D6 & D7 - ANS

Question 1

Parasympathetic nervous system

Answer 1

• connects to the CNS via 2 cholinergic nerves - meaning they synthesise, store and release acetyl choline
• pre ganglionic nerve in the CNS from cranial or sacral nerves
• post ganglionic nerve - in the autonomic ganglion

Question 2

Sympathetic nervous system

Answer 2

• pre ganglionic nerve is a cholinergic nerve
• post ganglionic nerves: most are adrenergic and some are cholinergic
• some nerves pass directly through the paravertebral ganglia without synapsing, and do directly to the adrenal medulla - which is stimulated to release adrenaline and noradrenaline into the blood stream which binds to adrenoceptors on cardiac, smooth muscle or exocrine glandular cells

Question 3

Adrenergic nerves

Answer 3

release noradrenaline

- most sympathetic post ganglionic nerves

Question 4

Cholinergic nerves

Answer 4

• release acetyl choline
• some sympathetic post ganglionic nerves
• all parasympathetic post ganglionic nerves

Question 5

Cholinoceptors

Answer 5

2 types

• nicotinic - ion channel
• muscarinic - g protein linked coupled receptor

Question 6

Muscarinic receptors

Answer 6

• 5 subtypes
• M2 - expressed mainly on cardiac cells, causes decrease in heart rate when activated by acetyl choline
• M3 - smooth muscle and glandular cells, smooth muscle contraction and glandular secretion

Question 7

Mascarinic receptors are stimulated by

Answer 7

Acetyl choline

Question 8

Nicotinic receptors are stimulated by

Answer 8

Acetyl choline

Question 9

adrenergic nerves

Answer 9

• release noradrenaline which bind to adrenoceptors

- exist alpha and beta

Question 10

alpha adrenoceptors

Answer 10

- Alpha
		○ A1
			§ Vascular smooth muscle cells 
			§ Noradrenaline and adrenaline will target to promote contraction 
			§ Vasoconstriction

Question 11

beta adrenoceptors

Answer 11

- Beta 
		○ B1
			§ Expressed on heart 
			§ Increase in heart rate 
			§ Increases force of contraction 
		○ B2
			§ Present on smooth muscle cells 
			§ Vascular smooth muscle cell relaxation - also in airways and uterus

Question 12

Modulating activity of end effect

Answer 12

1. Increase/decrease levels of neurotransmitters
   
   2. Mimic the actions of neurotransmitter - use drugs that activate receptors
   3. Inhibit the actions of neurotransmitter - use drugs that inhibit receptors

Question 13

Adrenoceptor Agonists

Answer 13

• Bind to and activate adrenoceptors
  
  • Endogenous compounds eg. adrenaline and noradrenaline - adrenoceptor agonists
  • Drugs can also do this
    ○ Phenylephrine
    ○ Salbutamol
  • Also called Sympathomimetics/adrenomimetics - adrenoceptor agonists
  • Target one or more of 5b subtypes of adrenoceptor

Question 14

2 adrenoceptor agonists

Answer 14

adrenaline, noradrenaline

Question 15

Adrenaline

Answer 15

○ Hormone and drug
○ Stimulate all of the adrenoceptor subtypes
○ Limitation
§ Inactive orally
□ Extensively metabolised in gut and liver by enzymes
□ Inactivate the compound - can no longer bind to and activate adrenoceptors
§ Typically given by injection in settings where blood pressure and ECG can be monitored

Question 16

adrenaline local infection

Answer 16

§ Dose dependant
□ At low doses, adrenaline binds to high affinity B2 on vascular smooth muscle - relaxation - mostly vasodilator effect
□ Increase concentration - binds to low affinity A1 - mostly vasoconstrictive effect
□ Because it has a higher affinity for B2 than A1
§ Net effect - at high concentrations, predominantly vasoconstrictive, but at low doses - vasodilatory effect
§ No adrenaline - status quo maintained
§ Local injection
□ Delivering initially high concentration locally
® Vasoconstriction
□ As it is metabolised
® Dose decreased
® Vasodilation

