Hypertension Flashcards
1
Q
Rationale for treatment and why?
A
Important preventable cause of premature morbidity and mortality
Why?
1. A symptomatic- people don’t know they have it
2. drug therapy- could cause side effects
2
Q
people with hypertension are at major risk for?
A
- stroke- block artery supplying brain
- MI- atherosclerosis build up, thrombosis, Heart attack
- HF- high HR, afterload increase
- chronic renal failure- kidneys control this through renal output and blood flow
- cognitive decline - dementia, small vessel changes in brain ischaemia
- premature death
3
Q
Hypertension facts
A
Increasing systolic BP by 2mmHg is associated with :
- 7% increase mortality- IHD
- 10% increased mortality from stroke
4
Q
Risk factors for increased BP
A
- height and age
- normally distributed through population
- top of normal range there is more risk to get high and would benefit from treatment
5
Q
Diagnosing suspected hypertension- clinical
A
Clinical BP = 140/90 or higher
6
Q
quality statement for hypertension
A
people with suspected hypertension are offered aambulatory blood pressure monitoring (ABPM) to confirm diagnosis of hypertension
- time against BP
- every half hour and hour at night
7
Q
Stages of hypertension
A
Stage 1
- clinic= 140/90
- ABPM-135/85
Stage 2
- clinic= 160/100
- ABPM= 150/95
8
Q
What are the primary treatments for hypertension
A
- lifestyle modification
2. antihypertensive drug therapy
9
Q
Treatments for secondary hypertension
A
LOOK AT PATIENT
- young person, resistant BP, signs and symptoms underlying
- reflective of another problem
- endocrine, hormonal, kidney disease
10
Q
Who to offer antihypertensive treatment to stage 1 people under 80 with one of these problems:
A
- target organ damage- eye, heart, kidney
- established CVD
- renal disease
- diabetes
- 10+ year of cardiovascular risk over 20%
*or anyone with stage 2
11
Q
goal BP to have
A
Under 80 - clinic <140/90, ABPM <135.85
over 80- clinic <150.90, ABPM < 145/85
12
Q
Why are the elderly BP targets slightly higher?
A
Blood vessels lose compliance (arteries_ arteries distend (stiffer) and contract back to form secondary pulse wave,
13
Q
Mechanism of BP control
Targets for therapy
A
- CO and periphery resistance - co= SV x HR
- interplay between
a) renin- angiotensin-aldosterone system
b) sympathetic NS - local vascular vasoconstrictor and vasodilator mediators
- peripheral resistance
14
Q
Angiotensin II vasoconstrictor effects
A
- vascular growth
- hyperplasia
- hypertrophy - salt retention
- aldosterone release
- tubular Na reabsorption
15
Q
Interfere
A
ACE inhibitors ARB BB renin inhibitor centralling acting ca channel blocker alpha blocker aldosterone antagonist
16
Q
What are the main clinical indications of ACE inhibitors?
A
Hypertension, HF, diabetic and nephropathy
17
Q
What are ace drugs?
A
Ramipril, perindopril, enalapril, trandolapril
18
Q
What are sartan drugs?
A
same mechanism of action as ACE inhibitors, vary due to duration and cost
ARB
19
Q
What are the main clinical indications for ARB inhibitors?
A
hypertension, diabetic and nephropathy and HF
20
Q
ARB drug names
A
Candesartan valsartan Losartan IREsartan telmasartan
21
Q
what are the main adverse effects of ARB inhibitors?
A
Sympotomatic hypotension hyperkalaemia potential for renal dysfunction rash angio-oedema * Contradicted in pregnancy, generally very well treated
22
Q
How does ARB work?
