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Unit 12 > Pharmacology of Hypertension 1 > Flashcards

Pharmacology of Hypertension 1 Flashcards

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1
Q

How is hypertension?

A

Persistently raised arterial blood pressure
Can be further classified at essential or secondary

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2
Q

What are the normal ranges of blood pressure?

A

Systolic - 90-120mmHg
Diastolic - 60-80mmHg
MAP - 70-93mmHg

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3
Q

What are the different stages of hypertension?

A

SP/DP
Stage 1: 140/90 until
Stage 2: 160/100
Stage 3: Systolic above 180 or Diastolic above 120

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4
Q

What range of blood pressures is considered pre-hypertension?

A

Systolic 120-139
Diastolic 80-89

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5
Q

What are the different varients of hypertension?

A

Isolated systolic hypertension
Isolated disatolic hypertension
Mixed hypertension

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6
Q

What are the features of isolated systolic hypertension?

A

Systolic BP above 140
But disatolic pressure remain 90 or below
Results in a high pulse pressure
This is the most common variant and normally occurs due to a loss of elasticity of blood vessels

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7
Q

What are the features of isolated diastolic hypertension?

A

Systolic BP is below 140
DBP is above 90
Reduced pulse pressure
Least common variant

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8
Q

What are the criteria for mixed hypertension?

A

Systolic BP above 140
Diastolic BP above 90

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9
Q

What is the prevalence of different types of hypertension?

A

ISH: MHT: IDH
4:2;1

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10
Q

What is the difference between essential and secondary hypertension?

A

Essential is more common (90%) no known cause (idiopathic)

Secondary is less common (10%), has a known cause

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11
Q

What are some of the causes of secondary hypertension?

A

Renal disorders
Endocrine
Drug induced
Pregnancy - pre-eclampsia

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12
Q

What endocrine conditions can cause secondary hypertension?

A

Primary hyperaldosteronism - (conns syndrome) too musch aldosterone inc Na+ and water reabsoprtion
Phaeochromocytoma - tumour on adrenal medulla - increase NA and A secretion (Sympathetic)
Cushing syndrome - cortisol inc adrenergic receptor expression

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13
Q

What are the drug induced methods of hypertension?

A

Cocaine - Sympathetic NS
Iatrogenic - combined oral contraceptive, glucocorticoids. (increase renin)

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14
Q

What are some potential exogenous factors causing hypertension?

A

Diet, smoking, stress, obesity

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15
Q

What are some endogenous factors causing hypertension?

A

Metabolic/hormonal
Renal (RAAS)
CNS
Arterial
Ethnicity.

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16
Q

What are some consequences of hypertension?

A

Increased risk of cardiovascular disorders including:
Coronary artery disease
Stroke
Heart failure
Peripheral arterial disease
Vascular dementia
Chronic Kidney disease

Decreasing BP by 10mmHg closer to nrmal range has a 10% reduction in the risk of cardiovascular adverse events.

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17
Q

What are some of the pathophysiological mechanisms controlling BP?

A

Cardiac output
Peripheral resistance
Autonomic Nervous System
Endothelium
Vasoactive peptides
Renin-angiotensin-aldosterone system.

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18
Q

How do you calculate mean arterial blood pressure?

A

MAP = Cardiac output x Total peripheral Resistance

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19
Q

How to calculate cardiac output?

A

CO = SV*HR
CO = MAP/SVR

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20
Q

What physic factors may influence hypertension in essential hypertension?
CO, SVR, MAP

A

Most patients have a normal CO and increased TPR - may be due to loss of arteriolar resistance, lack of elastic tissue, underused become less elastic and loss of smooth muscle

Very early - TPR may be normal and CO increased, leads to chronic adaptive response to inc TPR to decrease CO, irreversible and causes hypertension.

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21
Q

What are the basic principles of how ANS regulates heart function linked to hypertension?

A

Noradrenaline
Beta 1 receptors
SAN - inc HR
Contractily cells - increased contractility
Leads to increased cardiac output.

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22
Q

How does the ANS regulate vessel function?

A

Arteriole tone mainly controls TPR (beta 2, alpha 1 - vasoconstriction and vasodilation)
Venular tone regulates Central venous pressure - (decreased when veins dilated, decreased preload, decreased CO)

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23
Q

What is the short term regulation of blood pressure and flow?

A

The baroreceptor reflex mediated through the autonomic nervous system

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24
Q

How is control of the autonomic nervous system link to essential hypertension?

