Pharmacology 1 - Drugs Affecting Vasculature and Blood Pressure Flashcards
What confers the ability for muscle contraction?
Concentration of intracellular calcium
By which two methods can calcium levels within vascular smooth muscle be elevated?
- Opening L-type calcium channels (depolarisation)
- Release of Ca2+ from sarcoplasmic reticulum (mediated by Gq11)
How is myosin light chain kinase activated?
When calcium binds to calmodulin it can activate MLCK
What happens to myosin light chain during relaxation?
Myosin light chain phosphotase will will dephosphorylate MLC allowing for relaxation
How is myosin light chain phosphotase activated?
Protein kinase G (activated by cGMP)
Name 3 vasodilating substances found naturally in the body
- Bradykinin
- ADP
- 5-HT (hydroxytryptamine) - serotonin
In vascular smooth muscle cells which G protein coupled receptor is activated upon to mediate vasodilatation?
Gq
Describe fully, the process involving calcium that results in vasodilatation in vascular smooth muscle
- Activation of Gq results in increased intracellular calcium concentration
- Calcium bind to calmodulin and activates endothelial nitric oxide synthase (eNOS)
- eNOS converts L-arginine (with oxygen) to nitric oxide (NO)
- NO diffuses across endothelium and promotes conversion of GTP to cGMP by activating guanylate synthase
- cGMP can activate protein kinase G which activates MLC phosphotase
- MLC is dephosphorylated and relaxation occurs
eNOS also directly stimulates potassium channels (calcium dependent) causing potassium efflux, hyperpolarisation and the prevention of an AP
Which pathway is utilised by the organic nitrates?
The pathway for vascular smooth muscle relaxation
How do organic nitrates induce vascular smooth muscle relation?
- Organic nitrates readily diffuse into smooth muscle cells
- Enzymes and thiol groups will convert the organic nitrates to nitric oxide and citrulline
- This allows the nitric oxide produced to act as normal and cause relaxation
At low doses organic nitrates preferentially act on the ______ system
Venous
Why is venorelaxtion, due to organic nitrates, of benefit?
Large veins dilate and venous return to right atrium decreases
Preload and stroke volume decrease
At modest doses cardiac output is maintained by an increase in heart rate
What 3 main effects does organic nitrate adminsitration induce?
- Venorelaxation
- Arteriolar dilatation
- Increased coronary flow
Organic nitrates are used as a treatment for ______ ______ and also _____ ________ ________
Stable Angina
Acute Coronary Syndrome
Which two effects allow organic nitrates to be a useful treatment for angina?
- Decreases myocardial oxygen requirement (decreases pre and afterload)
- Redirects blood flow from healthy to ischaemic zones using collateral vessels
How do organic nitrates affect coronary circulation?
They do not further dilate occluded vessels - these are already at maximum dilatation due to local factors
In long standing CAD vasculature remodelling occurs to bypass the occulsion - it is these collateral vessels which can be dilated
What are the three main organic nitrates?
- Glyceraltrinitrate - used for all forms of angina
- Isosorbide mononitrate
- Isosorbide dinitrate - must be metabolised first
What are the four types of angina?
- Stable - presents with exertion and relieved by rest
- Unstable - presents acutely at rest
- Decubitus - presents when lying flat
- Variant (Prinzmetal’s) - due to coronary artery spasm
Why can GTN not be administered orally?
Through its first circulatory pass through the portal system it is inactivated
How should GTN be administered? (4)
Spray - towards back of mouth
Sublingual tablet
IV (in ACS)
Transdermal patch with aspirin (in ACS)
What is isosorbide mononitrate primarily used for?
Prophylactic treatment of angina
What are some side effects of organic nitrates?
- Tolerance
- Postural hypotension
- Heachaches (dilatation of cranial circulation)
- Formation of methaemoglobin - unable to release oxygen
To avoid the problems associated with tolerance, how can organic nitrates be adminstered?
For morning/mid-afternoon use
This can reverse tolerance alowing the drug to be deplated from the body during the night
What is endothelin-1?
A vasoconstrictor produced in response to vasoconstricting substances
Name 3 vasoconstricting substances that initiate endothelin-1 production
- ADH
- Adrenaline
- Angiotensin II
What substances/events can suppress endothelin-1 production?
