biop211 sn10 lecture drugsactingperipheralns · membrane; adrenergic receptor ... o skin and mucous...

BIOP211

www.endeavour.edu.au

Session 10

Pharmacology:

Drugs Affecting the

Peripheral Nervous

System

Department of Bioscience

© Endeavour College of Natural Health www.endeavour.edu.au 2

BIOP211 - PHARMACOLOGYSESSION OUTLINE: Drugs acting in the Peripheral NS

o Neurotransmitters and their agonists and antagonists in

the Peripheral Nervous System.

o Review neurotransmitters involved in both the

Sympathetic Nervous System and Parasympathetic

Nervous System.

o Anti-muscarinic drugs and their effects.

o Adrenergic and anti-adrenergic drugs and their effects.

o Review the Somatic Nervous System and the

Neuromuscular Junction.

o Acetylcholinesterase activity and the drugs used to block

this enzyme (AChase Inhibitors).


The Nervous System


Autonomic Nervous System

o The autonomic nervous system (ANS) is responsible

for regulation of the internal viscera such as the heart,

blood vessels, digestive organs, kidneys and

reproductive organs.

o The ANS regulates homeostasis (maintains an optimal

internal environment).

o It cannot function independently of the CNS.

o ANS functions are not under direct conscious control

(e.g. regulation of heartbeat).


The Autonomic

Nervous System

sub divisions The ANS has 3 subdivisions:

Parasympathetic NS Conserves energy and restores body

resources (e.g. reduces heart rate,

and increases GI activity).

Sympathetic NS Dominates body in stress and

emergency. Responsible for “fight or

flight” response (e.g. ↑ in blood

[sugar], heart rate and BP).

Enteric NS (ENS)

Functions independently of CNS.

(Controls motility, secretion,

microcirculation).


Neurotransmitters

o To date, over 50 different endogenous chemicals have

been identified as neurotransmitters (or presumed

neurotransmitters).

o Key neurotransmitters include:

• Acetylcholine (ACh).

• Noradrenaline (NA).

• Adrenaline (A).

o Others include dopamine, 5-HT (serotonin), histamine,

substance P, endorphins, enkephalins.

o ACh and NA are the principle neurotransmitters in the

autonomic nervous system (ANS).


Basic Principles - ACho Nerve fibres that release acetylcholine (ACh) are said

to be cholinergic.

o ACh is the neurotransmitter released from:

• Preganglionic neurons in both P-SNS and SNS.

• Postganglionic parasympathetic nerve fibres.

• Sympathetic postganglionic neurons that innervate

sweat glands.

o ACh is the key neurotransmitter involved in

parasympathetic NS function and activity

(conservation of energy / restoration).

o ACh activates 2 types of receptors:

• Muscarinic [M1 (neural), M2 (cardiac & presynaptic),

M3 (glandular or smooth muscle type)].

• Nicotinic [Nn (neuronal) , Nm (muscle)].


Basic Principles - NAo Nerve fibres that release noradrenaline (NA) (or are

sensitive to adrenaline) are said to be adrenergic.

o NA acts as the neurotransmitter between sympathetic

postganglionic nerves and the organs they innervate.

o NA and A are the key neurotransmitters involved in

the sympathetic NS and functions (stress response /

“fight-flight”.

o There are two types of adrenergic receptors:

• Alpha (1 and 2).

• Beta (1, 2 and 3).


Cholinergic

transmission


Noradrenaline and adrenergic

transmission

o The term catecholamine refers to a group of

chemically related compounds:

• Noradrenaline (NA).

• Adrenaline (A).

• Dopamine (DA) – precursor to NA and A; also has a

principle role as a neurotransmitter in the brain. It is

important in diseases such as Parkinson’s and

schizophrenia.


Adrenergic Transmission


Adrenergic Receptors – α1 & α2

o There are two types of adrenergic receptors → alpha (α)

and beta (β):

o Alpha 1 (α1) receptors - situated on the post synaptic

membrane; adrenergic receptor stimulation leads to:

• vasoconstriction of peripheral blood vessels.

• dilation (contraction) of pupil.

• increased contractility of heart (inotropic effect).

o Alpha 2 (α2) receptors are located on pre-synaptic nerve

terminals (and also on liver, platelets and blood vessel

smooth muscle cells; adrenergic stimulation leads to:

• Inhibition of transmitter release.

• Aggregation of platelets.

• Contraction of smooth muscle.


Adrenergic Receptors, Beta (β)1 & 2

o Beta 1 (β1) receptors are located primarily in the heart.

