Lecture 12 - Cardiovascular Pharmacology Flashcards
What is hypertension?
Elevated blood pressure
What is the blood pressure of a healthy person?
120/80
Why does blood pressure increase with age?
Lifestyle effects
Natural aging process
Hardening of arteries (less distensible)
What is blood pressure controlled by?
Integrated system P
What are the primary contributors of blood pressure?
Cardiac output
Stroke volume
Heart rate
Total peripheral resistance
What can each of the factors that contribute to blood pressure be manipulated by?
Drug therapy
What happens when blood pressure goes down?
The sympathetic vasomotor centre activity increases in the brain due to activation of baroreceptors
What elevates blood pressure?
Cardiac stimulation
Activation of sympathetic nervous system
Venous constriction
Increasing venous rerun
Increase preload and force of contractility
How does cardiac stimulation increase cardiac output?
In terms of heart rate and force of contraction
What happens when blood pressure decreases?
Cause renin release
Due to reduced blood flow through juxtaglonerular apparatus
What are the effects of Angiotensin II?
Venous constriction (elevate venous return) Arterial constriction Knock on effect of aldosterone
What are the processes that bring BP down?
Arterial constriction
Increase in sympathetic vasomotor centre activity
Renin release
Venous constriction
What is the vasomotor centre?
Influences sympathetic outflow
Alpha 2 adrenoceptor agonist
Presynaptic modulation of neurotransmitter release
What does the sympathetic nerve terminal release?
Noradrenaline
Influences postsynaptic receptors
Where are alpha 2 adrenoceptor located?
Sympathetic nerve terminal
What happens when alpha 2 adrenoceptor is stimulated?
Negative effect mediated via influence on ca2+ channel opening
Decreases continued release of noradrenaline
What is Beta receptor antagonist (blockers)?
Direct effect on the heart (Beta 1 receptors)
Reduce contractility of the heart (reduce cardiac output - reduce BP)
What is vascular smooth muscle?
Vasodilators
Ca2+ channel antagonist
Angina and treatment of hypertension
Some diuretics - some vasodilatory effect
What is AT1 receptors?
Block synthesis of Angiotensin II or blocking the receptors itself
What is the effect of ACE inhibitors?
Influence adrenal cortex
Reduce effect of Angiotensin II
In the kidney, what does diuretics have an effect in?
Reducing overall circulating blood volume
Reduce blood pressure
What is the therapeutic approaches to treatment of hypertension?
Vasomotor centre Sympathetic nerve terminals Beta-adrenoceptors on heart Sympathetic Ganglia Angiotensin receptors on vessels Alpha-adrenoceptors on vessels Vascular smooth muscle Adrenal cortex Kidney tubules Juxtaglomerular cells that release renin
Vasomotor centre
Alpha 2- Adrenoceptor agonists
Imidazoline receptor agonist
Sympathetic nerve terminals
Adrenergic neuron Antagonist
Beta-adrenoceptors on heart
B-adrenoceptor Antagonist
Sympathetic Ganglia
Ganglion blockers
Angiotensin receptors on vessels
ACE inhibitors
AT1 receptor antagonist
Alpha- Adrenoceptor on vessels
Alpha 1 Antagonist
Vascular smooth muscle
Diuretics Vasodilators Nitrovasodilafors Calcium channel Antagonist Potassium channel openerds
Adrenal cortex
ACE Inhibitors of Angiotensin II formation
AT1 receptor antagonist
Kidney tubules
Diuretics
ACE inhibitors
Juxtaglomerular cells that release renin
B-Adrenoceptor Antagonist
B-adrenoceptor Antagonist
Pindolol
Atenolol
Propranolol
What is B-adrenoceptor Antagonist most important actions
B1 receptor blockade
Decreased heart rate and cardiac output
Reduced renin secretion
What is adrenoceptor Antagonist aided by?
Vasodilation of blood vessels supplying skeletal muscle
What happens when Beta receptors are stimulated?
Vascular muscle relaxation
What does some of Beta adrenoceptor agonist have?
Partial antagonist and partial agonist activity
What is pindolol?
Used for hypertension
Beta 1 Antagonist and Beta 2 partial agonist
What are some examples of alpha-adrenoceptor Antagonist?
Prazosin
Doxazosin
Phenoxybenzamine
What is alpha-adrenoceptor Antagonist?
Involves the reduction of arteriolar resistance
By reducing sympathetic input
Mediated by alpha 1 receptors
What is the result of stimulating alpha 1 receptors?
Contract smooth muscle
What is the result of blocking alpha 1 receptors?
Relaxation
Dilation of venous capacitance vessels
What happens at rest of alpha-adrenoceptor antagonist?
Ongoing sympathetic tone
Governing the overall diameter of blood vessels
What is the problem of alpha-adrenoceptor Antagonist?
Induce a reflex tachycardia
Marked with non-selective compounds
Can increase HDL
What is prazosin?
Short acting
What is doxazosin?
Long acting
What are the side effects related to the relaxtory effect upon smooth muscle (alpha-adrenoceptor Antagonist)
Postural hypotension (venous pooling)
Legarthy (drowsy and dull)
Palpitations
What are ACE inhibitors?