Question 17

adrenaline instravascular injection

Answer 17

§ Effects on cardiovascular system
□ When adrenaline is injected, the net effect is dependant upon
® Dose
® Rate of administration
□ Intravenous infusion
® Delivering adrenaline at a constant rate into the blood stream
® Starting
◊ Increase in heart rate
} Adrenaline will activate B1 - cause heart rate increase
◊ Associated with an increase in systolic blood pressure - also stimulated B1 receptors that cause heart muscle to constrict more strongly
◊ No change in mean arterial blood pressure
} Increase in systolic blood pressure is counteracted by a decrease in diastolic pressure
– Decrease in diastolic is because when given as IV infusion - decreases total peripheral resistance
– Because adrenaline is activating B2 receptors causing vasodilation in skeletal muscle - will override
– constriction effect in other parts of the body

Question 18

adrenaline slow bolus injection

Answer 18

§ Large amount of adrenaline directly into blood vessels
§ Dose will decrease with time as adrenaline is metabolised and redistributed
§ Effects on heart rate and blood pressure and total peripheral resistance are more complex
§ Delivering high concentration
§ Predominant effect is alpha adrenoceptor mediated vasoconstriction
§ Associated with an increase in total peripheral resistance
□ Will cause an Increase is diastolic blood pressure
§ Increase in mean arterial blood pressure because the systolic blood pressure is also increased - because adrenaline is stimulating cells in the heart to constrict more strongly
§ Heart does not beat more quickly
□ Because Increase in mean arterial blood pressure causes reflex release of acetyl choline to decrease heart rate to counteract increase in mean arterial blood pressure
§ Lower concentrations of adrenaline over time
□ Vasodilator effect - by B2 adrenoceptors
® Decrease in TPR
® Decrease in diastolic blood pressure
® Return mean arterial blood pressure to normal
□ Direct effects of adrenaline on heart rate
® Increase

Question 19

clinical uses of adrenaline

Answer 19

○ Related to effects on blood vessels, heart, other smooth muscle
○ Adrenaline added to local anaesthetic
§ prolong action and delay systemic absorption of local anaesthetics
§ Especially in dentistry
§ Causes constriction to localise the anaesthetic in the region
○ Used in cardiac arrest
§ Helps to restore cardiac rhythm
§ Increase TPR during resuscitation
§ In the community
□ Better to use deregulator and CPR
□ Adrenaline can only be given in a hospital situation
○ Treatment of Acute anaphylactic reaction
§ Massive release of histamine
□ Causes constriction of the airways
§ Adrenaline relaxes airways by targeting B2 receptors on smooth muscle
§ Inhibits mast cell degranulation

Question 20

○ Adrenaline added to local anaesthetic

Answer 20

§ prolong action and delay systemic absorption of local anaesthetics
§ Especially in dentistry
§ Causes constriction to localise the anaesthetic in the region

Question 21

○ Used in cardiac arrest

Answer 21

§ Helps to restore cardiac rhythm 
			§ Increase TPR during resuscitation
			§ In the community 
				□ Better to use deregulator and CPR 
				□ Adrenaline can only be given in a hospital situation

Question 22

○ Treatment of Acute anaphylactic reaction

Answer 22

§ Massive release of histamine
□ Causes constriction of the airways
§ Adrenaline relaxes airways by targeting B2 receptors on smooth muscle
§ Inhibits mast cell degranulation

Question 23

Noradrenaline

Answer 23

○ Not the same as adrenaline
○ Nor is also not active orally due to extensive metabolism in the gut and liver
○ Adrenaline activates all 5 adrenoceptor subtypes
○ Nor can do most of them but not B2 adrenoceptor
○ Nor does not cause vasodilatation in (esp. in skeletal muscle vascular beds)

