NO from nitrates by enzymic reaction involving tissue SH groups

  2. NO activates guanylate cyclase in SM

  3. GC converts GTP to cGMP

  4. leads to dephosphorylation of myosin light chain

  5. leads to sequestration of Ca2+

  6. relaxation of vascular SM

What is the mechanism of action of beta blockers for angina?

-olol

atenolol, metaprolol, propanolol

effect: decreased HR, force of contraction

mechanism

• prevent NA/A from binding beta-1 adrenoceptors

• decresed SA node firing → decreased HR

• decreased AV conduction → decreased conduction

• decreased contractility → decreased force of contraction

• also decreased renin release → decrease BP

What is the mechanism of action of Ca2+ antagonists for angina?

-pine

amlodipine, diltiazem, nifedipine, verapamil

effect: decreased HR and force of contraction

mechanism:

• block Ca2+ channels

• this reduces Ca2+ intracellular levels in heart

• decreases action potentiality

• decreased HR

• confined to CVS since they bind alpha 1 subunit of L type channel which is only found in blood vessels and cardiac muscle (myocyte)

What is the mechanism of action of K+ channel activators for angina?

nicorandil

effect: arterial and venous dilation + activation of K+ channels in SA node (decrease HR)

mechanism:

• KATP activation: efflux of K+ hyperpolarises membrane → decreased action potentiality

• NO → arterial and venous dilation → slows heart (decreased preload and afterload)

what are the side effects and contraindications for nitrates?

• arterial dilation

• headaches

• postural hypotension

• reflex tachycardia

• prolonged dosage = methaemoglobinaemia - oxidation of Hb reduces O2 carrying capacity → cyanosis, dyspnea

• tolerance due to depletion of tissue SH groups

  • use lowest does possible and have 10hr or longer nitrate free per day

• do not use with sildenafil citrate (viagra) → huge drop in BP

what are the side effects and contraindications for beta blockers?

• bronchroconstriction - bleeding over into B2 receptors

• insomina

• depression

• AV block

• fatigue

• bad dreams

• sexual dysfunction

contraindicated in patients with asthma

what are the side effects for Ca2+ antagonists?

• headache

• constipation - L type Ca2+ channels present in intestinal SM

• ankle oedema - nifedipine

• heart failure - verapamil/diltiazem

what are the side effects and contraindications for K+ channel activators?

• headache

• flushing

• dizziness

contraindicated in people with cardiogenic shock, left ventricular failure and hypotension - drop in BP

Explain why tolerance occurs with the use of nitrates and two strategies to overcome it. 

due to the depletion of tissue SH groups

1. use lowest dose possible

2. have a 10 hour or longer nitrate free period per day

What side effects occur with large doses of nitrates?

methaemoglobinaemia

• oxidation of Hb reduces its O2 carrying capacity → cyanosis, dyspnea

Which of the following can be given orally and which has the shortest duration of action? Isosorbide dinitrate, glyceryl trinitrate

isosorbide dinitrate

• can be orally given

• T1/2 = 4 hours

• 2x day for prophylaxis

glycerol trinitrate

• suffers first pass metab - use sublingual or transdermal admin

• 30 mins

The major effects of calcium antagonists are on the heart and vascular smooth muscle. Why don’t they block skeletal muscle contraction, neurotransmitter release, hormonal release etc since all require an influx of calcium?

since they bind alpha1 subunit of L type Ca2+ channels

• which are only found in blood vessels and cardiac muscle (myocyte)

What are the main sites of action of verapamil, nifedipine and diltiazem?

verapamil

• targets heart → target rate for force of contraction

nifedipine

• targets SM → vasodilation → causes reflex tachycardia (homeostatic)

diltiazem

• targets both blood vessels and heart

What are the clinical uses of calcium antagonists? Indicate the basis of their use in each condition specified.

