W2 CVS Flashcards
1-23 is blood pressure control molecular basis
What is blood pressure? (arterial)
- Pressure exerted on the walls of blood vessels (largely referred to as arterial pressure)
- Pressure is essential to perfuse all the cells of the entire body (constant & consistent)
- Measured as systolic/diastolic mmHg
- BP varies with age and pathological conditions
Systolic BP: MAP during heart contraction
Diastolic BP: MAP during heart relaxation
(Systemic: 120/80 mmHg; Pulmonary: 25/8 mmHg, Venous: 6-8 mmHg)
MAP= Mean arterial pressure
What is the blood pressure calculation?
BP= Cardiac output x Peripheral Resistance
What is the Cardiac Output calculation?
Cardiac output = Heart Rate x Stroke volume
= 70/min x 70 ml
= 4900 ml/min = 5L/min
CO- how much blood the heart pumps out
If artery size is larger…
If artery size is smaller…
….BP is lower
…BP is higher
What is blood pressure?
- Pressure exerted on the walls of blood vessel (largely referred to as arterial pressure)
- Pressure is essential to perfuse all the cells of the entire body (constant & consistent)
- Measured in mmHg
- BP varies with age and pathological conditions
Systolic BP: MAP during heart contraction
Diastolic BP: MAP during heart relaxation
(Systemic: 120/80 mmHg; Pulmonary: 25/8 mmHg, Venous: 6-8 mmHg)
Blood pressure
Factors:
What is the calculation for blood pressure?
What is the cardiac output equation?
BP= CO X PR
blood pressure= cardiac output x peripheral resistance
Cardiac output= Heart Rate x Stroke Volume
= 70/min x 70mL
= 4900 ml/min = 5L/min
Autoregulation process:
What is autoregulation?
What do changes in blood flow lead to?
Normal resting conditions redistribute blood as needed by tissues.
Body wants to maintain normotension
Change in blood pressure leads to Vasodilatation- dec BP (when hypertension) and Vasoconstriction- inc BP (when hypotension)
Autoregulation of perfusion:
When organ/body tissue has low O2 what occurs?
- CO2 , potassium (K+) or hydrogen (H+) ions
(acidic pH)
Lactic acid
(by-products of cell metabolism)
Histamine (Inflammation)
Body temp - Stimulates endothelial cells to release endothelin (peptides)
Platelet secretions and prostaglandins - Vasoconstriction of pre-capillary sphincters
Autoregulation of perfusion:
When organ/body tissue has High O2:
What takes place?
CO2 , potassium (K+) or
hydrogen (H+) ions (acidic pH)
Lactic acid
(by-products of cell metabolism)
Histamine (Inflammation)
Body temp
tissues
Stimulate endothelial cells to release NO (nitric oxide)
Vasodilation of precapillary
Myogenic response
Stretching of the smooth muscle in the
walls of arterioles
Blood flow (High): Stretch
Blood flow (low): Constrict
Localised protective function to maintain
the blood flow:
Ischemia (hypoxia) Vs Excessive perfusion
What is Neural regulation?
Short-term regulation of blood pressure, especially in responses to transient changes in arterial pressure, via baroreflex mechanisms
Neural Regulation of LOW Blood pressure
(hypotension)
Baroreceptors sense low BP and reduce firing rates (so vagus nerve is inhibited)
CVC in brain stem:
1. Reduce vagal activity
2. CVC inc Sympathetic cardiac activity (to inc HR)
Heart contraction and HR inc
Cardiac Output inc
Blood pressure raises and homeostasis restored
(vagal activity suppresses hr so we want to stop that to inc hr)
Opposite for hypertension occurs
RAAS:
How is Low BP regulated by hormonal regulation?
Sensed by kidney. Renal hypoperfusion. Granular cells (juxtaglomerular) stimulate production of/ release of hormone Renin.
Liver synthesises Angiotensinogen. Converted into Angiotensin l and ll by ACE
Lungs- Angiotensin converting enzyme (ACE) is created.
Angiotensin ll stimulates aldosterone release which inc peripheral resistance which inc BP
Hormonal: Erythropoietin (EPO) action when there is low blood pressure:
- Kidney becomes hypoxic (renal arterial
oxygen drops) triggering EPO release - EPO stimulate the red bone marrow to
produce more erythrocytes (RBC) - Erythrocytes increase O2 transport and
restore O2 level
Too much EPO is a risk:
EPO is a vasoconstrictor.