Question 24

Slow IV infusion Noradrenaline

Answer 24

§ Mainly - increase in TPR
□ Activate A1 adrenoceptor and cause them to constrict and increase TPR
□ No B2 mediated vasodilator effect
§ Increase in diastolic and systolic blood pressure
§ Increase in mean arterial blood pressure
§ slowing of heart rate (again due to mediated reflexes)
§ Noradrenaline increases mean arterial blood pressure
□ Used to correct acute hypotension in septic shock where there is significant hypotension
□ Infusion of nor
§

Question 25

Selective Adrenoceptor Agonists

Answer 25

- Fewer side effects - Developed to be effective orally - don’t undergo metabolism in the gut and liver - Phenylephrine - binds to and activates A1 adrenoceptor - Salbutamol - activates B2 adrenoceptor

Question 26

2 selective adrenoceptor agonists

Answer 26

phenylephrine, salbutamol

Question 27

Phenylephrine

Answer 27

○ Selective alpha 1 adrenoceptor agonists ○ Only difference from adrenaline is it lacks a hydroxyl group at the 4 position ○ Binds selectively to A1 - not to other adrenoceptors ○ Predominantly on vascular smooth muscle cells ○ Primarily produces vasoconstriction ○ Used clinically for relief of nasal congestion associated with acute and chronic rhinitis § Eg. Sudafed § Given orally or topically drops/spray

Question 28

Salbutamol

Answer 28

○ Only binds effectively to B2 § Has a bulky butyl group - creates steric hindrance - it doesn’t fit in the other receptors ○ Selectively ○ B2 on smooth muscle - airway, uterine, vascular ○ Relaxation of smooth muscle ○ Clinically to relieve bronchoconstriction and asthma § Ventolin inhalers ○ Topical - aerosol to site of action ○ Given topically directly to site of action because § rapid response § low overall dose needed ○ Safe ○ Only side effect is skeletal muscle tremor - goes away with continued use

Question 29

Adrenoceptors Antagonists

Answer 29

• Antagonists • Prevent adrenaline or noradrenaline from binding to and activating their adrenoceptors • Antagonists occupies receptors without activating it which causes reduced binding/activation • Antagonism of A1 and B1 may be clinically useful • A2 and B2 is not clinically useful ○ Associated with adverse side effects • A1 - hypertension • B1 - many cardiovascular diseases

Question 30

3 adrenoceptor antagonists

Answer 30

prazocin, propanolol, metoprolol

Question 31

Prazosin

Answer 31

○ Inhibits A1 receptor ○ 5000x higher affinity for this receptor than the A2 - very selective ○ Doesn’t block A2 adrenoceptor ○ Vascular smooth muscle cells ○ Reverse alpha adrenoceptor mediated contraction of vascular smooth muscle § Vasodilator effect § Lowers blood pressure ○ Anti hypertension § No longer a first line treatment for hypertension □ Exist Better drugs with fewer side effects □ Causes dizziness when first administered □ On standing □ Postural hypotension □ Most evident when initially used and In the elderly □ Solutions ® Make initial dose lower ® Administer drugs when postural hypotension is less of an issue ◊ Before going to bed ○ Also used to reverse alpha adrenoceptor mediated contraction of prostatic smooth muscle § Alpha adrenoceptors on the prostate are a slightly different sub type § This sub type is better targeted with Tamsulocin than Prazocin § By blocking prostatic smooth muscle contraction - improved urine flow in men with benign prostatic hypertrophy

Question 32

Propranolol

Answer 32

○ First ○ Treats angina and arrythmias ○ Also reduces blood pressure and increase survival in those who have had a myocardial infarction ○ Non selective b adrenoceptor antagonist ○ Binds beta 1 and 2 ○ Cant tell the difference between B1 and B2 ○ By inhibiting B1 § Decrease heart rate and contractility § Decrease blood pressure § Management of angina, arrythmias, hypertension, post-myocardial infarction ○ By inhibiting B2 § May exacerbate bronchoconstriction on patients with asthma □ Because B2 mediates bronchodilatation § Impair circulation in peripheral arterial disease § Worsen glycaemic control in diabetes ○ Adverse side effects for patients with co morbidities

Question 33

propanolol inhibiting B1

Answer 33

○ By inhibiting B1 § Decrease heart rate and contractility § Decrease blood pressure § Management of angina, arrythmias, hypertension, post-myocardial infarction