Angina → decrease HR and force of contraction, arteriolar dilation

dysarrhythmias → antidysarrhythmic action, impaired AV conduction, cardiac slowing

hypertension → arteriolar dilation → reduces PR → decreases BP

Why are b-blockers contraindicated in asthmatic patients?

cause bronchoconstriction → worsens asthma symptoms

When and why is nicorandil (K+ channel activator) used for angina treatment? 

when: patients remain symptomatic in spite of other meds

How does acetylcholine induce vasodilation?

• binds M3 receptors (vascular SM)

• signals Gq pathway

• activates PLC

• increases IP3

• increases intracellular Ca2+

• activates eNOS

• produces NO

• activates guanylate cyclase

• increases cGMP

• decreases intracellular Ca2+

• relaxation

Describe the actions of the adrenoceptor subtypes in blood vessels.

alpha 1 = vasoconstriction

alpha 2 = vasodilation/constriction

beta 2 = vasodilation

Write the equation that describes the determinants of blood pressure. What factors alter cardiac output?

Arterial pressure = CO x PR

1. heart rate

2. force of contraction

3. blood volume

4. venous return

What actions does angiotensin II have on the cardiovascular system?

1. incresae aldosterone release → increase sodium and water reabsorption → increase BV → increase BP

2. vasoconstriction

3. CNS → NA release

How is hypertension diagnosed?

systolic BP >140mmHg

diastolic BP >90mmHg

What are the antihypertensive agents used to treat hypertension?

1. ACEI

2. AT1 antagonist

3. Ca2+ channel blocker

4. beta blocker

5. alpha 1 adrenoceptor antagonist

6. thiazide diuretics

what is the mechanism of action, side effects and contraindications of ACEI for hypertension?

-pril

captopril, enalapril, quinapril

mechanism:

• blocks RAAS → inhibit ACE to prevent formation of AT II

  • causes vasodilation → decrease PR

  • decrease aldosterone release → decrease BV

side effects:

• first dose hypotension

• cough → ACEI inhibits inactivation of bradykinin → causes irritation in throat

• hyperkalaemia → increased retention of K+

• fetal injury

• angiodema → linked to bradykinin

contraindications:

• renal stenosis → kink in blood coming into kidney and vasodilation causes pressure problems → renal failure

• avoid potassium sparing diuretics

• stop potassium supplements

what is the mechanism of action and side effects of AT1 antagonists for hypertension?

-sartans

candesartan, irbesartan

mechanism:

• block RAAS

  • vasodilation →

  • decreased aldosterone release → decrease BV

• good for ACEI patients who suffer from cough

side effects:

• headache

• hypotension

• GIT disturbances

• hyperkalaemia

what is the mechanism of action and side effects of Ca2+ antagonists for hypertension?

Nifedipine, amlodipine

mechanism:

• relax vascular SM → dilation → decrease PR → decrease BP

side effects:

• headache

• constipation

• ankle oedema

• heart failure

what is the mechanism of action, side effects and contraindications of beta blockers for hypertension?

Propranolol, atenolol, metoprolol

mechanism:

• decrease HR and force of contraction → decrease CO → decrease BP

side effects:

• bronchoconstriction

• insomnia

• depression

• AV block

• fatigue

• bad dreams

• sexual dysfunction

contraindications:

• asthma

what is the mechanism of action and side effects of alpha 1 adrenoceptor antagonists for hypertension?

-zosin

prazosin, doxazosin, terazosin

mechanism:

• block sympathetically mediated vasoconstriction

  • reduce arteriolar and venous resistance

side effects

• postural hypotension

• nasal congestion

• pupil constriction

• fatigue

• sexual/badder dysfunction

  • urethra held closed by A1 usually

what is the mechanism of action, side effects and contraindications of thiazide diuretics for hypertension?

