DRUG A CTING

ON A NS
Saurabh Maru
Assistant Professor,
SPTM, SVKM’S NMIMS, Shirpur
• Pharmacology of drugs acting on peripheral nervous system
• a. Organization and function of ANS.
• b. Neurohumoral transmission, co-transmission and classification of neurotransmitters.
• c. Parasympathomimetics, Parasympatholytics, Sympathomimetics, sympatholytics.
• d. Neuromuscular blocking agents and skeletal muscle relaxants (peripheral).
• e. Local anesthetic agents.
• f. Drugs used in myasthenia gravis and glaucoma.
CLASSIFICATION OF THE N.S.

The general outlay of efferent autonomic nervous system. The transmitter released and the
primary postjunctional receptor subtype is shown at each synapse/neuroeffector junction
ACh= Acetylcholine, NA= Noradrenaline, N = Nicotinic, M = Muscarinic, alpha = alpha adrenergic, beta = beta adrenergic
TRANSMISSION OF NERVE MESSAGE
AUTONOMIC NERVOUS SYSTEM (ANS)
Differences between sympathetic and parasympathetic divisions of the
autonomic nervous system
ANS - ARCHITECTURE
SYMPATHETIC
• Dilates Pupils
• Improves hearing
• Slows down Salivary production
• Increases Hrt Rate
• Increases Resp. Rate
• Inhibits Digestion
• Increases glucose release
• Slows Large intestine
• Relaxes bladder
• Inhibits genitalia.

9
PARASYMPATHETIC
• Constricts pupils
• Dulls hearing
• Stimulates saliva
• Decreases Hrt Rate
• Decreases Resp. Rate
• Stimulates digestion
• Inhibits glucose release
• Stimulates L. Intestine
• Contracts Bladder
• Stimulates Genitalia 10
CHEMICAL
IMPULSE
TRANSMISSION
TRANSMISSION ACROSS SYNAPSE
NERVE IMPULSE TRANSMISSION
• Cells are set up as electrically polarized.
– They are in “resting state”
– Ready to do work.
– A more + charge outside the cell then inside
– Created by Na+/K+ pumps

14
 Membrane Potential
The cell membrane separates two “compartments”, the internal and + + +
external. + +
_ __
+ _ _
Each compartment contains charged components.
_ _
These can be DNA, RNA, proteins and ions. +

Collectively the internal compartment tend to carry more negative

charges than the external compartment.

Most of the positive charge is carried by mobile ions and the negative
charge by stationary structures.
Generally this charge difference is separation of charges produces a “potential” of from +5 to
-100 mV in cells

For neurons it is between -40 and -90 mV with -70 mV being the common value seen. 15
 Membrane Potential

MEMBRANE PUMPS:
ACTIVE TRANSPORT

Membrane Ion Channels:

Diffusion
16
NERVE IMPULSE TRANSMISSION
– Cells which are electrically polarized
have “resting potential”
• ACTION POTENTIAL
– These resting neurons are easy to
knock off balance
– Electrical, chemical, or mechanical
stimulus can move them to an action
state.
– Once the “threshold” level is met,
signal is sent.

17
 MEMBRANE ION CHANNELS
Passive, or leakage, channels
-always open

Chemically (or ligand)-gated channels

-open with binding of a specific
neurotransmitter (the ligand)

Voltage-gated channels
-open and close in response to
changes in the membrane potential

Mechanically-gated channels
-open and close in response to
physical deformation of receptors
18
NERVE IMPULSE TRANSMISSION
– Stimulus causes the Sodium gates to open.
– Cell depolarizes as Na floods in.
– As signal moves to another area, K+ floods out beginning
the process of resetting the nerve.

19
20
21
• Drugs acting on Adrenergic Nervous system
 Sympathomimetic
 Sympatholytic
SYMPATHOMIMETIC AGENTS

• Produces actions like biologic catecholamines…

• Receptors…
• G-protein coupled receptors
– Alpha () receptors
– Beta () receptors
SYMPATHOMIMETIC AMINES

• Drugs used to raise blood pressure

• Used for inotropic actions on heart
• Drugs used as central stimulants
• Smooth muscle relaxants
• Drugs used in allergic reactions
• Local vasoconstrictor
• Appetite suppressants
STRESS AND THE ADRENAL GL ANDS
ADRENAL MEDULLA:
A MODIFIED SYMPATHETIC GANGLION
MECHANISM: NOREPINEPHRINE
RELEASE AND RECYCLING
REVIEW OF EFFERENT PATHWAYS: MOTOR AND AUTONOMIC
ACTIVITY OF EPINEPHRINE
DALE’S VASOMOTOR REVERSAL
SYMPATHOMIMETICS

