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Unit 12 > Pharmacology of Hypertension 1 > Flashcards

Pharmacology of Hypertension 1 Flashcards

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
Q

How is the endothelium indicated in essential hypertension?

A

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)

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26
Q

How does nitric oxide cause vasodilation of blood vessels?

A

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.

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27
Q

What is the effect of an atheroma on blood vessel diameter mediators?

A

Atheroma - decreases NO production (vasodilator) - resulting in maintained vasoconstriction

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28
Q

What are the effects of sodium nitroprusside on blood vessel diameter?

A

Increase NO levels (vasodilator)
Used in hypertensive emergencies

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29
Q

What is the effect of sildenafil on blood vessel diameter?

A

Inhibits PDE5
Results in increased levels of cGMP
Promotes smooth muscle relaxation
Vasodilation

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30
Q

What are the effects of prostacylin PGI2 on blood vessel diameter?
How is this utilised in the therapeutic world?

A

Causes vasodilation of blood vessels
Structural analgues such as iloprost can be used to treat pulmonary hypertension

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31
Q

How does endothelin affect blood vessel diameter?
How is this utilised in therapeutic world?

A

Is produced by endothelial cells
Cause vasoconstriction
ET receptor antagonists (macitentan) used to treat pulmonary hypertension

32
Q

How does achetylcholine cause vasodilation?

A

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
Q

What are some different vasoactive peptides?

A

Bradykinin
Natiuretic peptides (ANP from atria, BNP from brain ventricles and CNP from endo and heart)
Vasopressin

34
Q

How does bradykinin affect blood vessel diameter?
How is this ultilsed therapeutically?

A

Released from mast cells mainly during inflammation
Cause vasodilation
ACE inhibitors prevent the breakdown of bradykinin
resulting in increased vasodilation, combat hypertension.

35
Q

What is the role of natriuretic peptides in controlling blood pressure?

A

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
Q

What is the result of a malfunctional NRP1 receptor?

A

Natriuretic peptides (ANPetc) have no effect
Results in fluid Retention and hypertension.

37
Q

What is the affect of vasopression on blood pressure?

A

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
Q

What is the role of the Renin-Angiotensin-Aldosterone System in essential hypertension?

A

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
Q

How is angiotensin 1 converted to angiotensin 2?

A

ACE enzyme cleavage of C-terminal dipeptide

40
Q

Angiotensin 2 is a what as At1 receptors?

A

Full agonist

41
Q

What are the pharmacological features of ACE1?

A

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
Q

What are the properties of ACE2 enzymes?

A

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
Q

What are the features of the AT1 receptor?
What effects does it bring about when activated?

A

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
Q

What is the difference between AT1/AT2 and AT-I and AT-II?

A

AT1/2 - angiotensin receptors
AT-I / II - angiotensin peptides

45
Q

What is the pharmacology of aldosterone?

A

Is a steroid/ mineralcorticoid
Full agonist at intracellular mineralcorticoid receptor in principle cells of the DCT

46
Q

What are the features of the mineral corticoid receptor that aldosterone acts on?

A

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
Q

What are the features of ENaCs related to blood volume?

A

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
Q

How does sodium reabsoprtion link to arterial blood pressure?

A

Increase Na+ reabsoprtion
Increased water reabsoprtion
Increased ECF volume
Increased stroke volume
increased cardiac output
Increased Arterial blood pressure

49
Q

What is amiloride?

A

A channel blocker
Blocks ENaCs in the DCT.
Prevents reabsorption of Na+ hence water.

50
Q

What are the features of the Na+/K+ pump related to RAAS?

A

Multimeric ATP-dependent active transporter
Expressed throughout the renal tubule
Sustains Na+/K+ gradient across membrane (regulate intracellular and intersistial conc)

51
Q

What is the role of cardiac glycosides in relation to RAAS?

A

Example is digoxin
Inhibit Na+ K+ Pump
prevent Na+ hence water reabsoprtion - decrease blood volume.

52
Q

What is Liddle Syndrome?

A

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
Q

What is the appropriate treatment for Liddle syndrome?

A

Amiloride
ENaC channel blockers

54
Q

What drug class is spironolactone?

A

Potassium sparing diuretic
Competitive antagonist of nuclear mineralcorticoid receptors in the DCT - prevent action of aldosterone.

55
Q

What is the use of ganglion blockers as drugs?

A

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
Q

What are the different classifications of drugs that may be used as hypertensive drugs?

A

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
Q

What different vasodilators can be used to prevent hypertension?

A

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
Q

**What is the use of an aliskiren in the treatment of hypertension?

A

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
Q

What naming indicates a renin inhibitor?

A
  • Ren suffix
60
Q

What is the use of enalapril in treating hypertension?

A

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
Q

Are ACE inhibitors pro-drugs?

A

Most are esters and must be converted to carboxylic acids by hepatic esterases
Only captoprile and lisinopril are not pro-drugs

62
Q

What naming indicates an ACE inhibitor?

A
  • pril suffix
63
Q

What is the use of Valsartan in treating hypertension?

A

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
Q

Suggest why an angiotensin receptor blocker may be given over an ACE inhibitor?

A

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
Q

Describe the structure of a voltage gated calcium ion channel.

A

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
Q

How do gabapentin and pregabalin target the VGCa2+ channel?

A

Target the alpha 2 delta auxillaary subunits
Treat anxiety and epilepsy.

67
Q

What is the physiological role of a VGCa2+ Channel?

A

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
Q

Give an overview of type 1 voltage gated Calcium ion channels?

A

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
Q

Give an overview of the different types of voltage gated calcium ion channels.

A

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
Q

What are the different types of calcium channel blockers?

A

All target L-type channels
Differ by their chemistry
1. Phenylalkylamines
2. Benzothiazepines
3. Dihydropyridnes

71
Q

What is the use of phenylalkylamines?

A

Example Verapamil
Channel blocker of L type VGCa2+ channels
Used as an anti-dysrhythmic

72
Q

What is the use of benzothiazepines?

A

Example - diltiazem
Channel blocker of inactivated state L type VGCa2+ channel
used to treat angina

73
Q

What si the use of dihydropyridines?

A

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
Q

What are the different classes of anti-dysrhthmic drugs?

A

Vaughan-Williams Classification
Class 1 - local anaesthetics
Class 2 - Beta blockers
Class 3 - K+ Channel blockers
Class 4 - Ca2+ channel blockers

75
Q

What is the main clinical distinction between dihydropyridines v phenylalkamines?

A

Dihydropyridines are more vessel selective
Phenylalkalimes are more cardio-selective.

76
Q

What is the use of amlodipine in treating hypertension?

A

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
Q

Why are dihydropyridines selective for smooth muscle?
Compared to phenyalkylamines which prefer cardiac muscle

A

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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