Cardiovascular Pharmacology Flashcards
What is angina and when were drugs developed to treat it?
Angina= blockage of the coronary arteries that causes pain (unstable) during exercise but is relieved at rest (stable)
Causes lack of perfusion due to lesions, arterial contractions or blood clots.
Beta antagonists and calcium channel blockers were developed during the 1950s and 1960s to help treat angina
What increases contractions and activity of the heart?
Adrenalin and noradrenalin increase the contraction of the heart
Calcium causes an increase in heart muscle activity
What do adrenalin and noradrenalin act through, and what type of receptor is it?
Act via alpha and beta adrenergic receptors, which are GPCRs
By who and when were beta blockers introduced?
1964
The first beta blocker to be developed and introduced for clinical use was propranolol. Propranolol was discovered by British pharmacologist Sir James Black, who later won the Nobel Prize in Physiology or Medicine in 1988 for his discoveries concerning “the development of beta-blockers as a treatment for heart disease.”
What effects does adrenaline have on different tissues?
Adrenaline is part of the fight or flight response and thus has different actions on different tissues. E.g. it relaxes the gut but causes contractions in the heart
These different responses are due to the different receptors.
How are adrenoceptors categorised?
Split into classes based on agonist potency
And subclasses based on antqgonist selectivity
How was propanolol created?
In the 1950s, it was found that beta-receptos could be blocked by dichloririsoprenaline. This had no clinical utility due to the chlorine attached however
Removal of the chlorine created pronethalol, however this caused carcinogenesis in mice
Pronethalol was modified and an oxymethylene group was included to create propanolol in 1964. This had a higher potency but fewer side effects.
Why was the creation of propanolol so special?
- The discovery of propanolol was the first new treatment for angina for almost 100 years. It became the worlds biggest selling drug
- It was hailed as the greatest breakthrough in the treatment of heart disease since the discovery of digitalis
- The drug also demonstrated that new major classes of drugs could be developed by applying basic knowledge of receptor-driven cell signalling systems to clinical problems.
What is a side effect of propanolol?
It is not a selective beta blocker and blocks both beta-1 and 2 adrenergic receptors
This meant it could produce off target side effects e.g. in the airways
Since propanolol, what other beta-blockers have been created?
Atenolol- beta-1 selective drug also used to treat osteoporosis, infection and metastatic caner
Nebivolol- beta-1 selective that can stimulate the kidney to cause diuresis and vasodilation, reducing BP
Long acting and short acting beta-blockers also been developed
What do beta-blockers bind to?
They bind to the same site as catecholamines through hydrogen bonding which is reversible
What gives beta-blockers the flexibility to fit into the binding site?
The oxymethylene bridge gives it flexibility so it can fit into the binding site.
Through what pathways do beta-blockers act?
Beta receptors are linked to the Gs protein, however evidence has been published that they also act through the beta-arrestin pathway
Kim et al. found that in addition to its antagonist activity, alprenolol stimulated β1-AR-mediated activation of the epidermal growth factor receptor (EGFR) and activation of extracellular signal-
regulated kinase (ERK) through beta arrestin pathways
Both an antagonist and an agonist
The therapeutic benefits of these drugs may be the result of their dual activities–inhibition of G protein signaling and promotion of β-arrestin-mediated signaling, which activates a pathway that has been implicated in cardioprotective effects of β1-AR signaling
New drugs are being tested that exploit ligand dependent signalling bias.
What are calcium channel blockers used for?
Calcium channel blockers (CCBs) are a class of medications primarily used to treat various cardiovascular conditions by blocking the influx of calcium ions into cardiac and smooth muscle cells through voltage-gated calcium channels. By doing so, they dilate blood vessels and reduce the workload of the heart
How was it discovered that calcium was required for contraction and that CCBs were useful?
Concentration-response curves found that decreasing the concentration of calcium reduced contraction in rabbit mesenteric artery (1969, Godfraind and Kaba).
Fleckenstein et al then did a study on verapamil and found it produced similator curves to decreasing calcium concentrations. He used the term calcium antagonist to describe verapamil.
What are examples of current CCBs in use?