• Drugs that partially or completely mimic the actions or norepinephrine (NE)

and epinephrine (Epi).
• Act either - directly on α- and/or β-adrenoceptors or indirectly on presynaptic
terminals, usually by causing the release of NE.
• β2-Adrenoceptor Agonists – cause bronchial dilation - used for the treating
asthma, prevent pre-term labor (relaxing uterine muscle).
• β1-Adrenoceptor Agonists – (e.g., dobutamine) sometimes used to increase the
force of heart contraction in severe low-output heart failure.
• α1-Agonists – (e.g., phenylephrine) – used as mydriatics, decongestants.
• α2-Agonists – (e.g., clonidine, methyldopa) – centrally acting hypotensive
drugs.
• Sympathomimetics act mainly by causing release of NE (e.g., amphetamine)
have the α1/α2 selectivity of NE.

• β-Adrenoceptor antagonists (β-blockers) – used to treat hypertension, angina,

cardiac arrhythmias, CHF, and glaucoma.

• α-Adrenoceptor antagonists (α-blockers) – limited clinical application – prazosin

(selective α1-antagonist – used to treat hypertension.

• Adrenergic neuron blocking drugs – either deplete the nerve terminals of NE or

prevent its release – used as hypotensive agents.
Metabolism of
Norepinephrine
• Reuptake

• Monoamine Oxidase

• Catechol-O-methytransferase (COMT)

• α1-Adrenoceptors – in several tissues (e.g., smooth muscle, salivary glands)  incr

IP3 and [Ca2+]in  vasoconstriction or glandular secretion

• α2-Adrenoceptors – on noradrenergic nerve terminals. Activation by NE  inhibit

AC, decr cAMP, Ca2+ channels close  decr further nt release.

• β-Adrenoceptor – stim AC  incr [cAMP]  2nd messenger intracellular signaling

 physiol response.
CPR – CARDIOPULMONARY RESUSCITATION

• Confirm Unconsciousness
• Shout for help
• Apply external cardiac massage
• Clear oropharynx
• Mouth to mouth breathing
• Hospitalise
 INDIRECTLY-ACTING SYMPATHOMIMETICS – E . G . T Y R A M I N E , A M P H E TA M I N E

• Transported into nerve terminals where they displace vesicular NE into the cytoplasm.
Some is metabolized by MAO, but the remainder is released by carrier-mediated
transport to activate adrenoceptors.

• Amphetamines – resistant to MAO.

- Peripheral actions - tachycardia, hypertension - mainly caused by catecholamine

release.

- Dexamphetamine and methylphenidate used for hyperactive children.

• Cocaine – NE reuptake inhibitor (also dopamine) – Intense central stimulant  popular

drug of abuse.
Acute and chronic
effects of Indirectly
acting
sympathomimetics

G = Guanethidine
Mechanism of action
of cocaine and reserpine
DIRECTLY-ACTING SYMPATHOMIMETICS – ISOPRENALINE, PHENYLEPHERINE,
M ET H O X A M I N E , X Y LO M ETA Z O L I N E , S A L B U TA M O L

• Effects in humans depends on their receptor specificity (α and/or β) and on the compensatory
reflexes they evoke.

• Epinephrin increase bp by stimulating the rate and force of the heart beat (β 1 effects).

• Stimulation of vascular α-receptors causes vasoconstriction (viscera, skin), whereas…,

• Stimulation of vascular β2-receptors vasodilation (skeletal muscle) …

• And the total peripheral resistance may actually decrease.

• NE has little-to-no effect on the vascular β2-receptors; thus, the α-mediated vasoconstriction is
unopposed.

