Cardiovascular Disease & Risk Factors (1) Hypertension, the silent killer

Question 1

Components of Blood Pressure (BP)

Answer 1

BP = Cardiac output (CO) x Total peripheral resistance (TPR)

CO = Heart rate (HR) x Stroke Volume (SV)

TPR affected by
>Humoral control
>Sympathetic nervous system control
>Local control

Question 2

Autonomic nervous system

Answer 2

Sympathetic (fight or flight, Noradrenaline)
>Heart
>Adrenal medulla
>Blood Vessels
(important for moment to moment control of BP - important to remember for different drug classes)

Parasympathetic (rest and relax, ACh)
>Heart
>Genitalia BV
>NOT INVOLVED IN BV TONE except in genetalia

Question 3

Control of Cardiac Output

Answer 3

Venous inflow
>Filling pressure of right heart (preload)
>any drug that influences the calibre of the great vein affects preload
>70% of blood volume at any time is contained in venous circulation
>any small change in its calibre will affect preload and filling pressure of the right heart and CO

Arterial outflow
>Resistance to outflow from left ventricle (afterload - TPR)

Extrinsic innervation of Heart
>Sympathetic
>Heart rate and contractility
(SA, AV nodes, Cardiac muscle - contractile strength)

> Parasympathetic
Only Heart rate
(SA, AV nodes)

Question 4

Total peripheral resistance

Answer 4

Sum of all vascular resistances in systemic circulation
>TPR = BP/CO

Arteries supply tissues and organs in parallel circuits

Changes in resistance in these circuits determine relative blood flow

Question 5

Arterial and arteriolar network

Answer 5

As artery branches into the arterioles, incredibly dense network of small arterioles
>a lot more resistance that the small vessels offer to flow
>Effects of drugs on resistance and therefore BP

Question 6

Haemodynamics - Resistance to flow

Answer 6

Poiseuille’s Law
>Resistance is inversely proportional to 1/r^4
(r = vessel radius)

Arteriole diameter determines resistance (R) to local blood flow in a particular vascular bed

Question 7

TPR & medial hypertrophy

Answer 7

If hypertension is untreated, medial hypertrophy results
>inward remodeling
>blood vessel thickens and grows inwards
>lumen of vessel becomes smaller
>smaller artery internal radius
>at rest, hypertensive vascular bed will already cause an increased resting resistance
(This is to protect BV from increased BP and prevent them from bursting under increased BP)

> > > BP increases more in hypertensive patients for any given constrictor stimulus because of this
(Can be reversed with good management of BP with antihypertensive drugs)

Question 8

Vascular tone

Answer 8

Arteriolar diameter determines resistance to local blood flow
>BV responds to vasoactive stimulus by increading or decreasing internal radius
>arteriolar walls very thick in relation to lumen diameter, so more (or less) contraction affects R powerfully

Basal degree of vascular smooth muscle contraction (or tone)
>allows for both increase and decrease in resistance by external influences

Influences - 3 categories
>Local (e.g. nitric oxide or dilator prostaglandins)
>Neural (e.g. sympathetic)
>Hormonal (e.g. angiotensin II)

Question 9

Baroreceptor control of BP

Answer 9

Homeostatic mechanism to maintain BP at individual’s set point (usually resting BP level)

Most important moment-to-moment regulation of resting BP

Baroreceptors (pressure receptors) are stretch receptors that respond to BP-induced stretching of the artery in which they are located
>aortic arch & carotid sinuses

Question 10

The barorecptor reflex

Answer 10

1) Baroreceptors detect changes in BP
2) Impulses sent to control centres in brainstem
3) BP increase will decrease sympathetic stimulation of heart (HR and SV falls)
4) BP increase will increase parasympathetic stimulation of heart (HR falls)
5) BP increase will cause vasomotor centre to decrease sympathetic tone (stimulation) of blood vessels, causing dilatation (TPR decreases)

[For BP decrease, opposite effects will occur]

Question 11

Cardiovascular disease: World’s #1 cause of death

Answer 11

Major health and economic burden throughout the world, especially in developed countries
>Coronary heart disease will become the single leading public health problem for the world by 2020

Question 12

Blood pressure measurements

Answer 12

Systolic (heart pumping) vs Diastolic (heart filling) pressures

DBP is the lowest BP that the system sees
>if this is chronically raised, then the vessels will start to hypertrophy to protect themselves