Question 34

propanolol inhibiting B2

Answer 34

○ By inhibiting B2 § May exacerbate bronchoconstriction on patients with asthma □ Because B2 mediates bronchodilatation § Impair circulation in peripheral arterial disease § Worsen glycaemic control in diabetes ○ Adverse side effects for patients with co morbidities

Question 35

metprolol

Answer 35

○ Selectively binds B1 ○ Higher affinity for B1 ○ Reverse B1 mediated increases in heart rate and contractility § Reduce cardiac output and lower blood pressure ○ Useful in management of cardiovascular diseases ○ Doesn’t block B2 at safe doses - lower affinity ○ Doesn’t harm patients with co morbidities - asthma, diabetes, peripheral vascular disease ○ Selectivity for B1 is not absolute - increasing dose will cause binding to B2 ○ Should be used with caution in patients that cant have B2 blockage

Question 36

Beta Blockers

Answer 36

○ Decrease heart rate and contractility - binding to B1 ○ Many beta blockers have other desirable pharmacodynamic actions ○ Some have vasodilatory activity - useful for hypertension § Labetalol □ Beta blocker that also blocks alpha receptors □ Causes vasodilation § Celiprolol □ Blocks B1 but partial agonist for B2 - vasodilation § Nebivolol □ Blocks B1 □ Releases NO which is a vasodilator

Question 37

Cholinoceptor Agonists

Answer 37

- Mostly those targeting M3 subtype ○ Muscle contraction and glandular secretion - Available drugs lack selectivity ○ Will also bind to M1 and M2 receptors and have adverse effects ○ Some may also activate nicotinic receptors - widespread effects - Limited number of drugs used clinically to ○ Activate muscarinic cholinoceptors § Pilocarpine ○ Block muscarinic cholinoceptors § Atropine, tiotropium, solifenacin

Question 38

cholinoceptor agonists - low selectivity

Answer 38

○ Very few agonists used clinically due to low selectivity § Activate multiple subtypes of nicotinic and muscarinic receptors § Also activate nicotinic receptors - widespread effects ○ Limit side effects by § administering topically to site of action - to only activate receptors in the vicinity of the drug

Question 39

1 cholinoceptor agonist

Answer 39

pilocarpine

Question 40

Pilocarpine

Answer 40

○ Muscarinic cholinoceptor agonist ○ Given topically to the eye in the form of eye drops ○ Less systemic actions ○ Activate M3 receptors on constrictor pupillae muscle § Constrict pupil § Promotes drainage of aqueous humour from the eye § Reduced intraocular pressure ○ Used clinically to treat glaucoma § A condition of the eye associated with increase intraocular pressure ○ There now exist better drugs § No longer first or second line treatment § Beta adrenoceptor antagonist and prostaglandin analogues

Question 41

4 Cholinoceptor Antagonists

Answer 41

atropine, tiotropium, tropicamide, solifenacin

Question 42

Atropine

Answer 42

○ Non-selective beta adrenoceptor antagonist ○ Naturally occurring substance discovered in a plant § Atropa belladonna § Has black berries that contain atropine ○ Block all muscarinic cholinoceptor subtypes § Dries up secretions - saliva, sweat, tears, gut and lung § Inhibits smooth muscle contraction (gut, lungs, eye) § Increases heart rate (M2) ○ Crosses into CNS to block muscarinic receptors producing excitatory effects § Hyperactivity and body temp § Restlessness § Difficult to have organ selectivity, causes side effects which limits clinical uses § Crosses blood brain barrier ○ Used to treat poisoning with anticholinesterase agents (pesticides, war gases)

