Practical pharmacology CNS

PRACTICAL PHARMACOLOGY2ND YEAR MEDICAL STUDENTS

MODULE IX

BYDR. HAZEM ABO SHOUSHA

Main rules

•ABP: pressure of blood on arterial wall

ABP= COP X PVR

COP= HR X SV

Main rules

HEART RATE

β1

Main rules

M2

Main rules

β1 Agonist M2 blockerβ1 blocker M2

agonist

HEART RATE

Main rulesBLOOD VESSELS

α1

β2

M3

Main rulesBLOOD PRESSURE (Bl.V)

VCα1 agonistβ2 blocker

VDα1 blockerβ2 agonistM3 agonist

Main rulesBARORECEPTORS

VD

VC

NORADRENALINE

α1 β1

Observation: increased ABP with minimal effect on HR, which increases only with high doses

Explanation of effect of NE on ABP & HR: NE acts mainly on 1 receptors vasoconstriction PVR

With higher doses of NE, it activates also cardiac 1 receptors some increase in the heart rate

PRAZOSIN

α1 blocker

What is the effect of Prazosin on ABP and HR?

• it blocks 1 adrenoceptors vasodilationPVRABP•ABP slight reflex tachycardia

Noradrenaline cause very minimal in HR β1 stimulation minimal in BP

α1 β1 β2

ADRENALINE

Observation: ABP & HR late The ABP before returning to base line level Explanation of the effect of epinephrine on HR &

ABPEpinephrine stimulates 1 , 1, 2 adrenoceptors Beta receptors are more sensitive to the effect of epinephrine On heart: 1 activation +ve inotropic & chronotropic effects COP leading to increased ABPOn BV : - 1 activation vasoconstriction PVR.

- 2 activation vasodilatation PVR

•The net effect of these two opposing effects (1 & 2 ) on bl.v is an in PVR

(1 wins at 1st )

•At High concentration:

EPI stimulates 1 •At Low concentration:

EPI stimulates 2

Adrenaline Noradrenaline parameters

More increase Mild or no increase Heart rate

Less increase than noradrenaline More increase Blood pressure

BP decreases before reaching base line Reach base line directly BP before Base line

β1 blockerCardioselective beta blocker

ATENOLOL

Observation: blocking 1 receptors by atenolol blocks the effect of epinephrine on HR & decreases the effect on ABP

block alpha1 & beta1 receptors & then inject epinephrine

EPINEPHRINE REVERSAL:

The presser effect of epinephrine is reversed due to

1 & 1 blockade, leaving the 2 vasodilating effect acting

ABP

β1 + β2 blockerNon-selective beta blocker

PROPRANOLOL

How to confirm the cause of epinephrine reversal?

No epinephrine reversal since propranolol blocks not only cardiac 1 receptors but also vascular 2 receptors

What is the effect of propranolol on ABP and HR?

Propranolol mechanism as antihypertensive:1-Block β1 in heart so low COP BP2- central sympathetic discharge BP3- Block β1 in kidney Renin BP4- resetting of Baroreceptors BP5- Block β2 presynaptic NE release BP

β1 + β2 agonistNon-selective beta agonist

ISOPRENALINE

Observation: • Isoprenaline increases HR• Isoprenaline initially decreases ABP. • As HR reaches its maximum increase, ABP shows minimal increase before returning to normal Explanation for the effect of isoprenaline on HR

& ABP • Isoprenaline activates mainly beta adrenoceptor • It activates cardiac 1 receptors leading to increase in HR & force of contraction

(which increases COP)• Activation of 2 receptors—Vasodilation decrease in PVR • The net effect of the two factors (COP & PVR) is a decrease in blood pressure

initially.• However, when force of contraction is markedly elevated, the increase of COP

overcomes the effect of decrease in PVR and thus ABP starts to increase.

Design an experiment to prove the explanation for the effect of Isoprenaline on HR & ABP

Observation: atenolol abolishes the effect of isoprenaline on HR The initial ABP-lowering effect of isoprenaline is maintained, while its pressor effect is abolished

PROPRANOLOL FOLLOWED BY ISOPRENALINE

Observation: Propranolol blocks 1 & 2 receptors thus abolishes the effect of isoprenaline on ABP

α1 agonistselective Alpha agonist

PHENYLEPHRINE

Observation: Small dose phenylephrine leads to slight increase in ABP with no effect on HRHigh dose phenylephrine increases markedly ABP with decrease in the HR ( reflex bradycardia)

Explanation of the effect of phenylephrine on ABP & HR

•Activation of 1 receptors vasoconstrictionPVR

•High dose of phenylephrine marked elevation of ABP reflex in sympathetic activity. Parasympathetic activity will take the upper hand HR

prove the explanation of the effect of phenylephrine on HR and ABP

Observation: prazosin abolishes the effect of phenylephrine on ABP & reflex bradycardia disappears

prove that reflex bradycardia is due to relative increase in

parasympathetic activity

Observation: decreased HR is abolished by atropine despite of elevation of ABP

Nicotinic Nn , Nm

ACETYLCHOLINE ( Ach )

Muscarinic M1 , M2 ,M3

Observation: small doses of acetylcholine lower only ABPHigher doses produce both in the HR & more significant lowering of ABP

Explanation for the effect of acetylcholine on HR and ABP

•on heart: M2 activation - ve chronotropic effect COP

•on BV: endothelial cells M3 activation release of NO from vascular endothelial cells vasodilatation PVR• Decrease in heart rate & decrease in PVR lead to ABP

Inject ATROPINE & then test the effect of ACETYLCHOLINE

ACETYLCHOLINE REVERSAL 1. Inject a test dose of Ach2. Inject atropine

3.Inject the same dose of acetylcholine

4.Inject a dose of Ach which is 10 times the test dose

Explanation for acetylcholine reversal

• Atropine injection A parasympatholytic blocks muscarinic receptors. It blocks the effect of small dose of Ach.

• Ach injection [big dose] Stimulates nicotinic receptors Nn after muscarinic receptors have been blocked by atropine ABP

• Due to activation of Nn at : • Adrenal medulla release epinephrine BP• Autonomic ganglia release of catecholamines from post-synaptic adrenergic nerve endings BP

• The BP by Ach [big dose] after muscarinic receptor block [by atropine] Ach reversal

oAch reversal by : Nn receptorsoEPI reversal by : β2 receptors

Reversible anticholinesterase

S o A c h ‘ ’ a u g m e n t A c h e ff e c t ‘ ’

NEOSTIGMINE

prove the mechanism of action of neostigmine