Question 13

Hypertension Guidelines

Answer 13

Optimal BP in adults Systolic/Diastolic <120/<80mmHg

Coronary artery disease risk group: Maintain BP

Question 14

The hypertension continuum

Answer 14

Hypertension
>endothelial dysfunction
>artherosclerosis
>Coronary artery disease
>Myocardial ischaemia
>Coronary thrombosis
>Stroke (Myocardial infarction)
>Arrythmia and loss of muscle
>Remodelling
>Ventricular dilation
>Congestive heart failure
>End stage heart disease

Elevated BP causes pathological changes in vasculature and hypertrophy of left ventricle
>Treatment not only to decrease BP, but also to prevent these lethal and disabling cardiovascular sequelae

Question 15

Hypertension - Causes

Answer 15

1) Primary/essential (90-95%), no apparent cause
>old age, genetic predisposition, diet, stress, etc

2) Secondary (5-10%), identifiable cause
>renal disease (augments renin-angiotensin system)
>endocrine disorders (e.g. adrenal medulla tumour > high adrenaline secretion)
>preeclampsia in pregnancy
(life threatening hypertension in late gestation to both mother and child)

Question 16

Hypertension - Treatment

Goal DBP <80 mmHg

Answer 16

First choice therapy
>lifestyle modification

Treatment is lifetime project to decrease cardiovascular risk over many years

Drugs (long term)
>all have some adverse effects

Drug choice depends on patient progile
>associated risk factors
>concomitant disease
>age
>side effects

Question 17

Antihypertensive drugs

Answer 17

> B1-adrenoceptor antagonists
A1-adrenoceptor antagonists
Centrally acting antihypertensives (A2-adrenoceptor agonists)
Diuretics
Angiotensin-converting enzyme (ACE) inhibitors & Angiotensin AT1 receptor antagonists
Calcium antagonists

> > understand rationale for combination drug therapy

Question 18

B1-adrenoceptor Antagonists

Answer 18

Affect CO (HR and SV) through direct action

Affect TPR through kidneys (Renin-Angiotensin system
Does not affect direct nervous innervation of TPR)

Question 19

Control of Heart Rate

Answer 19

Sympathetic
>Increase sympathetic activity
>increase in NA

> > causes adrenal gland to increase circulating adrenaline

> > NA and Adr act on B1 adrenoceptors in heart nodal tissue
>SA node (positive chronotrophy, increase HR)

Parasympathetic
>Increased parasympathetic activity
>Increase in ACh
>M2 receptors in heart nodal tissue
>>SA node (negative chronotrophy, decrease HR)

Question 20

Control of Stroke Volume

Answer 20

Same as control of HR
>increase sympathetic activity (also causes increase in adrenal medulla activity)
»Increase in circulating NA and Adr
»B1-adrenoceptors in cardiac muscle
»Positive ionotropy (increased force of contraction)
»Increased stroke volume

> > Force of contraction not affected by parasympathetic NS

Question 21

B1-Adrenoceptors increase cardiac myocyte contractility but also enhance relaxation

Answer 21

Agonist binding to B1-ARs on cardiac myocytes
>Ga protein to activate adenylate cyclase
>catalyse conversion of ATP to cAMP

> cAMP activates multiple protein kinases, including PKA

> PKA phosphorylates membrane Ca2+ channels, thereby increasing cardiac myocyte contractility
(also activate MLC-Kinase, convert MLC (inactive) to MLC-P (active))

> PKA phosphorylates phospholambin and disinhibits SERCA pump which pumps Ca2+ from cytosol back into SR
>increased rate of Ca2+ sequestration enhances cardiac myocyte relaxation (left ventricle is able to fill again before next heartbeat)

I.E. heart beats harder, but slower

Question 22

B1-AR stimulation supports cardiac performance

Answer 22

1) B1-agonists increase B1-AR mediated increases in Ca2+ entry during systole
>increases fractional shortening of cardiac muscle during contraction
»positive ionotropic effect
»higher stroke volume for any given end-diastolic volume

2) B1-agonists increas HR in linear dose-dependent manner
(Positive chronotropy)

3) B1-agonists enhance rate and extent of diastolic relaxation (positive lusitropy)
>facilitates maintenance of adequate LV filling (preservation of LV end-diastolic volume) despite less diastolic filling time available as HR increases

Question 23

B1-AR Antagonists - Mechanism

Answer 23

Antagonise CARDIAC B1-adrenoceptors

> SA node
(decrease HR)