Bendrofluazide, *hydrochlorothiazide, chlorothalidone, indapamide

mechanism:

• decrease BV → decrease CO

  • act on kidney to increase urine flow

  • reduce reabsorption of electrolytes by tubules

  • increase electrolyte excretion

  • increase water excretion by osmosis

• most effective at loop of henle

thiazide diuretics:

• moderately strong

• early segments of distal tubule

• binds Cl- site of Na+/Cl- co-transport system and inhibits NaCl reabsorption

• increased Na+ load in distal tubule

  • stimulates Na+ exchange with K+ and H+

  • increased excretion of K+ and H+ induces hypokalaemia and metabolic alkalosis

adverse effects:

• weakness

• skin rashes

• hypokalaemia

  • use potassium supps or combine therapy with K+ sparing diuretics

• increased uric acid levels - gout

• increase plasma cholesterol levels

• male impotence

• hyperglycaemia

contraindications:

• causes metabolic alkalosis

If two antihypertensive agents are required which combinations are recommended and why? Which combinations are not recommended?

1. ACEI or sartan (block RAAS) + Ca2+ channel blocker (arterial vasodilation)

2. ACEI or sartan + thiazide diuretic (decrease BV)

3. ACEI or sartan + beta blocker (slow heart)

4. beta blocker (slow heart) + dihydropyridine Ca2+ channel blocker (arterial vasodilation)

5. thiazide diuretic (decrease BV) + Ca2+ channel blocker (arterial vasodilation)

6. thiazide diuretic + beta blocker (slow heart)

AVOID:

1. ACEI or sartan (causes hyperkalaemia) + K+ sparing diuretic (worsens hyperkalaemia)

2. verapamil (Ca2+ antagonist → targets heart) + beta blocker (further slows heart)

3. ACEI + sartan (additive effect → extreme BP drop)

Discuss the choice of antihypertensive agents in patients with comorbidities.

ACEI

• do not use in people with renal stenosis → vasodilation causes pressure problems → renal failure

• do not use in people with coughing problems?

beta blockers

• do not use in people with bradycardia

A1 adrenoceptor antagonist

• do not use in people with bladder dysfunction/micturition → will further increase urination and leakage

thiazide diuretics

• do not use in people high cholesterol → worsens hyperglycaemia

What is the advantage of AT-1 antagonists over ACEI?

AT-1 antagonists avoid side effects such as cough and angiodema

• since not inhibiting ACE therefore allows breakdown of bradykinin (which is causing these effects)

Which calcium antagonists can cause reflex tachycardia, how can it be prevented?

nifedipine

• sudden decrease in BP causes tachycardia (homeostatic effect)

prevent by using a diff Ca2+ antagonist or combine with beta blocker

Which drugs would be used in an hypertensive crisis?

alpha 1 adrenoceptor antagonist

How does the body obtain cholesterol? (Endogenous and exogenous sources)

exogenous (diet)

• Chylomicrons transport cholesterol and triglycerides from GIT to tissues (muscle/adipose)

• TG hydrolysed by LPL and tissues take up released FFA

• C taken to liver and endocytosed and stored or oxidised to bile acids or released to VLDL (endogenous path)

endogenous

• VLDL transports C and synthesised TG from liver to tissues (muscle/adipose)

  • TG = energy source

  • VLDLs → LDLs

• LDL provides C for incorporation into cell membrane or synth into steroids and bile acids

• cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins

• HDL absorbs C from broken down cells and transfers them to LDLs or VLDLs

Discuss the common types of hyperlipoproteinaemia. What form increases the risk of ischaemic heart disease?

Type IIa

• high cholesterol + LDL

• ischaemic heart disease common in this type

• use statins ± ezetimibe

Type IIb

• high VLDL + LDL

• leads to high TG + cholesterol

• ischaemic heart disease may result but not as common

• change diet and use fibrates, statins or nicotinic acid

Type IV

• high VLDL

• hypertriglyceridaemia

• peripheral vascular disease and ischaemic heart disease

• use fibrates

What are the target plasma levels of cholesterol, LDL, HDL and triglycerides in people with and without cardiovascular disease.

	Chol	LDL	TG	HDL
No prior CV disease	<5	<3.5	<2	>1
CV disease	<4	<2.5	<2	>1
High TG’s			<4

mmol/L

What is the mechanism of action of cholestyramine and simvastatin? How do they affect lipid profiles?