Increase
Blood viscosity, resistance, and
pressure
Decrease
Blood flow
Catecholamines: Adrenaline/Nor-adrenaline effects on low BP
- Released by the adrenal medulla
- Enhance and extend the body’s sympathetic activity (“fight-or-flight” response)
Increases:
Heart rate
Force of contraction
Vasoconstriction (non-essential organs)
Energy mobilisation to the liver, muscle and heart
“Fight or Flight”
Sympathetic Vs Parasympathetic activity?
Voluntary Vs Involuntary
Fight or Flight Vs Rest and Digest
Hormonal: Antidiuretic Hormone (ADH)/ Arginine Vasopressin (AVP)
When there is Low BP:
Hypovolemia: Increase in tissue fluid osmolarity (loss of blood volume) triggers ADH release
- ADH is secreted by the cells in the
hypothalamus, transported to the posterior
pituitary and stored until nervous stimuli. - ADH signals kidneys to reabsorb more water
- Prevent the loss of fluids in the urine.
- Increase overall fluid levels
- ADH constricts peripheral vessels.
- Restore blood volume and pressure.
What are some causes of Hypovolemia? (5)
Haemorrhage
Dehydration
Diarrhoea
Burns
Diuretics
What are some causes of Structural dysfunctions? (leading to low HR) (5)
Valves disease- valves dont open/close fully
Ischemia- blood flow and thus oxygen is restricted
Myopathy- disease that affects the muscles that control voluntary movement in the body.
Pulmonary hypertension
Pericardial disease
Regulation of Blood pressure control
Includes:
- Autoregulation
- Changes in blood flow detected by the local receptors during micro perfusion
- Neural
Short-term regulation of blood pressure, especially in responses to transient changes in arterial pressure, via baroreflex mechanisms - Hormonal
Long-term regulation of blood pressure - Renin-Angiotensin-Aldosterone
- Anti-diuretic hormone (ADH; arginine vasopressin)
- Atrial natriuretic hormone/peptide/factor
- Erythropoietin
- Adrenaline/Noradrenaline
Neural Regulation of HIGH Blood pressure
Baroreceptors firing rates inc
Vagal activity inc (which suppresses HR-we want this)
Parasympathetic activity inc
Sympathetic activity dec
HR dec
Heart contraction dec
CO dec
Blood pressure dec and homeostasis restored
RAAS high BP
Juxtaglomerular cells (granular cells) sense high BP in kidney
JG cells are suppressed so no Renin is released
No Angiotensin l secreted to be converted by ACE into Angiotensin ll and thus no stimulus for Aldosterone release from Adrenal cortex
Atrial Natriuretic Peptide (ANP)
Where is it synthesised and released?
What is its function?
Synthesised and Released by Atria
Inc sodium in urine
What are the risks of Hypertension? (8)
- heart disease
- heart attacks
- strokes
- heart failure
- peripheral arterial disease
- aortic aneurysms
- kidney disease
- vascular dementia
Side effects of antihypertensives:
ACE inhibitor- Dry cough
Beta-blocker- bradycardia
Calcium channel blocker- Ankle swelling, flushing palpitations
ARB- Dizziness, headache, fatigue,
Name some HMG-coA reductase inhibitors (Statins):
Atorvastatin
Simvastatin
Rosuvasatin
Pravastatin
Medicines for hypocholesterolaemia:
- Ezetimibe
- Bempedoic acid
- Inclisiran (subpopulation of patients in Wales)
specialist care:
alirocumab
evolocumab
volanesorsen
What can influence drug distribution in the body?
Body weight
Which enzyme system is responsible for the metabolism of many antihypertensive drugs?
Cytochrome P450 (or CYP450)
How can grapefruit juice affect the pharmacokinetics of antihypertensive drugs?
It inhibits drug metabolism
Which class of drugs can potentially decrease the effectiveness of antihypertensive drugs?
NSAIDs
How can diuretics interact with antihypertensive drugs?
they can enhance antihypertensive effects
Angiotensin II Receptor Blockers (ARBs)
- ARBs are receptor antagonists that
block type 1 angiotensin II (AT1) receptors on blood vessels and other tissues such as the heart. - AT1 receptors are coupled to the Gq-protein
and IP3 signal transduction pathway that
stimulates vascular smooth muscle
contraction
The outcome/effect is similar to ACEi’s
ARB drugs are usually classed by name such as…
‘sartan’ drugs
Candesartan (prodrug)
irbesartan
Losartan (prodrug)
valsartan
olmesartan
Dihydropyridines more vascular smooth muscle target
Non- Cause cardiac muscle inhibition at the heart.