Receptor stimulation leads to:

• Increased heart rate (chronotropic effect).

• Increased contractility of heart (inotropic effect).

o Beta 2 (β2) receptors are located in the smooth muscle in

bronchioles, blood vessels and other visceral organs.

Receptor stimulation leads to:

• Relaxation of uterus.

• Glycogenolysis (breakdown of glycogen).

• Dilation of bronchial smooth muscle.

o Beta 3 (β3) receptors are localized to adipose tissue.


NA and A

o Noradrenaline excites mainly Alpha (α) receptors, butexcites Beta receptors to slight extent as well.

o Adrenaline excites Alpha (α) and Beta (β) receptors equally.

o The extent to which NA and A will excite various organs isdependent on the relative numbers of alpha (α) and beta (β)receptors that the organ contains (e.g. the heart containsmainly β1 receptors – affected mostly by adrenaline.


Drugs at Cholinergic receptors

o Drugs that antagonise or block the action of

acetylcholine, ACh, at the muscarinic receptor sites (M)

are referred to as: Muscarinic receptor antagonists or

Antimuscarinic drugs or Anticholinergic drugs.

o Use of these drugs means acetylcholine cannot bind to

the muscarinic receptor site and thus fails to produce a

cholinergic effect.

o parasympathetic system of the autonomic nervous

system use acetylcholine as the main neurotransmitter,

Anticholinergic action = anti-parasympathetic response

(= parasympatholytic).

o Cholinergic action = increased parasympathetic

response.


Cholinergic Drugso Drugs that mimic the action of ACh on the

Parasympathetic Nervous System (PSNS) are also

known as muscarinic receptor agonists or

parasympathomimetic drugs.

o Only three of these are used clinically

• Bethanechol (used systemically for urinary and

gastro-intestinal symptoms – promotes micturition

and gastric motility).

• Carbachol (eye drops or intraocular injection used in

glaucoma).

• Pilocarpine (eyedrops used in glaucoma).


Anticholinergic drugs – anti-

muscarinicso The best known muscarinic antagonists are atropine and

hyoscine.

o Atropa belladonna (Deadly nightshade) contains atropine.

o Hyoscyamus niger (henbane) and Datura stramonium

(jimsonweed) contain hyoscine.

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Atropineo Prototype muscarinic antagonist (very little action on nicotinic

receptors).

o Used for > 50 years.

o Often the adverse effects of anticholinergic drugs are referred to as“atropine-like” adverse effects.

Atropine can produce a wide range of pharmacological effects becauseof the widespread distribution of parasympathetic cholinergic nerves inthe body:

o Eyes: pupil dilation (mydriasis = Belladonna, beautiful lady).

o Skin and mucous membranes: inhibits secretions.

o Respiratory system: relaxes muscle of the bronchial tract.

o Cardiovascular system: low doses decreases HR.

o GIT: high doses inhibits GI motility.

o Urinary tract: relaxes smooth muscle & ↑ sphincter constriction.

o CNS: excitement and mania.


Hyoscine hydrobromide

o Hyoscine is a muscarinic receptor antagonist, similar in

chemical structure to atropine.

o The peripheral effects are similar to atropine but

because it is rapidly absorbed through the BBB, it has

marked effects on the CNS.

o Indications: Used for motion sickness (prevents nausea

and vomiting), and as an adjunct medication with general

anaesthesia to reduce respiratory tract secretions.

o Adverse effects: Causes drowsiness, euphoria,

memory loss, relaxation, sleep, relief of fear and

depresses CNS. Does not increase blood pressure or

respiration.


ANTICHOLINERGIC ADVERSE EFFECTS

(Seen with many drugs including atropine, antihistamines,

tricyclic and tetracyclic antidepressants)

o Tachycardia

o Heart palpitations

o Decreased bronchial

secretions

o Antispasmodic effects

o Mydriasis (expanding

pupil) and blurred vision

o Dry mouth

o Urinary retention

o Male impotence

o Decreased gut motility

(leading to constipation)

o Dizziness


Anticholinergic Drugs, C/I and

Drug-drug interactions

Drug Interactions

o Additive effects with TriCyclic Antidepressants (TCAs),

some antihistamines (promethazine).

o Impair absorption of other drugs (due to reduction in

gastric motility).

Warnings & Contraindications

o Many C/I including myasthenia gravis, severe cardiac

disease, GI obstructive disease, narrow angle glaucoma.

Caution in Down’s syndrome, elderly, hepatic and renal

disease.