A
it inhibits angiotension II to AT1 receptor
highly specific blocker
Block ACE reduce angiotensin II so substrate of enzyme increase so overcome drug effect as it competes
23
Q
What are the main indications for calcium channel blockers? and the drugs you would use with each one
A
hypertension- amlodipine, felodipine, nifedipine, lacidipine
Ischaemic heart disease and arrhythmia- diltiazem and verapamil
attach the peripheral resistance with CCB
24
Q
L type calcium channel blockers
A
- Dihydropyridines-: nifedipine, amlodipine, felodipine, lacidipine
- Phenylalkylamines: verapamil
- Benzothiazepines: diltiazem
25
Action of L type Ca channel blockers- dihydropyridines
Preferentially affect vascular smooth muscle
peripheral arterial vasodilators
Not used as much for hypertension as they are shorter acting
26
Phenylaklylamines action
Main effects on the heart
negatively chronotropic and ionotropic
Has the opposite effect, has major effect on heart (conducting tissue and muscle of heart)- used for arrhythmias and angina
27
Benzothiazepines Ca channel blocker action
Intermediate heart and peripheral vascular affects
| halfway
28
4 main adverse effects of Ca channel blockers
1. due to peripheral vasodilation= flushing, headache, oedema, palpatations
2. due to negatively chronotropic effects= bradycardia (feel faint), atrioventricular block
3. negative ionotropic effects= worsening of cardiac failure
4. verapamil causes constipation
29
Name 3 other antihypertensives
1. a-1 adrenoreceptor blocker
2. centrally acting anti-hypertensives
3. direct renin inhibitor
30
A-1 adrenoreceptor blockers drug names and how they work
- doxazosin, indoramin, terazosin, nazosin
peripheral vasculature in under sympathetic tone- A blocker relaxes that reduces BP
Postural hypotension= problem
31
Centralling acting anti-hypertensives names and how they work
1. Monoxidine- imizoline type 1 receptor agonist
2. methyldopa- (old and used in pregnancy)- activates pre synaptic alpha 2 receptors to decrease noradrenaline release and competitive inhibitor of dopa decarboxylase
3. Clonidine- activates pre synaptic alpha 2 receptors ti decrease noradrenaline
32
direct renin inhibitor names and and effect
```
Aliskiren
- hyperkalaemia= raised blood K
- dizziness
arrhythmia- joints, aches and pains
- diarrhoea
- caution with other RAA inhibitors, combination not recommended
```
33
treatment steps for hypertension
step 1
under 55- ACE or angiotensin blocker
over 55- Ca channel blocker
Step 2
- ACE/ARB + CCB
Step 3
- ACE/ARB+CCB+ thiazide- like diuretics
Step 4
- resistant hypertension
- spironolactone
- high doze thiazide diuretic
- alpha and beta blockers
34
What is our pulmonary circulation?
Highly dense network of arteries and veins
capillaries allow gas exchange
Right= Lung
Left= to body
35
What is pulmonary hypertension?
increase in blood pressure from lungs
gas exchange is much less efficient in the lungs
Less O2 around the body -double pressure that would happen normally
36
Pulmonary artery pressure in normal and PAH?
pulmonary artery
- normal= 15-30mmHg
- Pulmonary artery= 35->100
same for the right ventricles
37
What is pulmonary arterial hypertension?
cause by an increased mPAP in PH
38
consequences of pulmonary hypertension?
- right ventricular hypertrophy
- right heart failure
- high morbidity and death ~2.8 years
39
What causes pulmonary hypertension?
```
shunting of systemic blood pressure
thrombus formation
sustained pulmonary vasoconstriction
pulmonary vascular remodelling
* conditions or idiopathic
```
40
What is the most common form of pulmonary hypertension?
schistosomiasis
represents 1%
autoimmune disorders PH can occur in up to 15%
41
What happens if there is a hole in the heart?
lots of pressure build up on right side of the heart
42
If there is a blood clot>
Pulmonary embolism blocks blood flow and increases pressure of blood
43
Sustained pulmonary vasoconstriction?
vessels constricted so don't relax and narrow areas of blood flow
44
Remodelling causing PAH?
cells not in normal state
constricted
can trigger number of things to happen
45
Clinical presentation of PAH?
24hour old female
progressive external breathlessness and chest pains
syncopal episode after excretion
46
How can you see if someone has PAH?
ECG= right heart strained, raised pulmonary artery systolic pressure and dilated right heart
CxR= Normal lungs, increased PA and heart size
lung function tests= normal lung function
+ CTPA/HRCT/MRI/Q scan
47
What is diastolic and systolic?
```
Diastolic= between beats
systolic= pressure ion contraction
```
48
What is the mean pressure?