Question 43

Tiotropium

Answer 43

○ Better selectivity and side effect profile than atropine ○ Used for chronic obstructive pulmonary disease COPD ○ Used in asthma ○ Dilates airway smooth muscle ○ Reduce mucous secretion ○ Given by aerosol - delivers drug directly to the site of action § Cant affect the CNS because it has positively charged nitrogen so it cant cross the blood brain barrier (unlike atropine - no CNS effects) ○ Some selectivity for M3 § Less cardiovascular effects ○ Good side effect profile - better selectivity ○ Long duration of action § Used for maintenance therapy - given just once daily § Doesn’t produce rapid reversal of bronchoconstriction - not a reliever medication in an asthma attack

Question 44

Tropicamide

Answer 44

○ Quick acting muscarinic cholinoceptor antagonist ○ Used for retinal examination ○ Relaxes ciliary muscle and iris sphincter ○ Given as drops, short duration of action

Question 45

Solifenacin

Answer 45

○ Relaxes smooth muscle of bladder to increase bladder capacity - reduces sense of urgency ○ Used for urinary incontinence ○ Administered orally ○ Selectivity for M3, less CNS side effects

Question 46

Drugs that act indirectly by altering levels of neurotransmission

Answer 46

- Some drugs can block the metabolism/removal or neurotransmitters from synaptic region eg. Amphetamine blocks removal of noradrenaline, neostigmine blocks metabolism of acetylcholine - Increases synaptic levels of neurotransmitter - More activation of receptors and increased response Don’t bind to and activate receptors themselves ○ Alters level of neurotransmitter ○ Act indirectly May also increase neurotransmitter levels in other cholinergic or adrenergic synapses ○ Cholinergic and adrenergic are not just in the autonomic nervous system § Cholinergic nerves innovate skeletal muscle cells in CNS § Adrenergic synapses in the CNS § Primary use of these drugs relate to Effects somatic and CNS § Primary clinical uses relate to effects on the somatic and central nervous systems, effects on the ANS are considered side effects

Question 47

Adrenergic nerves | ○ Synthesise store and release noradrenaline

Answer 47

○ Synthesise store and release noradrenaline ○ Initial substrate in synthesis is the amino acid tyrosine § Taken up by a transporter, decarboxylated and hydroxylated to form dopamine § Stored in synaptic vesicles and converted into noradrenaline § When nerve is stimulated, noradrenaline is released which binds to and activates adrenoceptors on the post synaptic membrane § Has a short half life in synaptic region □ Taken up by noradrenaline transporter (NAT) which pumps it back up into the cell □ Some of it will be repackaged, some will undergo metabolism by monoamine oxidase on the surface of mitochondria § Rapid uptake is a regulatory process by the CNS to control activity of post synaptic nerve

Question 48

Amphetamine - adrenergic nerves

Answer 48

§ Noradrenaline is taken back up by noradrenaline transporter (NAT) § Amphetamine also uses this transporter □ Some amphetamine gets pumped into the vesicles through VMAT (vesicular monoamine transporter) and displaces noradrenaline in the vesicles □ Breaks down monoaminoxidase MAO □ Induces elevated levels or noradrenaline □ Induces reverse operation of noradrenaline transporter NAT - pumps noradrenaline into the synapse instead of back into the nerve § Causes vasoconstriction, increase in heart rate and contraction - not used clinically for these effects on ANS § Used for effects on CNS in children in ADHD

Question 49

Pseudoephedrine - adrenergic nerves

Answer 49

§ Causes noradrenaline increase release from adrenergic nerves § Use is constricted - can be converted into methamphetamine § Nasal decongestant

Question 50

Cholinergic nerves

Answer 50

○ Use acetyl choline ○ Formed by conjugation of acetyl CoA and choline through the action of choline acetyl transferase ○ Acetyl choline is stored in vesicles and released during action potential ○ Acetyl choline in the synapse is hydrolysed by acetyl choline esterase ○ Acetylcholine esterase § hydrolyses acetyl choline into choline and acetate which are inactive § Rapid inactivation of Ach is the process by which the CNS controls the activity of postsynaptic cells ○ Some drugs inhibit acetylcholine esterase - anticholinesterases § Increase levels of acetyl choline in the synapse § Accumulates in the synapse and causes increased activation of receptors and larger response