• The resulting rise in bp reflexively slows the heart, usually overcoming the direct β 1-stimulant
action on the heart rate.
DOPAMINE
• Naturally occurring precursor to Adrenaline.
• Acts as a central neurotransmitter.
• Also has sympathomimetic actions – through its own receptors – D1 – D5.
(D1 and D5 are alike, D2, D3, D4 are alike)
• Weak actions through alpha and Beta receptors.
• Can not cross BBB.
 DOBUTAMINE
• Structurally related to Dopamine
• Selective Beta 1 agonist with prominent activity on cardiac contractility.
• Useful in refractory, chronic, congestive heart failure.
EPHEDRINE
• Noncatecholamine of natural origin (Ma Huang)
• Acts by indirect release of Adrenaline, but also has some direct actions on alpha & Beta receptors.
• Pharmacological actions –
– Cardiovascular – Increase in force of myocardial contraction, cardiac output and may cause
tachycardia. Rise in BP, due to vasoconstriction and cardiac output.
– Smooth muscles – relax bronchial smooth muscles.
– CNS – Stimulation through RAS. - Insomnia, anxiety and tremors. Increases depth and rate of
respiration.
– Eye - Mydriasis
• ADME – orally absorbed, relatively resistant to MAO, largely excreated in urine unchanged.
• ADR –
– Tachyphylaxis
Ephedrine
• Preparation and Dosage –
– Tablet 15 – 30 mg tid, Elixir15mg/5ml, 5 – 10 ml / day, SC or IM injections – 15 – 45 mg
– Nasal drops 1% solution
• therapeutic uses –
– Bronchial asthma
– Nasal decongestion
– Hypotension
– Strokes Adams syndrome
– As a mydriatic
AMPHETAMINE
Β-RECEPTOR-SELECTIVE DRUGS
• Isoprenaline – stimulates all β-receptors  incr rate and force of heart beat and  vasodilation
 full diastole and MAP, with little change in systolic pressure.

• β2-Adrenoceptor Agonists – relatively selective class of drugs that produce bronchodilation –

used for asthma (resistant to MAO, not uptaken into neurons).
SYMPATHOMIMETICS AND
SYMPATHOLYTICS AT A GLANCE…

Alpha 1 Alpha 2 Beta 1 Beta 2

Agonist Adrenaline, Adrenaline, Adrenaline, Adrenaline,
Noradrenaline, Clonidine, Noradrenaline, Orciprenaline,
Phenylepherine, Apraclonidine, Dobutamine, Salbutamol,
Methoxamine, Methyldopa, Isoproterenol Terbutaline,
Metaraminol, Guanfacine Isoetherine
Mephenteramine
Antagonist Prazocine, Yohimbine Propranolol, Proporanolol,
Indoramin Pindolol, Atenolol, Pindolol
Metoprolol
• CASE STUDY

A 46-year-old woman sees her physician because of palpitations and headaches. She enjoyed good
health until 1 year ago when spells of cardiac palpitations began. These became more severe and were
eventually accompanied by throbbing headaches and drenching sweats. Physical examination reveals a
blood pressure of 150/90 mm Hg and heart rate of 88 bpm. During the physical examination, palpation
of the abdomen elicits a sudden and typical episode, with a rise in blood pressure to 210/120 mm Hg,
heart rate to 122 bpm, and facial pallor. This is accompanied by severe headache and profuse sweating.
What is the likely cause of her episodes? What caused the blood pressure and heart rate to rise so high
during the examination?

• What treatments might help this patient?

 SYMPATHOLYTIC AGENTS
• Drugs that induce depletion of catecholamine from various body tissues -
– Reserpine, Tetrabenazine

• Drugs that interferes with synthesis of adrenergic transmitter –

– Aalpha methyl paratyrosine

• Drugs that interefer with transmission of impulses across postganglionic adrenergic neurons
– Guanithidine

• Drugs that block adrenergic receptors.

– Alpha blockers -

– Beta blockers -
ADRENOCEPTOR ANTAGONISTS - Α-BLOCKERS

• Decrease artiolar and venous tone  decrease peripheral resistance  hypotension.

• Reverse the pressor effects of Epinephrine, because its β 2-mediated vasodilator effects are
unopposed by α-mediated vasoconstriction  peripheral resistance falls (Epinephrine reversal).
• Cause reflex tachycardia – this is greater with non-selective drugs that also block α 2-presynaptic
receptors on the heart, because the augmented release of NE further stimulates the cardiac β-
receptors (e.g., prazosin).
ALPHA RECEPTOR BLOCKERS