Verapamil, diltiazem, mibefradil and dihydropyridines (e.g. nicardipin)
What is the primary route for Ca2+ entry into cardiac, skeletal and smooth muscles
- L type calcium channels are the primary route for Ca2+ entry into cardiac, skeletal and smooth muscles
- Different drugs all bind to different sites on the calcium channel
How have the death rates rom CVD changed?
1950- 307.4 per 100,000 people
1996- 134.6 per 100,000 people
What are side effects of calcium channel blockers?
Reduced BP
Headache
AV block
Abdominal discomfort
Peripheral oedema
What is verapamil selective for?
Relatively selective for myocardial Ca2+ channels. Reduces rate and strength of heart contractions
What were the top two global causes of death in 2016?
Atherosclerosis and ischaemic heart disease
What is the basic pathogenesis of atherosclerosis?
Response to injury hypothesis=
- Artery trying to repair itself in response to injury. The injury may be accumulation of cholesterol or turbulent blood flow.
- Leukocytes adhere and enter sub-endothial space. Monocytes transform into macrophages and take up lipids turning into foam cells. This is a normal process- babies have fatty streaks.
- If the insult continues it cannot be contained and inflammatory cells build up. Fibrous cap forms over the top of the lipid core
- The smooth muscle starts to release extracellular matrix. Small blood vessels grow and rupture and eventually cap can rupture at the edge of the plaque and cause thrombus to form, blocking the artery
What preventative treatment can stop atherosclerosis?
Lipid lowering therapy
Via diet- reducing cholesterol or drugs
How is cholesterol carried around the body?
Cholesterol is synthesised in the liver.
LDL (lipoprotein) transports this to peripheral organs and arteries.
HDL brings it back and removes excess cholesterol
What are drugs that affect cholesterol levels in within the digestive system?
Ezetimibe= blocks absorption of cholesterol from the small intestine
Bile acid resins= bile acid resins increase the excretion of cholesterol in the stool
What is the best selling pharmaceutical in history?
Statins
Generated $125 billion over ~14.5 years and has made up 1/4 of Pfizers annual income over several years
What is the mechanism of action of statins?
It inhibits the rate limiting step of the mevalonate pathway, the cholesterol forming pathway in the liver
What study initially assessed the effectiveness of statins and what did it find?
The MRC/BHF heart protection study
1994-2001
Found simverstatin decreased the incidence of major vascular events and reduced total LDL, triglycerides with no difference in HDL levels
What are the side effects of statins?
Muscle pain and weakness (myopathy), Rhabdomyolysis, renal failure, liver toxicity and increased risk of diabetes mellitus.
What lipid lowering drug is available over the counter?
Statins
What are lipid lowering drugs for patients intolerant to statins?
Bempedoic acid and PCSK9 inhibitors
How does bempedoic acid work?
- Works on the same pathway as statins, just blocks the pathway higher up
- Blocks the enzyme (ATP-citrate Lyase) that converts citrate to Acetyl-CoA at the start of the pathway
- can reduce cholesterol levels further in a patient already on statins
What is the PCSK9 pathway?
PCSK9 is a protein that binds to LDL receptors and targets it to a lysosome, where the receptor is degraded
Inhibition of PCSK9 allows to receptor to be reycled and uptake more plasma LDL
What drugs are currently targeting PCSK9 pathway?
Monoclonal antibodies
Include Alirocumab, evolocumab and bococizumab (withdrawn in 2016)
Also siRNA (incliseran
What trials have studied the effects of PCSK9 monclonal antibody inhibitors?
The ODYSSEY trial= gave alircoumab 75mg subcutaneously every two weeks to statin intolerance patients
Caused a substantial drop in PCSK9 levels
What is incliseran?
A small interfering RNA (siRNA) that interferes with the production of PCSK9
What trial studied the effects of incliseran?
The ORION-10 and ORION 11 trials gave incliseran subcutaenously every 6 months to patients that had elevated LDL despitw being on max statin treatment
Reduced LDL by ~50% with only mild adverse events at the injection site.
It was a placebo controlled trial
Study duration was 540 days
How has overexpression of PCSK9 helped with studying atheroscleorsis?