> Cardiac muscle
(decrease SV)

> > lead to decreased CO
Decreased BP

At kidneys:
>B1 inhibition decreases renin secretion
>thus decreased production of angiotensin II
>decreases volume and vascular tone

Question 24

B1-AR Antagonists - Examples of drugs

Answer 24

Gradual fall in BP in hypertensive patients, takes several days to develop
>decrease in CO
>less renin release from kidney juxtaglomerular cells

Non-selective (B1 and B2) antagonists
>propranolol (lipophilic - cross BBB easily)
>oxprenolol (lipophilic)

B1-selective antagonists (Cardioselective - NOT cardiospecific)
>atenolol (hydrophilic - generally preferred for hypertension to limit CNS effects)
>metoprolol (lipophilic)

Question 25

B1-AR Antagonists - Adverse effects

Answer 25

1) Cold extremities >peripheral vasoconstriction due to decreased CO and possibly loss of B2 receptor mediated dilatation of skeletal muscle vessels 2) Fatigue >due to decreased CO and exacerbated by B2 receptor inhibition (with a non-selective Beta blocker) >>skeletal muscle vessels unable to dilate during exercise (less likely with B1 receptor-selective blockers) 3) Dreams and insomnia >CNS effects (lipid solubility) 4) Cardiac depression >particularly in elderly 5) Bradycardia (slow HR) >can lead to life-threatening heart block in PTs with coronary disease 6) Bronchoconstriction >B2 receptor inhibition >life threatening in PTs with asthma or obstructive lung disease >Contraindicated (COPD or asthma = major contraindication for particularly the non-selective Beta-antagonists)

Question 26

Beta-Adrenoceptor Antagonists - Hypoglycaemia

Answer 26

Side effect >glucose released in response to adrenaline important for diabetic patients prone to hypoglycaemic attacks >sympathetic response to hypoglycaemia causes symptoms (esp, tachycardia) that warn patients of urgent need for carbohydrate >Beta-AR antagonists reduce the tachycardia symptoms, so hypoglycaemia may go unnoticed by PT >>>>Beta-AR antagonists avoided in patients with poorly controlled diabetes In diabetics, use of Beta blockers increases likelihood of exercise-induced hypoglycaemia as adrenaline-induced release of glucose from liver is diminished

Question 27

Beta-AR Antagonists (Summary)

Answer 27

Contraindications >asthma/COPD >SA/AV node dysfunction (one of the 2 main MOAs) >Hypertensives with heart failure (not initial therapy, can cause cardiac depression or bradycardia) >Peripheral vascular disease (atherosclerosis and narrowing of arteries serving skeletal muscles in legs, dont want to compromise it further, particularly with B2 antagonists) >PTs with poorly controlled diabetes Drug withdrawal (dosage must be tapered over weeks to months) >Withdrawal symdrome: upregulation of B-receptors during blockade >>increased sensitivity to endogenous catecholamines >>rebound hypertension to higher levels Drug choice >B1 preferred (limit side effects) and hydrophilic (limit CNS effects) >>i.e. atenolol

Question 28

A1-Adrenoceptor Antagonists

Answer 28

Affect TPR >Direct nerve innervation >Circulating regulators (catecholamines and AngII)

Question 29

Sympathetic vasoconstrictor fibres

Answer 29

Innervate arterioles in all systemic organs and provide most important means of reflex control of vasculature >backbone of TPR control system and essential in regulating BP (baroreceptor control) >sympathetic vasoconstrictor nerves release NA in proportion to their electrical activity >NA increases vascular tone via A1-AR on smooth muscle (contraction) >Sympathetic nerves normally have continual or tonic firing activity >>this tonic activity (neurogenic tone) increases contractile tone of arterioles above basal levels >>decreased sympathetic tone (withdrawal) causes increased flow (and vice versa) A1-AR Antagonists have a very powerful systemic effect, not normally a first choice of antihypertensive drug

Question 30

Autonomic control of vascular tone

Answer 30

Sympathetic vasoconstriction >Venous system >>effect on increasing venous return and so end-diastolic volume >>increased cardiac preload and increased cardiac output >Arterial system >>increased tone shunts blood to metabolically-active organs, as well as maintaining critical cardiac and cerebral perfusion We might want to decrease venous tone but not arteriolar tone