Cholestyramine

• bile acid resin - inhibits cholesterol reabsorption

• by binding bile acids in GIT and preventing their reabsorption → force liver to increase utilisation of cholesterol into formation of bile acids → increase uptake from plasma/blood

• reduce LDL by 15-25%

Simvastatin

• HMG-CoA reductase inhibitors (statins) - inhibit cholesterol synthesis

• HMG-CoA reductase = rate limiting enzyme → inhibit this enzyme → inhibits HMG-CoA conversion to mevalonic acid → stops endogenous cholesterol synth → forces liver to uptake LDL from plasma/blood

• reduces LDL by 30-50%

What are the adverse effects associated with statin therapy.

• GIT disturbance

• increased liver enzymes

• insomnia

• rash

• myalgia

• rarely rhabdomyosis or angiodema

What bile-resins are currently in use? What are their mechanisms of action and main side effects? What effect do they have on plasma lipid profiles?

cholestyramine, colestipol

mechanism:

• inhibit bild acid reabsorption → force liver to make more bile acid → increase uptake of LDL from plasma/blood

• reduce LDL by 15-25%

side effects:

• nausea, abdominal bloating, constipation/diarrhoea

• interfere with absorption of some drugs (fat soluble vitamins, chlorthiazide, digoxin, warfarin)

• may worsen hypertriglyceridaemia if 3 mmol/L

Discuss the actions of fibrates and its major side effects and contraindications. Include how it affects lipid profile

gemfibrozil, fenofibrate

mechanism

• agonists of PPAR alpha

• stimulate LPL activity → increase TG breakdown and reduce VLDL prod

• inhibits vascular SM inflam

• decrease TG by 40-80%

• decrease VLDL

• decrease LDL (10%)

• increase HDL (10%)

side effects:

• myositis

• mild GIT symptoms

contraindications:

• severe renal impairements

• combo with statins → increases risk of serious side effects

Discuss the actions of fish oils and its major side effects and contraindications

for hypertriglyceridaemia

mechanism

• unknown

• may increase cholesterol

• decreases VLDL TG

• reduces blood clotting and inflam

side effects

• increased BT

contraindications:

• type II hypolipoproteinaemia due to increased LDL

Discuss the actions of ezetimibe and its major side effects. Include when it is used

• used for hypercholesterolaemia when statin alone is inadequate or not tolerated

mechanism:

• inhibits biliary and dietary absorption of cholesterol from GIT

• blocks transport protein NPC1L1 in enterocyte brush border

  • therefore does not alter absorption of fat soluble vitamins

• decrease LDL by 18%

side effects:

• headache

• diarrhoea

• rare allergic reactions

Which diuretics may exacerbate gout?

thiazide - increased uric acid levels

Which diuretics may cause metabolic alkolosis?

thiazide - increased Na+ load in distal tubule

• stimulates Na+ exchange with K+ and H+

• increased excretion of K+ and H+ will induce hypokaelamia and metabolic alkalosis

Describe how thiazide compounds induce their diuretic actions. What are their adverse effects?

inhibit NaCl reabsorption by binding Cl- site of Na+/Cl- cotransport system

→ increases excretion of NaCl → increase excretion of water by osmosis

what do these terms mean: inotropic, chronotropic, dromotropic

inotropic = change in force of myocardial contraction

chronotropic = changes in HR

dromotropic = change in conductance of electrical impulses through myocardium

Discuss the actions of PCSK9 inhibitors

Alirocumab, evolocumab

• monoclonal Abs - injected

mechanism:

• bind to PCSK9 and inhibits its actions

• normally PCSK9 binds to LDL receptors and promotes its degradation following LDL uptake into liver

• PCSK9 inhibitors prevent LDL receptor breakdown → increases LDL uptake from blood

Discuss the actions of nicotinic acid and its side effects. Include its effects on lipid profile

mechanism:

• decrease hepatic lipoprotein synthesis (TG and VLDL secretion)

• decreases LDL by 15-30%

• increases HDL by 20-35%

side effects:

• flushing

• headache

• skin rash