Question 51

Anticholinesterase effects on ANS

Answer 51

§ Mimic stimulation of parasympathetic nervous system □ More glandular secretion, smooth muscle contraction, slowing of heart rate § Also inactivates acetyl choline in somatic and central nervous system □ Effects of drug are widespread and complex Anticholinesterase 3 major groups § Distinguished on the basis of duration of action

Question 52

i. Long acting

Answer 52

□ Days □ Organophosphate pesticides (dimethoate) and organophosphate war gasses (sarin) □ Long duration of action - irreversible covalent bond with active side on the enzyme □ Toxicological relevance □ Poisoning - people that are exposed typically have ® DUMBBELSS ® Diarrhoea, urination, miosis, bronchorrhea, bronchoconstriction, bradycardia, emesis, lacrimation, salivation/sweating, seizures □ Killer Bs ® Bronchorrhea, bronchoconstriction, bradycardia ® Producing too much mucous and bronchoconstriction ® Deadly □ Atropine ® Frontline therapy ® Blocks symptoms mediated my muscarinic cholinoceptors ® Crosses blood brain barrier ® Reduces CNS nervous symptoms

Question 53

Medium and short acting agents

Answer 53

Medium and short acting agents □ Form reversible ionic bonds □ Clinically useful 1) Medium acting □ neostigmine 1) Short acting □ Edrophonium

Question 54

□ Killer Bs

Answer 54

® Bronchorrhea, bronchoconstriction, bradycardia ® Producing too much mucous and bronchoconstriction ® Deadly

Question 55

DUMBBELSS

Answer 55

® Diarrhoea, urination, miosis, bronchorrhea, bronchoconstriction, bradycardia, emesis, lacrimation, salivation/sweating, seizures

Question 56

Clinical uses of anticholinesterases

Answer 56

Myasthenia gravis □ Used for action on neuromuscular junction □ Skeletal muscle weakness - autoimmune disease targeting nicotinic receptors on muscle, causing a reduction in the number of receptors □ Reduced sensitivity to acetyl choline □ Overcome by agents increasing acetyl choline in the junction □ Short acting - edrophonium for diagnosing ® If you give it to them and they get better (increased muscle strength) - diagnose ® Doesn’t cause increase in muscle strength with people who don’t have it □ Medium - ® neostigmine ◊ Needs injection ◊ Variable/low oral bioavailability ® Pyridostigmine ◊ Orally active ◊ Chronic treatment ◊ Used as a medium acting anti cholinesterase Other uses of anticholinesterase □ routinely used to reverse neuromuscular blockage caused by non-depolarising neuromuscular blockers □ Eg. pancuronium ® Used during general anaesthesia - there will also be a muscle relaxant used ® At the end of the procedure this must be reversed - neostigmine given by IV which outcompetes pancuronium ® Effects of neuromuscular blockers are overcome Effects on autonomic and CNS from anticholinesterases are unwanted side effects

Question 57

Myasthenia gravis

Answer 57

□ Used for action on neuromuscular junction □ Skeletal muscle weakness - autoimmune disease targeting nicotinic receptors on muscle, causing a reduction in the number of receptors □ Reduced sensitivity to acetyl choline □ Overcome by agents increasing acetyl choline in the junction □ Short acting - edrophonium for diagnosing ® If you give it to them and they get better (increased muscle strength) - diagnose ® Doesn’t cause increase in muscle strength with people who don’t have it □ Medium - ® neostigmine ◊ Needs injection ◊ Variable/low oral bioavailability ® Pyridostigmine ◊ Orally active ◊ Chronic treatment ◊ Used as a medium acting anti cholinesterase

Question 58

Other uses of anticholinesterase

Answer 58

□ routinely used to reverse neuromuscular blockage caused by non-depolarising neuromuscular blockers □ Eg. pancuronium ® Used during general anaesthesia - there will also be a muscle relaxant used ® At the end of the procedure this must be reversed - neostigmine given by IV which outcompetes pancuronium ® Effects of neuromuscular blockers are overcome Effects on autonomic and CNS from anticholinesterases are unwanted side effects