- Nitric oxide
- Natriuretic peptides (A, B and C)
- Shear stress on endothelium from blood flow
How is endothelin-1 produced by vasoconstricting agent release?
Vasoconstricting agents alter gene expression to allow for precursors of endothelin to be produced
How does the production of endothelin-1 lead to vasoconstriction?
- Endothelin-1 is exported from endothlial cells
- It binds to a g protein coupled receptor (Gq11) called ETA
- Intracellular calcium is increased causing contraction
In the therapeutic treatment of hypertension, which agents can be used as antagonists for endothelin-1
Bosentan and ambrisentan
(for pulmonary hypertension)
In what circumstances would renin be released?
- Decreased renal perfusion pressure
- Increase in renal sympathetic nerve activity
- Decrease in glomerular filtration
The renin-angiotensin-aldosterone system aims to restore ______ blood pressure
Higher/normal
Where is renin secreted from?
The juxtaglomerular cells (in the kidney)
What is the role of renin in the RAAS pathway?
It splits off 10 amino acids from angiotensinogen (produced in the liver) which comine to form angiotensin 1
How is angiotensin II formed?
Angiotensin converting enzyme coverted angiotensin I to angiotensin II
After angiotensin II is formed, how does it exert its effect?
Via AT1 receptors (G protein coupled) in vascular smooth muscle cells. Angiotensin II binds to sympathetic neurones increasing noradrenaline release (acts on alpha 1 receptors) which initiates vasoconstriction
Angiotensin II also stimulates aldosterone release from the adrenal cortex
Where is aldosterone released from?
Adrenal cortex
What does aldosterone do?
Causes salt and water reabsorption from the kidneys increases circulating volume and blood pressure
What is aliskiren?
A renin inhibitor
What is an ACE inhibitor?
An angiotensin converting enzyme inhibitor
Besides inhibiting ACE direcetly, how else can the action of angiotensin II be inhibited?
Blocking AT1
As well as converting angiotensin I to II, what else does ACE do?
Inactivates bradykinin - a vasodilator
Give an example of an ACEI
Lisinopril
Give an example of an angiotensin II receptor blocker
Losartan
ACE inhibitors have which two outcomes?
- Decreased preload by venous dilatation
- Decreased afterload and TPR due to arteriolar dilatation
Why is aldosterone production not completely abolished usder the influence of an ACEI?
Its release is also controlled by plasma potassium levels
Why do ACEIs lower blood pressure?
- Bradykinin is not inactivated - vasodilation can occur
- Aldosterone is reduced which decreases salt and water uptake by the kidneys decreasing blood volume
- Arterial and venous dilatation occurs
Why do healthy individuals have little response to ACEIs?
The RAAS system is not particularly active
Which two factors affect how active the RAAS system is except for health?
- Age
- Ethnicity - more active in black individuals
In which parts of the body will ACEIs have the biggest effect?
Brain, kidneys, heart
(tissues with highest levels of angiotensin I receptor)
What are some side effects of ACEIs?
- Initial hypotension
- Dry cough - build up of bradykinin in airways
Which key side effect is avoided by using a angiotensin receptor blocker (ARB) instead of an ACEI?
Dry cough
(bradykinin metabolism is not affected)
What three clinical uses are there for both ACEI and ARBs?
- Hypertension
- Cardiac failure
- MI
Beta blockers act on which type of receptor in the heart?
B1 adrenoceptors
(G protein coupled (Gs))
What are the two groups of adrenoceptors?
Alpha (I and II)
Beta (I, II and III)
What are B blockers used to treat and why?
Angina
They help to promote vasodilatation
Why is it recommended to use a selective beta blocker versus a non selective variant?
B1 adrenoceptor antaginists will promote vasodilatation
B2 adrenoceptor antagnists will block the natural vasodilation conferred by agonist binding
Blocking B2 adrenoceptors worsens which type of disease?
Variant angina
(caused by intermittent coronary artery spasm)
B1 blockers decrease myocardial ______ ___________.
Oxygen requirement
(by reducing HR, SV and CO)
How do beta blockers aid ventricular perfusion?
Ventricles can only be perfused during diastole as the coronary arteries become occluded during systole.
By slowing the heart rate, the length of time the heart is in diastole increases inceasing the time the heart is perfused
What are some of the side effects that have lead beta blockers to no longer be top of the list as a treatent for hypertension?