Sub-classes of Adrenergic Drugs

and anti-adrenergic drugs

1. Direct-acting sympathomimetic drugs (agonists)

• Mimics the effects of NA or A.

2. Indirect-acting sympathomimetic drugs

• Facilitate the release of NA or block the uptake of NA

into nerve terminals.

3. Adrenoreceptor antagonists (blockers) /sympatholytic

drugs

• Block action of sympathetic nervous system.


1. Direct-acting Sympathomimetic

Drugs

o Sympathomimetic drugs are those that mimic the effect

of NA (noradrenaline) on sympathetic effector organs.

o Use leads to a ‘sympathetic response’ (fight/flight) such

as an increase in cardiac output, vasoconstriction of

arterioles and veins, regulation of body temperature,

bronchial dilation.

o Naturally occurring catecholamines (adrenaline,

noradrenaline and dopamine) may be used as drug

therapies, as well as synthetic catecholamines (e.g.

isoprenaline and others).


1. Direct-acting Sympathomimetic

Drugs (adrenoceptor agonists)

o Responses mediated by and stimulation:

o -Stimulation leads to:

• Vasoconstriction in peripheral blood vessels leading

to increased blood pressure.

• pupil dilation.

• relaxation of the gut.

o -Stimulation leads to:

• Increased heart rate and contractility.

• Vasodilation of skeletal muscle arterioles.

• Bronchial relaxation and uterine relaxation.


Control of NA

release

Alpha2 (α2) receptors are

found on presynaptic nerve

terminals, and post synaptic

vascular and smooth muscle

cells. The presynaptic alpha2

(α2) receptors control the

amount of NA released per

nerve impulse (high

concentration prevents release

of more NA).


1. Adrenaline (as drug therapy)

o Stimulates both and receptors (dose dependent butat therapeutic doses primarily receptors of the heart,smooth muscle of the bronchi and the blood vessels.

o Positive inotropic effects (increase in myocardialcontraction).

o Positive chronotropic effect (increased cardiac rate).

o Dromotropic effect (improved atrio-ventricularconduction).

o Vascular effects are dose dependent but low dosesdecrease total peripheral resistance (lower bloodpressure) and high doses increase bp.

o CNS effects (restlessness, tremor, anxiety).


1. Other effects of Adrenaline

o Smooth muscle effects (relaxes but constricts sphincter

e.g. delay in desire to void urinary bladder).

o Respiratory effects, powerful bronchodilator (hence

indications later in allergic responses).

o Metabolic effects i.e. (increased availability of fuels,

glucose and free fatty acids in blood), increases O2

consumption.

o Effects on skeletal muscle (vasodilation).


1. Indications - Adrenaline

o Emergency treatment of acute anaphylactic shock and

severe allergic reactions.

o As an adjunct to local anaesthetics.

o As a haemostatic agent to control superficial bleeding.

o In ocular surgery to prevent bleeding.

o To treat cardiac arrest.


1. Adrenaline – ADR and Drug Drug

Interactionso Nervousness, insomnia, tachycardia, tremors, sweating,

hypertension, nausea, vomiting. High doses may cause

ventricular arrhythmias.

o Contraindications: include Diabetes mellitus,

Hypertension, Ischaemic heart disease, Hyperthyroidism,

Parkinson's disease.

o Drug Interactions include

o Anaesthetics, β-blockers, Digoxin, Oxytocics.

o TriCyclic Antidepressants (TCA), monoamine oxidase

inhibitors (MAOI) cocaine (potentiate the effect of

adrenaline).


2. Noradrenaline

o NA has a high affinity for receptors, producingvasoconstriction in skin and mucous membranes aswell as blood vessels in visceral organs(predominantly receptors ).

o Restores arterial blood pressure in acutehypotensive states.

o Also used as adjunct in cardiac arrest (IVadministration, as inactivated in GIT).

o Adverse reactions: include anxiety, dizziness,tremor.

o Contraindications: e.g. use with caution inatherosclerosis, hypoxia.


3. Isoprenalineo synthetic catecholamine and non-selective -

adrenoceptor agonist (stimulates 1 and 2 receptors).

o 1 receptors – leads to ↑ force of myocardial contraction

and heart rate.

o β2 receptors – leads to relaxation of smooth muscle of

bronchi.

o Indications: cardiac stimulant (adjunct e.g. in septic

shock, hypovolaemic states).

o Adverse reactions: (see adrenaline).

o Cautioned use in elderly, diabetics and in

hyperthyroidism.

o Contraindications: e.g.Tachycardia, myocardial infarct.