A

Little evidence to implicate adrenaline as a cause of essential hypertension
However, inhibition of the ANS can provide symptomatic relief for patients.

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25
How is the endothelium indicated in essential hypertension?
Is dysregulated in essential hypertension. Endothelial cells produce vasoactive agents A decrease in NO, PGI2 and increase in endothelin may contribute to hypertension (Vasoconstriction of blood vessel)
26
How does nitric oxide cause vasodilation of blood vessels?
Increase guanylyl cyclase activity Increase GTP conversion to cGMP Increase Protein Kinase G (activates myosin phosphatase resulting in dephosphorylation of myosin light chain) Resulting in smooth muscle relaxation.
27
What is the effect of an atheroma on blood vessel diameter mediators?
Atheroma - decreases NO production (vasodilator) - resulting in maintained vasoconstriction
28
What are the effects of sodium nitroprusside on blood vessel diameter?
Increase NO levels (vasodilator) Used in hypertensive emergencies
29
What is the effect of sildenafil on blood vessel diameter?
Inhibits PDE5 Results in increased levels of cGMP Promotes smooth muscle relaxation Vasodilation
30
What are the effects of prostacylin PGI2 on blood vessel diameter? How is this utilised in the therapeutic world?
Causes vasodilation of blood vessels Structural analgues such as iloprost can be used to treat pulmonary hypertension
31
How does endothelin affect blood vessel diameter? How is this utilised in therapeutic world?
Is produced by endothelial cells Cause vasoconstriction ET receptor antagonists (macitentan) used to treat pulmonary hypertension
32
How does achetylcholine cause vasodilation?
Acts on endothelial cells to cause NO release Activates guanylyl cyclase Increase conversation of GTP to cGMP Increase PKG activity Results in smooth muscle relaxation
33
What are some different vasoactive peptides?
Bradykinin Natiuretic peptides (ANP from atria, BNP from brain ventricles and CNP from endo and heart) Vasopressin
34
How does bradykinin affect blood vessel diameter? How is this ultilsed therapeutically?
Released from mast cells mainly during inflammation Cause vasodilation ACE inhibitors prevent the breakdown of bradykinin resulting in increased vasodilation, combat hypertension.
35
What is the role of natriuretic peptides in controlling blood pressure?
Result in increase Na+ and H2O excretion by dilating afferent and constricting efferent arteriole in glomerulus. Acts on NRP1 receptor - is a transmembrane guanylyl cylcase - inc cGMP - results in smooth muscle relaxation of afferent arteriole.
36
What is the result of a malfunctional NRP1 receptor?
Natriuretic peptides (ANPetc) have no effect Results in fluid Retention and hypertension.
37
What is the affect of vasopression on blood pressure?
ADH Released from posterior pituitary gland Causes vasoconstriction via V1 receptors V2 receptors in DCT/CD to increase permeability to water - increase water reabsoprtion Also in counter current multiplier an urea recycling. Increase blood volume.
38
What is the role of the Renin-Angiotensin-Aldosterone System in essential hypertension?
Regulates longer term blood volume and SRV hence blood pressure Is not considered a cause of essential hypertension with many patients having low levels of renin and AT-2. Local 'paracine' RAAS systems may regulate regional blood flow and contribute to essential hypertension. But can be targeted to cause relief
39
How is angiotensin 1 converted to angiotensin 2?
ACE enzyme cleavage of C-terminal dipeptide
40
Angiotensin 2 is a what as At1 receptors?
Full agonist
41
What are the pharmacological features of ACE1?
ACE is transmembrane, anchored extracellular (most EF). Widely expressed Two functional independent catalytic sites with different physiological functions (not just ACE enzyme) Each contain Zn2+ metalloproteinases also cleaves bradykinin and GnRH - therefore ACE inhibitors can have negative effects.
42
What are the properties of ACE2 enzymes?
Single pass transmembrane domain Widely expressed One catalytic domain (Zn2+ metalloproteinase) Cleaves 1 amino acid from angiotensin 2 to produce AT(1-7) These are antagonists for angiotensin 2 ACE2 is also the SARS-Cov-2 cell entry point.
43
What are the features of the AT1 receptor? What effects does it bring about when activated?