2/3 diastolic pressure + 1/3 systolic pressure
49
Pulmonary vascular resistance
(mPAP- PAWP)/ cardiac output
PAWEP= pulmonary arterial wedge pressure
usually patients have low CO and pressure drop
50
haemodynamic definition of PAH
mean artery pressure >25mmHg
PAWP/LVEDP < 15mmHg
PVR> 3
no evidence drugs work in any other groups
51
What are the 5 groups of hypertension
1. pulmonary arterial hypertension
2. PH-left heart
3. PH lung disease/hypoxia
4. chronic thromboembolic pulmonary hypertension
5. multifactorial/ unclear
52
Pulmonary arterial hypertension (group 1) causes
idiopathic, heritable, drugs, HIV, portal hypertension, congenital heart disease, schistosomiasis haemodynamic anaemia
53
PH-left heart (group 2) causes
Systolic dysfunction
diastolic dysfunction
Valvular disease
54
PH lung disease/ hypoxia (group 3) causes
interstitial lung disease
sleep disorder
alveolar hypoventilation
55
Chronic thromboembolic pulmonary hypertension (group 4) causes
operable
inoperable
- result of embolism
- happens when the blood clot goes, 1st/2nd branches easier to get to, remove with surgery - most distal is more difficult to treat
56
Group 1 prevalence and incidence
```
15-50% per million population
2-3 per million per year
-40% IPAH- don't know why
- 10% hentable disease- mutation in gene
- 40% APAH- 4x more common in women
```
57
What drug lead to an epidemic?
```
Diet pills
animal incidence of 25-50
PH with LHD is common
PH with lung disease is common
CTEPH= 40% of people after PE
```
58
PAH pathogenesis- compare what is seen in scans of a healthy lung compared to PAH?
- contrast imagine and MRI show crescent shape, 200 micron size in a healthy lung
- muscle stimulated to go from contractile state where they activate cell cycle and start proliferating
Whereas PAH lung
- unchecked proliferation of cells on muscle cells, contractile to unregulated proliferation state
- continually progressive
59
mechanism of PAH
1. vasoconstrictive mediators such as ET-1, thromboxane A2, Prostacylin and nitric oxide are dysregulated in PAH
2. Fatcors drive constriction and stimulate the initial proliferative response as resident PASMC and myofibroblast
4. increase turnover of ECM, endothelial remodelling- narrowing of lumen of artery
5. ultimately the remodelling requires the development of vasa vascrum to fuel this process- occlusion of lumen and cessation of blood flow
60
What drives remodelling?
Fatcors- BMPR2, Ion channels , endothelium, 5-HT, proteases. elastases. MMPs and TF
61
How much of a patients pulmonary vasculature tree can be lost before they become symptomatic?
2/3 r
| remodelling has consequences on heart
62
What happens if there is an increase in resistance to blood flow and increase afterload?
causes the right ventricle to undergo hypertrophy, to where it impinges the LV causing cardiac output to fail
63
Images of the different types of lung- SMC
```
Concentric= onions, made up of layers- endothelial in middle and some outside, collateral formation to cope with blockage
plexiform= rarer, end stages, haemodynamic pressure is too much so get inflammatory and apoptotic cells- loss of SMC
```
64
Elastin and ECM degradation
loss of elastin
- increases vascular stiffness
- promotes SMC proliferation and EC apoptosis
- loss of vascular integrity/ vascular leak
65
What happens if there is extensive neointimal PA lesion
Cells held in place by in and external lamina (rings of matrix)- if this lamina is burst it stimulates vessels/cells to grow and divide, breakdown elastin and increase proliferation
66
pulmonary artery remodelling in PAH
- elastin, EC and SMC
- EC dysfunction/ apoptosis- ecm breakdown
- Growth factors inflammation
- proliferation/migration
67
What happens in response to injury?