- Unfavourable effect on blood lipids encouraging bad cholesterol
- Increased triglyceride levels
If a patient suffers from both angina and hypertension which class of drug may be utilised that normally wouldn’t be for hypertension?
Beta Blocker
Why do beta blockers improve coronary circulation?
Heart rate is slowed, contractile force is reduced and the time the ventricles can be perfused (during diastole) is increased
How do beta blockers affect renin production?
They reduce renin production
Beta blockers are as effective at this in low renin concentrations as they are in high concentrations
Why are beta blockers administered at a very low initial dose?
Beta blockers have initially negative effects
To minimise this low doses are used which build to higher doses after the window for the most negative effects has passed
How do calcium channel blockers affect the vascualture?
Calcium influx is limited meaning contractile ability of smooth muscle is reduced allowing for vasodilatation
What three effects does a calcium antagonist have in the heart?
- Rate of SA node discharge is reduced
- AV node conduction is impaired
- Cardiac contractility is reduced (L-type channels in plateau phase blocked)
How are calcium channels normally activated in the vasculature?
When noradrenaline is released it activates alpha I adrenoceptors which activate non-selective cation channels open causing sodium influx hyperpolarising the cell and activating voltage gated calcium channels which allows contraction to occur
What are the three main type of calcium antagonist?
- Verapamil - act on L-type selectively (heart not vasculature)
- Amlodipine - selective for L-type channels in vasculature
- Diltiazem - intermediate selectively for channels in the heart and vasculature
Clinically which three conditions can calcium antagonists be used for?
- Hypertension
- Angina
- Dysrhythmias
Describe the effect amlodipine has on the vascualture
L-type channels are blocked reducing calcium entry
Vasodilatation is promoted
TPR and MABP are reduced
Arteries are most affected (more smooth muscle)
Why would it be bad for a calcium channel blocker to block all calcium channel types?
This would inhibit contraction to dangerous levels and negatively impact the heart
How are calcium antagonists used for angina?
Prophylactically
Why are calcium antagonist particularly useful for angina?
They cause peripheral arterioar dilatation reducing afterload and therefore myocardial oxygen requirement
Calcium antagonist allow for coronary _______________.
Vasodilatation
Why is amlodipine superior to other calcium antagonists for angina?
It is long acting and does not have any negative ionotropic effects
Verapamil is used in which instance?
Atrial fibrillation
But not in conjuction with a beta blocker or when heart failure is also present
How do potassium channel openers work?
- Intracellualr ATP is antagonised which normally closes the channels
- Potassium efflux occurs - the cell becomes hyperpolarised
- The hyperpolarised state inhibits L-type calcium channels
- This will therefore prevent contraction
Name two potassium channel openers
- Minoxidil - drug of last resort
- Nicorandil - used for angina
What 3 effects does activiting alpha 1 channels have?
- Activates non-selective cation channels for sodium influx
- Depolarised state activates calcium channels for calcium influx
- Increases calcium release from sarcoplasmic reticulum
Blocking alpha 1 receptors has what effect?
Vasodilatation occurs
(calcium channels cannot be activated)
MABP is decreased
What are two alpha 1 receptor antagonists?
- Prazosin
- Doxazosin
Which type of drugs will be used for benign prostatic hyperplasia?
Alpha 1 receptor antagonists
What is the main side effect of alpha 1 antagonists?
Postural hypotension
What are the two main classes of diuretics?
Thiazide and loop
What is the effect of thiazide diuretics?
NACL reabsorption is reduced in the distal renal tubules
This occurs as a result of blocking the Na/Cl co-transporter
This confers a moderate diuresis
What is the effect of a loop diuretic?
NaCl reabsorption is inhibited by blocking the Na/K/2Cl co-transporter in the ascending loop of Henle
This produces a strong diuresis
What is the negative effect of the diuretic class of drugs and how is this counteracted?
Too much potassium is lost
- Potassium supplements can be taken
- Potassium sparing diuretics can be used
Name a thiazide diuretic
Bendroflumethiazide
Thiazide diuretics are used in what types of disease?
- Mild heart failure
- Hypertension
- Severe resistant oedema (potentially also with loop)
(Also in pulmonary oedema)
Name a loop diuretic
Furosemide