GPCR Widely expressed in liver, kideny, adrenal gland, lung etc Activated by AT-II (angiotensin 2) Causes - vasoconstriction (smooth muscle contraction) - SANS stimulation central and peripheral - aldsoterone release from zona glomerulosa - ADH release - tubular Na+ reabsoprtion in PCT - endothelin release in endothelial cells.
44
What is the difference between AT1/AT2 and AT-I and AT-II?
AT1/2 - angiotensin receptors AT-I / II - angiotensin peptides
45
What is the pharmacology of aldosterone?
Is a steroid/ mineralcorticoid Full agonist at intracellular mineralcorticoid receptor in principle cells of the DCT
46
What are the features of the mineral corticoid receptor that aldosterone acts on?
Is an intracellular nuclear hormone receptor Expressed in epithelial with high electrical resistance e.g distal kidney tubular cells Selecitlvy changes transcription Increases transcription of ENaCs and Na+/K+ ATPase Increase water reabsoprtion and Na+ reabsoprtion to increase blood volume.
47
What are the features of ENaCs related to blood volume?
Widely expressed especially in distal kident tubules Increased expression of ENaC on apical membrane Leads to increased Na+ permeability Increased Na+ reabsorption from the tubular lumen into cell This is the rate limiting stage for salt reabsoprtion in this part of the nephron Therefore increase increase Na+ reabsoprtions.
48
How does sodium reabsoprtion link to arterial blood pressure?
Increase Na+ reabsoprtion Increased water reabsoprtion Increased ECF volume Increased stroke volume increased cardiac output Increased Arterial blood pressure
49
What is amiloride?
A channel blocker Blocks ENaCs in the DCT. Prevents reabsorption of Na+ hence water.
50
What are the features of the Na+/K+ pump related to RAAS?
Multimeric ATP-dependent active transporter Expressed throughout the renal tubule Sustains Na+/K+ gradient across membrane (regulate intracellular and intersistial conc)
51
What is the role of cardiac glycosides in relation to RAAS?
Example is digoxin Inhibit Na+ K+ Pump prevent Na+ hence water reabsoprtion - decrease blood volume.
52
What is Liddle Syndrome?
A rare autosomal dominant disorder Mutations in ebta and gamma subunit of ENaC prevents channel internalisation and degradation Results in overexpression of ENaCs leading to increased Na+ reabsoprtion Resulting in severe hy[ertension at an early age Treat with ENaC channel blockers
53
What is the appropriate treatment for Liddle syndrome?
Amiloride ENaC channel blockers
54
What drug class is spironolactone?
Potassium sparing diuretic Competitive antagonist of nuclear mineralcorticoid receptors in the DCT - prevent action of aldosterone.
55
What is the use of ganglion blockers as drugs?
No longer used Target nicotinic receptors on the post synaptic membrane are channels blockers. Prevent action potential generation on post-synaptic neruons Inhibits the parasympathetic and sympathetic nervous system transmission of impulses Prevents hypertension.
56
What are the different classifications of drugs that may be used as hypertensive drugs?
Diuretics : thiazides, loops and K+ sparing Renin inhibitor ACE inhibitor Angiotensin Receptor Blockers Calcium Channel blockers Beta blockers Centrally acting alpha 2 agonists Vasodilators
57
What different vasodilators can be used to prevent hypertension?
Nitroprusside - NO donor Phentolamine - non-selecitve alpha adrenergic antagonist Prazosin - selective alpha 1 adrenergic antagonist Minoxidil - potassium channel opener Hydralzine - MOA unknown - acts direclty on smooth muscle
58
**What is the use of an aliskiren in the treatment of hypertension?
Class: renin inhibitor Chemistry: non peptide small molecule Pharmacology: is a competitive inhibitor of renin Physiology: decreases conversion of angiotensinogen to angiotensin 1 - knock on = loss of RAAS effects Clinical: essential hypertension
59
What naming indicates a renin inhibitor?
- Ren suffix
60
What is the use of enalapril in treating hypertension?
Class: ACE inhibitor Chemistry: small molecule, pr-drug converted from as ester by hepatic esterases to a carboxylic acid called enalaprilat Pharmacology: competitive inhibitor of ACE Physiology: decreased conversion of angiotensin 1 to angiotensin 2, knock on = loss of RAAS effects Clinical: essential hypertension and heart failure Side effects: also prevents breakdown of bradykinin may lead to a cough
61
Are ACE inhibitors pro-drugs?
Most are esters and must be converted to carboxylic acids by hepatic esterases Only captoprile and lisinopril are not pro-drugs
62