Question 31

Basal vascular tone and control of TPR by sympathetic nerves

Answer 31

Tonic sympathetic (NA) nervous system activity >>Noradrenaline release >vascular A1-ARs >>>vascular constriction ``` >>Noradreanaline release >Renal B1-ARs >Angiotensin II production (via secretion of enzyme renin) >Vascular AT1 receptors >>>vascular constriction ``` >>>>>Increase in TPR

Question 32

Intracellular signalling in vascular smooth muscle cells by A1-ARs

Answer 32

Activation of A1-AR (Gq coupled GPCR) >stimulates membrane bound phospholipase C (PLC) >hydrolyse membrane bound PIP2 to IP3 and DAG >IP3 activates receptor in SR to release stored Ca2+ >DAG activates Protein Kinase C (PKC) PKC phosphorylates Ca2+ channels and components of contractile apparatus (promotes phosphorylation of myosin light chain kinase -> active MLC-P) to promote smooth muscle contraction via crossbridge cycling

Question 33

A1-AR Antagonists

Answer 33

Inhibit post-synaptic A1-ARs (A2-AR is pre-synaptic autoinhibitory) >used in moderate to severe hypertension in combination with other drugs Decrease sympathetic effects on vascular tone >arterial and venous dilatation A1-Selective examples >prazosin >terazosin >doxazosin

Question 34

A1-AR Antagonists - Adverse Effects

Answer 34

1st dose hypertension >within 90 min of initial dose, ~50% of PTs Initial reflex tachycardia and increase in plasma renin activity (baroreceptor reflex) Postural (orthostatic) hypotension >problem in elderly patients Nasal congestion Headache

Question 35

Postural (orthostatic) effects on BP

Answer 35

``` Change in posture >decrease in venous return (gravity) >decrease in stroke volume >decrease in Mean arterial pressure >Detected by baroreceptors ``` >>CNS medulla >Decrease parasympathetic efferent output to SA node >Increase heart rate >increase cardiac output (we want to increase afterload) >Increase sympathetic efferent output >Arterioles (contract - increase peripheral resistance) >Veins (contract - increase venous return - preload) >Ventricle (increase contractility) (increase stroke volume) >increase CO and SV All bring MAP back to normal *Prazosin blocks arterioles and veins from contracting (a1-ar antagonist) >any drug that influences sympathetic innervation of arteries and veins can cause orthostatic hypotension

Question 36

Centrally-acting Antihypertensives (A2-AR Agonists)

Answer 36

Act on sympathetic nervous control of cardiac system Affect Cardiac Output (CO) via >HR and SV (SA/AV nodes, Heart muscle contractility) Affect TPR via >Direct innervatin >Circulating regulators

Question 37

Centrally acting antihypertensives (A2-AR agonists)

Answer 37

Clonidine a-Methyldopa >prodrug converted to a-methyl NA >active transport into brain Both drugs >act in medulla (in cardiovascular control centre of brain) >A2-adrenoceptor AGONISTS >used for treatment of hypertension in pregnancy (drug of choice) >>>lack of documented effects on foetus (in contrast to ACEI, sartans (AngII AT1 receptor antagonist), and B1-antagonists)

Question 38

Methyldopa - prodrug

Answer 38

a-Me NA stored in secretory vesicles of adrenergic neurons, substituting for NA itself When adrenergic neuron discharges its neurotransmitter, a-Me released instead of NA >act at presynaptic A2-ARs a-Me NA is less active than NA at A1-ARs (in periphery) >less vasoconstriction >more active at presynaptic A2-ARs >>autoinhibitory feedback operates more strongly >>decrease transmitter release below normal levels

Question 39

Centrally acting antihypertensives - MOA

Answer 39

Stimulate (agonise) Central A2-ARs >decrease sympathetic (NA, A2 auto inhibitory) outflow from CNS to heart and BVs >Decrease cardiac B1 effects = decrease CO (HR & SV) >Decrease vascular A1 effect (sympathetic tone) = Decrease TPR >Decrease renin secretion from kidney = decrease angiotensin II >>>>>>>>>Decrease BP quite powerfully because it acts systemically

Question 40

Centrally acting antihypertensives: Adverse effects

Answer 40

CNS actions >dreams/nightmares >sedation (brainstem centres - wakefulness and alertness) >Depression (avoid in those at risk) >Dry mouth (medullary centres that control salivation) >Decrease in libido Marked bradycardia Postural hypotension (same as A1-antagonists, they decrease sympathetic innervation to BVs) Clonidine: >if suddenly withdrawn, very high rebound BP 12-36h later >related to catecholamine release