S2: Circulation: Drugs and Blood Vessels Flashcards
Why is regulation of blood pressure and flow important?
We need appropriate blood pressure:
Too low - Systolic <60mmHg, poor drive for end organ perfusion
Too high - This damages blood vessels and produces afterload (opposes contractility of the heart) which reduces cardiac output, increasing O2 demand of the heart. This also alters end organ perfusion.
Regulation of blood pressure and blood flow are important clinical objectives in treating cardiovascular disease e.g. Sepsis, hypertension
What factor is central for controlling BP and BF?
Regulation of vascular tone which produces different radius.
Poiseuille law: TPR=r4
Name 3 clinical conditions that a drop in blood pressure is a consequence of
Sepsis
- Systemic infection cause systemic excessive vasodilation decreasing TPR causing a large drop in BP so there is no drive for end organ perfusion resulting in end organ damage. This is very serious and complex with potential involvement of all those endothelium mediated vasodilation pathways.
Anaphylaxis
- Hypersensitivity reaction causes histamine to be released resulting in systemic vasodilation - decrease TPR, BP and poor organ perfusion occurs.
Heart Failure
- Poor cardiac output causes poor blood pressure and poor end perfusion
Does adrenaline and noradrenaline vasoconstrict/dilate vessels in most tissues and skeletal muscle/coronary circulation?
Explain the difference
Most tissues e.g. GI tract, skin:
- Adrenaline causes vasoconstriction
- Noradrenaline causes vasoconstriction
Skeletal muscle, coronary circulation:
- Adrenaline causes vasodilation
- Noradrenaline causes vasoconstriction
Skeletal muscle and coronary arteries have more B2 than a1 so adrenaline in these vascular beds are going to bind to more B2 receptors than a1 causing vasodilation (relaxation).
How do adrenaline and noradrenaline have different responses on resistance vessels?
- Adrenaline has higher affinity for B over a adrenoreceptors
- Noradrenaline has higher affinity for a over B adrenoreceptor
Adrenaline mainly acts at B2 to dilate vessels
Noradrenaline mainly act at a1 to constrict vessels
What effect does a1 and B2 receptors produce?
- a1 adrenoreceptors produce contraction
- B2 adrenoreceptors produce relaxation
Effect of intravenous adrenaline on the circulation
- Adrenaline acts at B1 to increase heart rate and contractility. Increase HR would increase SV and therefore CO would increase.
- The net effect is a small increase in BP but no increase in TPR due to vasodilation (normally decreases TPR ) and there is therefore no afterload. This is because adrenaline also acts on B2 receptors which causes relaxation in skeletal muscle arterioles.
Effect of intravenous noradrenaline on the circulation
- Noradrenaline acts on a1 receptors on vasculature which constricts them increasing TPR and therefore BP.
- A feedback mechanism (baroreceptor stimulation) occurs which switches off high HR and force of contraction to protect heart so there is a reduction in CO.
What are 3 important pharmalogical vasoconstrictor agents?
- NORAD
- Adrenaline
- Vasopressin (ADH)
Describe NORAD as a pharmalogical vasoconstrictor
- Given to increase BP when low
- NORAD is short for noradrenaline
It is given to primarily act at a1 adrenoreceptors on VSMCs to increase TPR and increase BP helping blood flow to end organs. It doesn’t have significant effects on the heart (B1) so it is cardiac protective as it doesn’t make the heart work too hard to increase BP
It is important in conditions such as sepsis, severe heart failure
Describe Adrenaline as a pharmalogical vasoconstrictor
- It is given in high concentrations to have an action on both B1 on the heart and a1 on VSMCs to raise BP (also B2 on the lungs for bronchodilation)
E.g. Epipen for anaphylaxis –> Physiological antagonism to hypersensitivity (to drive BP rise greater than BP reduction)
When is ADH used as a pharmalogical vasoconstrictor?
Sepsis
Why is high blood pressure a problem?
- Hypertension is a risk factor in many common CVS diseases e.g. Angina, Heart Failure
- It is a cause of endothelium dysfunction which causes reduction in important tonic vasodilation processes (e.g. NO, PGI2) causing poor end organ perfusion.
- It increases afterload causing poor CO so heart must work harder
Raised blood pressure is thought to be due to an imbalance of vasoconstrictor and vasodilator mechanisms such as an excessive vascular tone in arterioles supplying end organs
Explain how raised blood pressure does not mean greater drive and greater blood flow
It means a greater pressure drop across arterioles.
Excessive constriction causes higher pressure upstream and lower pressure (lower blood flow) downstream
Explain how drugs target prevent vasoconstriction in different ways
- They block vasoconstrictor receptors causing vasodilatation (Gq receptors). This prevents the Gq pathway from occuring so PKC cannot increase membrane excitability of VGNa+ channels and therefore VGCCs are inhibited.
- Nitrates are donors of NO and they produce vasodilation by increasing Ca2+ into the SR and outside membrane using the SERCA pump –> cGMP pathway
- Nitrates/Potassium channel openers also help activate potassium channels causing hyperpolarisation switching off VGCCs
- Blocking VGCCs also produce vasodilation