1. break in endothelial layer that permits extravasation of serum factors in the subepithelium which stimulates VSMC to produce endogenous vascular elastase
2. proteolytic action of elastase is enhanced by activation of MMPs - found at site of vascular remodelling
3. results in liberation of matric bound GF-
4. transcription and EC deposition of TN is associated with amplification of SMC proliferation
5. elastase stimulates SMC migration through the degradation of elastin stimulating production of glycoprotein fibronectin
68
Falling cost of whole gene sequencing
now around 1000 per patient
| start using this to treat diseases- gene therapy
69
What were the first identification of mutations in PAH
heterozygous germline mutation in BMPR2 encoding TGF-B receptors
cause familial primary pulmonary hypertension
70
KLK1 GENE
Subgroup of serine proteases having diverse physiological function
potential in noval cancer bromance
71
GGCX gene
codes enzymes that catalyses post transcriptional modification of Vit K (coagulation)- haemostasis mutations cause coagulation defect or Pxe disorders
72
Identification transcriptional regulation in disease
BMP
73
Vasodilatory drug treatment in PAH- got drug to target the 3 pathways
1. endothelin pathway
- signalling via G protein and PLC converts PIP2 into IP3
- causes ca influx and vasoconstriction/ proliferation
2. nitric oxide
- endogenous vasodilator produced by endothelial cells
- guanylate cyclase converts CTP- cGMP via PKG inhibits Ca influx
3. prostaglandin pathway
- endogenous vasodilator
- acts on IP receptors via G protein, activates cAMP and PKC to promote SMC relaxation
74
Vasodilator drugs
ERA- endothelium receptor antagonist- 2001, 2007, 2013
PDE-5i- Phosphodiesterase- 5 inhibitor- 2005, 2008
sGC stimulator- soluable guanylate cyclase- 2013
prostanoids- 1995- 2013
IP receptor agonists= 2015
75
3 major pathways involved
1. endothelium pathway
2. nitric oxide
3. prostacylin
76
Calcium channel blockers approved therapy for PAH- response and side effects
diltiazem and nifedipine
- evidence only in patients with acute vasodilator response= inhaled NO given during RHC, drop in mean PAP to 10mmHg
- side effects= systemic hypotension, bradycardia, peripheral odema
77
Phosphodiesterase type 5 inhibitors
sildenafil (Viagra) and tadalfil (adcira)
-PKG- multiple action
promoting vasodilation= activates MLCP, K channels and inhibits
K dependent Ca channel increasing
78
PDE5 inhibitors
first line monotherapy
- Viagra patient experied
- avoid in patients on nitrates
- useful combination with inhaled iloprost
79
Side effects of PDE5 inhibitors
```
headache
flushing
epistaxis
altered colour vision
rarely- non ischaemic optic neuropathy and priapism
```
80
Riocigulant
New class of agents
stimulate guanylyate cyclase
licensed for CTEPH
avoid combination with PDE5
81
Side effects of riociguat
headaches
dizziness
diarrhoea
indegestion
82
Endothelium receptor antagonists- names of drugs and what are they ?
Bosentan
ambrisentan
macitentan
endothelium converting enzyme (ECE) catalyzes conversion of ET to inactive precursor
ET binds ET and ETb - GPCR family ubiquitously distributed in the body
83
Effects of ET
determined by the receptor type they bind
Binding ETa and ETb on VSMC= vasoconstriction
Binding ETb on endothelial cells= vasodilation
induce fibrous, contraction and proliferation depending on location
84
ERA
often given in combination of oral therapy
| added to PDE5 inhibitor
85
Side effects ERAs
```
abnormal liver function- bosentan
headache
nasopharyngitis
peripheral odema
anaemia
```
86
What is macitentan called?
| endothelian receptor agonist
- slower receptor dissociation rate
| - enhanced tissue penetration due to greater lipid solubility
87
What is seraphin?
largest clinical trial
742 patients
delayed clinical worsening
88
What can receptor inhibition help to do?
| Problems with the drugs?
Can overcome with prolonged ET-1 stimulation
| underlying system with increased expression of agonist (competition) so efficacy of drug decreases
89
What are prostacyclin derivatives (4th approved therapy for PAH)
Epoprostenol- IV
Iloprost - inhaled
treprostinil- IV
Beraprost- oral
90
Prostacyclin pathway mechanism?
Arachadonic acid goes to prostaglandin H2 which activates Prostacylin (PGI2)
this increase IP2 which stimulates cAMP
- vasodilation and antiproliferation
91
What happens when there Is vasodilation of the pulmonary and systemic vascular beds?
- lower PAP+ PVR
- reduce ventricular afterload
- inhibits proliferation of human pulmonary artery SMC in vitro
92
Why was prostacyclin pathway therapy not used earlier ?