4. Dopamineo Dopamine is an immediate precursor to A and NA.

o It stimulates dopaminergic receptors, 1 receptors, and inhigh doses, 1 and 2 receptors.

o Actions of dopamine are dose dependent and complex.

o At low to moderate doses.

• Direct effect on 1 receptors and stimulates releaseof NA.

• Increased heart rate and stroke volume (cardiacoutput, CO).

o Indications – e.g. used in the treatment of circulatoryshock, Congestive heart failure (CHF).

o Adverse reactions: can include Headaches, nausea,vomiting, angina, ↓BP. Less frequently: hypertension.


Summary 1. Direct Acting

Sympathomimeticso Agonists at α1 α2 β1 β2 receptors.

o Adverse effects explained by non-selective effects at

other receptor types and subtypes.

o Adrenaline – dose related effects, α1 α2 β1 β2 ,indications

for asthma, local haemostasis, acute anaphylactic shock,

Open Angle Glaucoma (OAG), cardiac arrest.

o Isoprenaline – synthetic catecholamine.

o Noradrenaline, dose related effect kidney & other visceral

organs, α receptors stimulated at high dose; indications,

shock.

o Dopamine, dose related effect, D1 & direct & indirect

effects on β 1, high dose α1 & α2, indications, circulatory

shock, CCF.


2. Indirect-Acting Sympathomimetics

o This group of drugs trigger the release of noradrenaline

and adrenaline from their storage sites.

o These neurotransmitters then activate and receptors

o Agents in this class include:

• Ephedrine (used in cold and flu tabs, also some diet

pills).

• Pseudoephedrine (in cold and flu tabs).

• Amphetamines.

• Metaraminol.


3. Adrenoreceptor Antagonists

o Adrenoreceptor antagonists compete with

catecholamines at the receptor and inhibit (of block)

sympathetic stimulation and effect.

o These are generally classes according to which receptor

is blocked ie

• -Blockers (or adrenoceptor antagonists).

• -Blockers (or adrenoceptor antagonists).

o Drugs in this class may be selective or non-selective for

a specific receptor.


-Blockers

- adrenoreceptor antagonists (blockers) compete with

catecholamines (A and NA) at the -receptor sites and

inhibit sympathetic stimulation.

The main groups of drugs are:

o 1 -Selective antagonists (e.g. prazosin, terazosin,

doxazosin).

o Non-selective (1- 2) antagonists (e.g.

phenoxybenzamine, labetalol).

o Ergot alkaloids, which are partial –adrenergic blockers

(used to treat migraine).


1-Selective antagonist

o Examples: Prazosin, terazosin, doxazocin, tamsulosin.

o Indications: - Used for treatment of hypertension and

symptomatic relief of urinary obstruction in benign prostatic

hyperplasia (BPH).

o Mechanism of Action:

• Selective blockade of postsynaptic 1 receptors results in ↓

in peripheral vascular resistance due to inhibition of

catecholamine-induced vasoconstriction. Use only leads

to a minor increase in heart rate because these drugs

have low 2-adrenoceptor activity.

• Reduced resistance to urinary flow in neck of bladder due

to blockade of receptors on the smooth muscle.


Adrenoreceptor antagonists

o Also known as blockers.

o May be selective or non-selective (for 1 and/or 2

receptors).

o The prototype of blockers is propranolol which is non-

selective (blocks 1 and 2 receptors). It is thus also

associated with a higher incidence of adverse effects

(action is indiscriminate).

o At high doses, 1 selective blockers will also block 2

receptors (leading to unwanted effects).


β-Blockers

o Mechanism of Action: -blockers competitively block

receptors in heart etc blocking the actions of

catecholamines (A and NA) at these sites (mechanism of

ADR: Cardiac muscle contains principally 1

receptors and smooth muscle sites e.g. airways contain

mainly 2 receptor sites).

• Cardiac effects (anti-anginal, decrease all heart

parameters).

• Metabolic effects (if non-selective effects, blocks

responses to hypoglycaemia, increase triglycerides and

decrease HDL cholesterol in serum).


-Blockers - Indications

o Hypertension (Usually 1-selective blockers (also knownas cardioselective) e.g. atenolol, betaxolol, esmolol.

o Angina pectoris.

o Tremors and tachycardia associated withhyperthyroidism and anxiety.

o Myocardial infarction (MI).

o Phaeochromocytoma (rare catecholamine-secretingtumour of adrenal medulla).

o Glaucoma.