Keeter et al 2022
Developed a adenovrial concept which targeted PCSK9 to overexpress it
If combined this with a high cholesterol diet, get a large increase of lipids in animal models artery walls where would would expect to see atheroma to start e.g. the lesser arches where blood is more turbulent
How do statins exert their protective effects?
Not only due to lipid lowering effects
Statins have a wide range of effects independent of lipid lowering
It has anti-thrombotic, anti-inflammatory, angiogenesis, anti-oxidant and endothelial function
What do statins do to help endothelial function?
Statins opposed the effect of L-NAME, and increased NO concentrations, causing vasodilation and reduced blood pressure
This increased NO reduces inflammatory cell infiltration and SMC proliferation, stopping thickening of atherosclerosis plaques
What drug targets inflammation in atheroscelrosis?
Canakinub was a drug that blocked IL-1 beta and used to treated systemic juvenile idiopathic arthritis
It reduced atherosclerotic events
How does canakinumab exert its atheroscelrotic-protective effects?
Blocks IL-1Beta
This decreases activation and proliferation in SMCs
Also reduces expression of adhesion molecules and decreases leukocyte infiltration?
What trial looked at Canakinumab’s effects?
CANTOS trial
Double blind trial that looked at 10,000 patients in 40 countries
3 different doses and placebo given
Significantly reduced CV events independent of lipid lowering
However, there was no overall improvements in survival due to an increased risk of fatal infections
What are future targets of preventing/treating atherosclerosis?
MicroRNA are being developed for a range of different pathways to modify specific stages of atheroscelrosis or manage compliations
Effect cholesterol homeostasis, macrophage activation, or alter balance of pro or anti-inflammatory signalling pathways
What is an example of a microRNA that is currently being targeted in atherosclerosis treatment?
miRNA 143/45 reduced transcription regulators important in switching vascular SMCs from contractile to proliferative phenotypes
What is the pathway that induces arterial relaxation and what can inhibit this?
- Endothelium-dependent, nitric oxide-mediated relaxation can be abolished using pharmacological inhibitors: L-nitroarginine methyl ester (L-NAME) is a competitive inhibitor of nitric oxide synthase which blocks nitric oxide generation in the endothelium.
- Endothelium- independent, guanylate cyclase-dependent relaxation can be produced using nitric oxide donors such as sodium nitroprusside (SNP).
How does ACh cause vascular relaxation?
ACh binds to muscarinic (GPCRs) on the endothelial cells
Through activation of Gq enzymes and second messengers are activated, eventually leading to the activation of of endothelail nitric oxide synthase
This produces nitric oxide from L-arginine
NO diffuses to the vascular smooth muscles and induces vasodilation by stimulatinf the production of cGMP, which decreases Ca2+ levels
How does noradrenaline cause act in the arteries?
Binds to alpha-1 adrenoceptors in the smooth muscles of blood vessels
Activates a G protein response which eventually releases Ca2+ from intracellular stored
However, in some circumstances, noradrenaline can cause dilation by binding to beta-adrenergic receptors and helping eNOS function
The net effect on vascular tone depends on the balance between alpha and beta receptor activation and the specific context in which noradrenaline is released, but it is predominantly a vasoconstrictor
What experimental set up is useful for measurement of smooth muscle function?
Isolated tissue bath
Drugs- adrenergic agonists and antagonists can be used
The primary advantage of this technique is that the tissue is living and functions as a whole tissue
In what conditions is endothelial dysfunction present in?
Age
Smokers
Diabetic patientds
High cholesterol diet
What are the 3 layers of the vascular wall?
Externa/ adventitia= connects artery to. surrounding tissues. Lots of collagen to prevent expansion
Media= smooth muscle and elastic fibres (elastin) Intima= layer of endothelial cells on a basement membrane (monolayer)
Why are endothelial cells heterogenous?
Endothelial cell phenotypes vary between different organs, between different segments of the vascular loop within the same organ, and between neighbouring endothelial cells of the same organ and blood vessel type.
Have different protein expression
When ECs are removed from their native tissue and grown in tissue culture, they become uncoupled from critical extracellular cues and undergo phenotypic drift
For this reason, studies of cultured endothelial cells are fraught with limitations.
However some properties are epigenticially fixed- 50% of the vascular bed specific genes from tonsils were ‘washed out’ when cultured in vitro.