IV
| cost
93
What are stable prostacyclin analogues?
increased stability
longer half life
Only managed to get from 2 mins to a couple of hours - give often as not sustainable
94
What are the problems of prostacyclin therapy?
```
tolerance
diarrhoea, flushing, headaches
cost - £110k per person per year
continuous delivery
line related complications
made up daily and has to be kept cold
```
95
Problems with inhaled iloprost?
6-9 inhalations daily- compliance
side effects= diarrhoea, headache, cough
thereapy stopped overnight
96
problems with treprostinal- delivered?
Erthymia- redmess of skin, skin injury and infection
| induration- hard spot formed
97
What is selexipag?
Noval new non- prostanoid IP receptor agonist
in phase 3 clinical trial
drug hydrolysed in body
98
What is the max dose for patients taking selexipag?
Max dose is the best dose for the person to have- tolerance and efficacy
Personalise
99
Prostacyclin selectivity?
Poor
usually select IP3 but can also bind and activate prostanol receptor- EP3
These receptors counteract the IP signalling by decreasing cAMP through GI - thus inhibiting relaxation
100
Why can an IP receptor combat disease?
The Ip receptor is in PAH so down regulation can combat
| least selective to receptors they bind to
101
Binding to IP
IV forms bind slightly different receptors they bind the IP1 to cause vasoconstriction and cell proliferation
Least selective for receptors they bind
102
Other treatments for PAH
Anticoagulation-recommend to patients on IV, mainstay of treatment for CTEPH
oxygen- based of COPD trial, los O2 administered at rest
diuretics- treat odema due to right HF
103
What is the efficacy of current treatments?
5 year survival with 50%
| still 12/13% drop for 3/4 years when combined treatment in comparison to mono
104
What are disease triggers in pulmonary vascular remodelling?
Host factors
genetic mutation
sex hormones
Acquired
- somatic mutation
- inflammation
- hypoxia
- drug
injury
- shear stress
- pathogens
105
Molecular consequences of pulmonar vascular remodelling?
```
impaired BMP/TGF signalling
dysregulated miRNA
release GF
DNA damage
metabolic changes
increased cytokine production
```
106
Cell/ tissue phenotype in pulmonary vascular remodelling
```
Endothelial dysfunction
EC apoptosis
SVC proliferation
fibroblast proliferation
Ecm remodelling- elastin, collagen and fibronectin
```
107
Parr pathology in pulmonary vascular remodelling
```
pulmonary vasocontriction
hypertrophy
intimal thickening
plaxiform lesioning
vascular stiffness
perivascular inflammation
```
108
Targeting BMP signalling with FK506/ Tacrolimus induced BMPR2 signalling
looked to see if drugs could stimulate downstream of receptors in the signalling pathway
take animal- give drug- reverse so of symptoms
109
BMP9 as novel therapy
BMP9 effects on endothelial cells in PAH
inhibits endothelial cell proliferation induced by VEF-A
protects endothelial cells from apoptosis, stabilises endothelial network
110
What does BMP9 do?
- inhibits endothelial cell proliferation induced by VEF-A
- protects endothelial cells from apoptosis, stabilises endothelial network
- inhibits endothelial cell permeability induced by inflammation
- increase expression of BMPR-2
111
Sex hormones in PAH
gender bias
more women than men with PAH
acromatase- increase in lungs
112
Anaztrazole in PAH
safe and efficacy with patients with PAH
double blind placebo test
phase 2 84 patients
113
Oestrogen blockage for PAH
Tamoxifen therapy to treat pulmonary arterial hypertension
double blind, random
4 weeks
114
Endpoints in oestrogen blockage trial
1- change in TAPSE
| 2- ECKLO metrics- oxidant stress sex hormones
115
Elastase inhibitor in PAH
relative elastin deficiency despite HNE'ase-
- breakdown of elastin lamina
- elastin inhibited to treat PAH
116
OPG/TRAIL axis
Pathway related to TNF
2 proteins upregulated with PAH patients
higher level= worse prognosis
anti-OPG therapeutic antibody- give with existing drugs
117
Potential targets to modulate pulmonary vascular remodelling
```
inflammation
fibrosis
DNA damage
metabolism
kinase inhibitors
```