Reduce circulatory level of Angiotensin II
Block conversion from Angiotensin
What are examples of ACE inhibitors?
Captopril
Enalapril
What are the therapeutic effect of ACE inhibitors?
Hypotensive effect without reflex tachycardia (through relaxation of smooth muscle)
Reduced aldosterone release
Reversal of left ventricular hypertrophy
Prevention of vascular changes by inhibition of cellular growth
Reduced degradation of vasodilator kin in
What does Kinin have and is responsible for?
Vasodilatory effect
Responsible for inhibiting cough
What is Angiotensin receptor antagonist?
Block what Angiotensin II does at relevant receptor
AT1 receptor seen in vascular smooth muscles
What are examples for Angiotensin receptor antagonist?
Losartan
Valsartan
What are the side effects of Angiotensin receptor antagonist?
Headache
Legarthy
What is ACE inhibitor
Enalapril
What is Angiotensin inhibitor?
Valsartan
What are examples of directly acting vasodilators?
Calcium channel antagonist
Potassium channel activators
What does minoxidil lead to?
Hair growth
What are side effects of directly acting vasodilators?
Flushing and headache Reflex tachycardia Palpitations Salt and water retention Hirsutism (abnormal growth of hair on a woman’s face and body)
What is Hydralazine?
Produces relaxation
What are the side effects of Hydralazine?
Side effects include reflex sympathetic activation and SLE like syndrome
When is borderline hypertension more likely to be treated?
If patient has renal impairment
Ischaemic heart disease
Diabetes
Previous stroke
Young: treatment of hypertension
B-adrenoceptor antagonist/ACE inhibitors
Elderly: treatment of hypertension
Ca2+ channel antagonist
Diuretics
What is an example of centrally active hypertensive ?
Methyldopa
What are the approaches to treating hypertension?
Step 1: one/two drug in the young beta-blocker or ACE inhibitor
Step 2: getting no response, look at combining
Step 3: if there is still no response, combine 2-3 compounds
Step 4: look g at putting in another drug
What is the best approach to treating hypertension?
Single pill combining many different active compounds
What is Atherosclerosis?
Plaque formation
Plaque rupture
Thrombus formation
Death and disability caused by heart attack
How is Atherosclerosis formed?
Cholesterol ridge core
Where is cholesterol embedded in?
Plaque because of removal from circulation
Where does plaque protrude as it grows?
Lumen of the blood vessels
Reduces diameter of the blood vessel
Reducing BF to one region
What happens when cap is eroded and exposed to the core?
Aggregation and activation of platelets which adhere to the Atherosclerosis plaque
Why is platelet aggregation a problem?
Blood clotting mechanism get involved
Why is cholesterol important?
Constituent of cell membrane
Precursor of many important steroids (bile salt, steroid hormones)
Where is cholesterol mainly synthesised?
Liver
HMG-CoA reductase
Where are LDL taken up by?
Liver (receptor mediated l)
Taken up into peripheral tissues (non-receptor mediated)
Why are HDL classified as good cholesterol?
Promote transport from peripheral tissues to liver
Promote storage of LDL
Removal from circulation
What are two pathways by which cholesterol accumulates in the liver?
Exogenous pathway
Endogenous pathway
Where does cholesterol come from?
Diet (direct circulation through portal system)
Or with fatty acids in diet combined with glycerol and cholesterol which are absorbed into bloodstream
What does chylomicrons contain?
Both cholesterol and triglycerides
What are chylomicrons?
Lipoprotein lipase which acts upon triglycerides breaking them down into free fatty acids which can be absorbed into peripheral tissue
How is cholesterol moved out of the liver?
In the form of very low LDL
Why is the endogenous pathway favoured?
Majority of cholesterol is synthesised from acetyl cOA
What is Dyslipidaemia?
Condition where lipid processing is disrupted
Inherited disorder - altered synthesis of cholesterol familial hypercholesterolmia
Diseases affecting lipid metabolism
What does Frederickson classification define?
Six groups based on which lipoprotein is elevated
What groups are most at risk of atheroma?
Groups IIa and IIb
What groups are triglyceride elevated in?
Type IIb but not in type 2a
When are Statins prescribed?
When there is an incidence of increased LDL cholesterol
What are examples of statin?
Simvastatin
Lovostatin
Pravastatin
Atorvastatin
What does station reduce?
LDL cholesterol
Risk of death from cardiovascular events
Who should statins be considered for?
All patients at risk of any cardiovascular disease
When are Fibrates used?
Where there is an issue with cholesterol and triglycerides
What does fibrates have an influence upon?
Certain nuclear receptors
What is example of nuclear receptor?
PPARa
These nuclear receptors will translocate to the nucleus when a relevant agonist binds to them
Alteration in transcription of genetic material
What are examples of Fibrates?
Bezafibrate
Gemfibrozil
Ciprofibrate
What does Bezafibrate have significant effect upon?
Genes that code for lipases that can break down Chylomicrons