What naming indicates an ACE inhibitor?
- pril suffix
63
What is the use of Valsartan in treating hypertension?
Class: is a angiotensin receptor blocker (ARB) Chemistry: small molecule Pharmacology: is a competitive antagonist at AT1 receptors Physiology: angiotensin 2 unable to bind to receptors, loss of RAAS effects Clinical: essential hypertension, heart failure
64
Suggest why an angiotensin receptor blocker may be given over an ACE inhibitor?
ACE inhibitor: ACE breaks down bradykinin, when this is inhibited bradykinin accumulates and can cause a cough ARB ACE still functional, so no cough.
65
Describe the structure of a voltage gated calcium ion channel.
Has a principle alpha subunit with four homologous 6 alpha helicical transmembrane spanning regions. S4 region contains positively charged residues important for activation Subunit 3 to 4 loop has lysine residues acts to inactivate the channel Has variable regulatory beta, gamma and alpha 2 delta subunits,
66
How do gabapentin and pregabalin target the VGCa2+ channel?
Target the alpha 2 delta auxillaary subunits Treat anxiety and epilepsy.
67
What is the physiological role of a VGCa2+ Channel?
Normall there is a large difference between free Ca2+ conc in the ECF and the activated Ca2+ in the cytoplasm, this creates a concentration gradient for Ca2+ to rapidly move into the cell Depolarisations open the VGCa2+ channel and causes Ca2+ to rush into the cytoplasm. This has a role in: Cardiac action potential Smooth/skeletal muscle contraction Endocrine/insulin secretion Neurotransmitter release.
68
Give an overview of type 1 voltage gated Calcium ion channels?
Type 1 or L type - has three subtypes - Long open duration, inactivate slowly subtype 1 - skeletal muscle subtype 2 - excitable cells, cardiac, smooth muscle, endocrine cells subtype 3 - excitable cells (SAN/AVN), endocrine cells Subtype 4 - retina
69
Give an overview of the different types of voltage gated calcium ion channels.
Type 1 - long timer open, highly responsive to voltage Type 2 - P/Q, N or R type, some response to voltage Type 3 - T - low response to voltage, are open transiently, inactivate rapidly.
70
What are the different types of calcium channel blockers?
All target L-type channels Differ by their chemistry 1. Phenylalkylamines 2. Benzothiazepines 3. Dihydropyridnes
71
What is the use of phenylalkylamines?
Example Verapamil Channel blocker of L type VGCa2+ channels Used as an anti-dysrhythmic
72
What is the use of benzothiazepines?
Example - diltiazem Channel blocker of inactivated state L type VGCa2+ channel used to treat angina
73
What si the use of dihydropyridines?
Examples: amlodipine or nifedipine Are gating inhibitors (allosteric modulation of the channel causes it to close) This modification inhibits voltage-dependent activation (rather than directly preventing it) This stabilises the unresponsive state of the channel. Clinical use to treat hypertension/angina.
74
What are the different classes of anti-dysrhthmic drugs?
Vaughan-Williams Classification Class 1 - local anaesthetics Class 2 - Beta blockers Class 3 - K+ Channel blockers Class 4 - Ca2+ channel blockers
75
What is the main clinical distinction between dihydropyridines v phenylalkamines?
Dihydropyridines are more vessel selective Phenylalkalimes are more cardio-selective.
76
What is the use of amlodipine in treating hypertension?
Class: calcium channel blocker Chemistry: small molecule, dihydropyridine Pharmacology: preferentially affects smooth muscle over cardiac muscle, allosteric regulator, acts as gating inhibitor Physiology: modification stabilises inactivated channel state (prevents opening) when depolarisation occurs - this stabilises the hyperpolarised cell state This decreases Ca2+ influx into cytoplasm - prevents smooth muscle contraction Results in vasodilation Clinical: essential hypertension, angina.
77
Why are dihydropyridines selective for smooth muscle? Compared to phenyalkylamines which prefer cardiac muscle
DHP binding is highly voltage dependent Higher affinity for inactivated state Vessels: are depolarised more in a continuous state of contraction in order to maintain vascular tone, results in more open m and closed H gate - higher affinity for inactivation state change. Compared to cardiac muscle which depolarised and repolarises rapidly so less time spent in inactivation state of channel. Phenylalylamines are not as voltage dependent.

Unit 12 (23 decks)

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