What is the target of thiazide/ thiazide-like diuretics?
Sodium, chloride symporters in the DCT, to cause diuresis and excrete sodium
retain it in the urine and not reabsorbed.
What are the side effects of Thiazides and Thiazide-like diuretics?
*Hypokalaemia (Potassium loss due to increased sodium delivery to distal
tubule)- would expect opp effect but JG cells sense drop in sodium and this causes more sodium/potassium to be pumped in
*metabolic alkalosis (increased hydrogen ion loss in the urine)
*dehydration (hypovolemia),
*leading to hypotension
*hyponatremia
Beta-adrenergic receptor antagonist
Increases heart rate
Increasing cardiac muscle’s force of contraction
Adrenergic receptor ‘beta’ (B-1)
ACE Inhibitors:
How do they work?
(pharmaceutical def)
Block synthesis of Angiotensin II by inhibiting ACE (Enzyme Inhibitors)
- Ionic bond
- Interaction with the labile peptide bond
- Additional binding
- H-bond
Enalaprilat and Enalapril:
Carboxylic acid changed to Ester (EWG) so pKa of N has become less basic so wont be protonated, wont become zwitterion so can easily be absorbed
Enapril is a prodrug of Enaprilat
What drugs have the same general formula, similar to enalapril? (ACEi)
Lisinopril, Ramipril, Quinapril
Structure-Activity Relationship of ACEi
- N-ring must contain COOH to mimic the C-terminal COOH of Angiotensin I
B. Large hydrophobic heterocyclic rings (i.e., the N-ring) increase potency/PK
C. Zinc binding groups: SH (Captopril), COOH (Ramipril), or POOH (Fosinopril).
SH group shows superior binding to zinc but skin rash and taste→
disturbances
D. Mimic the Phe. Mimic the peptide hydrolysis transition state. Compensates for
lack of a SH
E. Esterification of COOH or POOH produces an orally bioavailable prodrug
F. X is usually methyl
G. Stereochemistry needs to be consistent with L-amino acids (natural
SAR of 1,4-dihydropyridine
A. 1,4-dihydropyridine ring: essential
B. Substituted phenyl ring at C4: optimise activity
C. Substituent X: need to be in ortho or meta. Lock active conformation essential for the activity
D. Ester groups at the C3 and C5 positions optimise activity.
Other EWG: decreased antagonist activity. May have agonist activity
E. If esters at C3 and C5 are non-identical: C4 is chiral→stereoselectivity between the enantiomers is observed (selectivity for specific blood vessels). Marked as racemic
F. All (except amlodipine) have C2 and C6 = CH3.
Enhanced potency of amlodipine : 1,4-DHP receptor can tolerate larger substituents at this position and that enhanced activity can be obtained
1,4-dihydropyridine; more info
Coadministration of 1,4-DHPs with grapefruit juice: increase the systemic concentration of the 1,4-DHPs. Due to inhibition of intestinal CYP450 by flavonoids and furanocoumarins specifically found in grapefruit juice
- do not drink grapefruit juice whilst taking this drug
Compound ending in -PIDINE
Diuretics
Increase the rate of urine formation targeting the kidney
Increased excretion of electrolytes (especially Na+ and Cl-) and water without
affecting protein, vitamin, glucose, or amino acid reabsorption
Treatment of oedema (excessive extracellular fluid) (e.g., congestive heart
failure) and in the management of hypertension
Classified by * chemical class (thiazides and thiazides-like)
* mechanism of action (carbonic anhydrase inhibitors and osmotic)
* site of action (loop diuretics)
* effects on urine contents (potassium-sparing diuretics)
Different efficacy (ability to increase the rate of urine formation, e.g increase
the excretion of Na+ filtered at the glomerulus ) and different site of action
within the nephron
🧬💊❤️
Thiazide-like Diuretics:
How do they work?
Example?
Acting on distal convoluted tubule: compete for Cl- binding site of the Na+/ Cl– symporter inhibiting reabsorption of Na+ and Cl-
Indapamide
Rapidly and completely absorbed from GI. Duration of action of up to 8 weeks.
Extensive binding to carbonic anhydrase in the erythrocytes
Anticoagualant Vs Antiplatelet?
What is the difference?
Anticoagulants slow down clotting thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.