There is a role for both tissue environment and epigentics in mediating differential gene expression
What is oxidative stress?
It is a situation associated with the excessive build up of free radicals (molecules containing an unpaired electron in its outmost shell) and molecules that cause unwanted oxidation of other molecules.
A common free radical is superoxide O2-
What are effects of oxidative stress?
Tissue damage
Necrosis and apoptosis
DNA damage
Inflammation
Lipid oxidation
Altered cell proliferation
How does oxidative stress cause CVD?
Involved in atherosclerosis, stroke, diabetes, hypertension and MI.
When LDL gets oxidised, it is much easier to take up into arterial wall.
NO reacts with superoxidide but this leaves less NO (NO half life depends on the amount of superoxide)
What can cause oxidative stress?
- Cellular respiration (Converting ATP-ADP, need a free radical reaction through the electron transport chain)
- Aging
- Inflammation (macrophages engulf pathogens, kill them via lysosomes which produce free radicals to kill the pathogen)
- Disease
- Drugs e.g. alcohol, paracetamol
- Smoking
- Radiation
What is an anti-oxidant and what are examples?
A molecule that prevents or reverses oxidation reactions of other molecules
Vitamin C (ascorbic acid), vitamin E, ubiquinol, glutathione
Does improving antioxidant levels prevent CVD?
Large trials such as the HOPE trial showed no significant improvements in CVD outcome from vit E
Other trials also show no benefit- ATBC, and GISSI
A few studies show improvements- CHAOS
What are the problems with anti-oxidant studies?
- Improvements in endothelial function does not necessarily translate to mortality reduction
- Confounding factors- dietary factors, health of participants, smoking, polypharmacy
- Negative results from smaller studies less likely to be published
- May need higher doses of anti-oxidants
- Treatment may not have been started early enough
What is the coagulation cascade?
- The intrinsic pathway is activated by trauma inside the vascular system.
- The external pathway is activated by external trauma that causes blood to escape from the vascular system.
- The intrinsic and extrinsic pathways converge into the common pathway.
- Factor X is activated by either pathway, leading to the formation of thrombin.
- Thrombin is a key enzyme that converts fibrinogen into fibrin, which forms a mesh that stabilizes the blood clot.
What is the pathway that leads to activation of platelets?
What anti-thrombotic drugs are used most often?
DOACS- $17.2 billion
What is the therapy routes for hypertension?
A= ACEi, C= Calcium channel blocker, D= thiazide diuretics
- ABEi First line therapy for people <55 year-olds
- CCBs first line therapy for people >55 years-old and black people of African or Caribbean origin of any age (may not be true now)
- TDs given in those where CCB is not suitable i.e. significant heart failure, oedema
What is the RAAS and what drugd act on it?
Renin-angiotensin- aldosterone system
ACEi- angiotensin converting enzyme inhibitor. Stops angiotensin I from becoming II
ARBs- angiotensin receptor blocker. Blocks angiotensin II from binding to its receptor
What is cardiac fibrosis and what does it cause?
Dysregulation between the synthesis and degradation of extracellular matrix proteins or ECM (e.g. collagen, matrix metalloproteinases), leading to a accumulation of ECM in the myocardium
Interstitial fibrosis is where ECM starts to accumulate between cardiomyocytes
Replacement fibrosis covers a gap created in the cardiomyocytes after injury
Fibrosis causes increased stiffness, impaired contractibility, heart rhythm dysregulation and abnormal myocardial perfusion
How do SGLT2 inhibitors exert their effect?
SCLT2 inhibition is benefical in non-diabetic cardiac disease
- Cardiac cell metabolism is the leading effect at the moment- cardiac cells think they are entering a starvation state and so switch from carb metabolism to ketone metabolism which is far more efficient at oxygen metabolism.
- SGLT2 inhibitors have been associated with improvements in arterial stiffness
- SGLT2 inhibitors may improve endothelial function, leading to better vasodilation and reduced vascular resistance.
- SGLT2 inhibitors have been associated with improvements in metabolic parameters, including reductions in body weight and visceral adiposity.
- Some studies suggest that SGLT2 inhibitors may have anti-inflammatory effects, leading to a reduction in systemic inflammation