-Blockers - Safety

Adverse effects

o Insomnia, nightmares, depression, nausea, diarrhoea,

dizziness, fatigue, hypotension, heart failure, heart block,

bradycardia, bronchospasm and shortness of breath,

(SOB).

Contraindications:

o Heart block, bradycardia, cardiogenic shock, asthma,

chronic obstructive airway disease (COAD) & severe

hypotension.


Sites of Action

of Drugs

affecting

Noradrenergic

transmission


Somatic Nervous System

o The somatic nervous system is a division of the

peripheral nervous system (PNS) that co-ordinates

consciously controlled functions, including movement

(gross and precise), posture and respiration.

o Drugs may be used to block neuromuscular

transmission e.g. As an adjunct to anaesthesia, leading

to muscle relaxation.

o In clinical practice, drugs known as anticholinesterase

agents are used to reverse this neuromuscular blockade.


Somatic Nerve Transmission - NMJ

o When a nerve action potential arrives at the

neuromuscular junction (NMJ), acetylcholine (ACh) is

released which diffuses across the synaptic cleft to act

on postsynaptic nicotinic receptors on the motor end-

plate of the muscle fibre, leading to muscular

contraction.

o The action of ACh is rapidly terminated by the enzyme

acetylcholinesterase.


Somatic Nerve Transmission

o The release and metabolism of ACh occurs according to

the same mechanisms described for the Autonomic

PNS.

o The difference is that in the somatic NS, ACh acts on

postsynaptic nicotinic receptors, whereas in the

Autonomic PNS it acts on postsynaptic muscarinic

receptors.

o Thus nicotinic receptors mediate the effect of ACh on

skeletal muscle.


Neuromuscular

Junction, NMJ


Neuromuscular Blocking Drugs

o Many sites where drugs and toxins can interrupt

neuromuscular transmission.

• Blockade of action potential generation in the motor

neuron.

• Inhibition of release of ACh.

• Blockade of postsynaptic receptors.


Neuromuscular Blocking Drugs There are two types of neuromuscular blocking drugs:

1. Non-depolarising (competitive) drugs that

competitively block the action of ACh at post and

presynaptic nicotinic receptors, which blocks the normal

feedback loop that increases the release of ACh under

conditions of enhanced stimulation. E.g.. Tubocurarine

(does not cross BBB nor placenta but release histamine

and rare ADR).

2. Depolarising drugs (nicotinic agonists) maintain the

depolarised state of the motor end-plate, thus

preventing transmission of another muscle action

potential. E.g.. Suxamethonium. For endotracheal

intubation and muscle relaxation for short procedures.


Anticholinesterases or AChE Inhibitors

o The enzyme acetylcholinesterase (AChE) hydrolyses

(breaks down) ACh, forming choline and acetate.

o There is a class of drugs known as anticholinesterases

or AChE inhibitors (act to stop hydrolysis of ACh).

o These drugs are used to reverse the effects of the

neuromuscular blocking drugs (non-depolarising) after

anaesthesia.

o They also have other clinical uses for some medical

conditions such as in glaucoma, Alzheimer’s disease

and myasthenia gravis.

o Some organophosphate pesticides contain irreversible

anticholinesterase agents (toxicity is a result of

accumulation of ACh and excess stimulation of the

somatic, autonomic and central nervous systems).


Tutorial / Forum Discussion SN10

Drugs Affecting the Peripheral NSDiscuss these medications acting in the Peripheral Nervous System, PNS. 10 marks for (i) examples (for adrenaline

hormone, give other catecholamines that are neurotransmitters but also used as drugs) (ii) indications (iii) mechanism

of action (iv) efficacy and limitations or cautions / contra-indications (v) adverse effects. Mark your own answer using

the Pharmacology text or online resources. Alternatively, peer review each other’s answers, allocating 10 marks per

drug class

o Adrenergic hormones as drugs, e.g. adrenaline (called epinephrine

in the USA)

o Synthetic adrenergic agents e.g. isoprenaline

o Indirect acting sympathomimetic agents

o Alpha-selective antagonists

o Beta blockers

o Neuromuscular blocking drugs

o Anticholinesterase drugs (also known as AChEase Inhibitors)


Bibliography

o Bryant B, Knights K. 2007. Pharmacology for health

professionals 3nd Edition. Mosby Elsevier

o Tortora, G.J. and Derrickson, B. 2013. Principles of

anatomy and physiology. 14th edition Wiley, USA.


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