• Nonselective alpha blockers –

– Beta Haloalkylamines – e.g. Phenoxybenzamine, dibenamine
– Natural and hydrogenated ergot alkaloids –
– Imidazoline derivatives – e.g. Tolazoline, Phentolamine
• Selective Alpha 1 blocker –
– Quinazolines – Indoramine, Prazosin, terazosin, doxazosin
• Selective Alpha 2 blocker –
– E.g. Yohimbine
PHENOXYBENZAMINE
• Irreversible, prolonged and stable blockade of adrenoceptors.
• Prodrug with active metabolite
• Blocking effect is produced after 1-2 hours, even after IV administration, and lasts for 3 – 4
days.
• Little reduction of diastolic BP in normal, but significant effect in patients with
pheochromocytoma.
• Can produce tachycardia due to inhibition of presynaptic alpha 2 receptors.
• Can prevent but can not reverse cardia arrhythmias. (It is not a beta blocker).
• Not highly specific against adrenoceptors, hence can block Ach, 5-HT and histamine.
• Produces sedation on slow infusion, (anti-histaminic action)
• ADME
– Oral absorption irregular, IM / SC – produces irritation, so given IV or oral. Lipophilic accumulates
in fat. Elimination 50% in 12 hours and 80% in 24 hours in urine.
PHENOXYBENZAMINE
• ADRs
– Miosis, dryness of mouth, nasal stuffiness, Dales vasomotor reversal,
– Inhibition of ejaculation, palpitation, giddiness, postural hypotension.
– Large doses  nausea, vomiting, increased excitability, convulsions.
– MAY CAUSE ACUMULATION TOXICITY
• Preparation and dosage: -
– Used in preparation of a patient for surgery of pheochromocytoma and its management.
– Preparation is 10 mg capsule in a maintenance dose of 20 – 60 mg/day.

https://www.youtube.com/watch?v=6LcX7fGaUe0
ERGOT ALKALOIDS
• Ergotamine, ergosine, ergocornine, ergocrystine, ergocryptine and dehydrogenated derivatives
of these are alpha antagonist.
• Direct stimulant on vascular and uterine smooth muscles. This activity is high in natural
alkaloids and less in derivatives.
• Alpha blocking activity is high in derivatives as compared to natural forms.
• Semisynthetic derivatives produce reduction in BP by direct alpha blocking and depression in
vasomotor centre.
• Dihydroergotamine (DHE) is a vasoconstrictor with alpha blocking activity. This effect is used
in treatment of orthostatic hypotension due to autonomic neuropathy.
• Can induce bradycardia by central vagal stimulation and myocardial depression.
• Can induce vomiting by direct stimulation of CTZ.
• Can also block 5-HT
ERGOT ALKALOIDS
• ADME: -
– Poor absorption by oral route. Parenteral dose is partially metabolised. Most of drug is excreted in
urine unchanged.
• ADRs: -
– Nausea, vomiting and postural hypotension
– Anginal pain due to coronary constriction
– Prolonged administration  parasthesiae, frank gangrene due to peripheral vasospasm
– Headache, diarrhoea, confusion, drowsiness, hemiplegia, cerebral haemorrhage.
• Preparation and Dosage: -
– Ergotamine tartrate tablets – 1mg – Dose: - 1 – 2 mg orally / 3 – 4 mg sublingually.
– Ergotamine tartrate injection – 0.5 mg – Dose: - 0.25 to 0.5 mg SC or IM.
– DHE – 1 – 1.5 mg SC or IM
– DHE tablets – up to 20 mg/day to treat orthostatic hypertension due to autonomic neuropathy.
• Prazosin
• Yohimbine
ADRENOCEPTOR ANTAGONISTS - Β-BLOCKERS

• Vary in lipid solubility and cardioselectivity

• All block β1-receptors and decr bp and prevent angina.
• Higher Kow-drugs  more rapid absorption from GIT, 1st-pass hepatic elimination  more
rapidly eliminated.
• Also more likely to enter CNS and cause central effects (e.g., nightmares).
• Cardioselectivity diminishes with higher doses.
• selective β1-blockade  less peripheral vasoconstriction (cold hands and feet) and does not
reduce the response to exercise-induced hypoglycemia (stim of gluconeogenesis in liver is
mediated by β2-receptors).
• Cardioselective drugs may have sufficient β2-activity to precipitate severe bronchospasms in
patients with asthma – these patients should avoid β-blockers .
• Some possess intrinsic sympathomimetic activity (partial agonists), but this is debatable.
 BETA RECEPTORS BLOCKERS

• Cardioselective beta blockers (Beta1) – e.g. Acebutalol, atenolol, metoprolol, bisoprolol, esmolol
• Nonselective beta blocker –
– Beta blocker with membrane stabilising activity – e.g. propranolol
– Beta blocker with membrane stabilising activity and intrinsic sympathomimetic activity – e.g.
Oxprenolol, Pindolol
– Selective beta blockers – e.g. timolol, nadolol
– Miscellaneous – e.g. sotalol
• Beta blocker with intrinsic alpha blocker activity – e.g. Labetolol, Celiprolol, carvedilol
PHARMACOLOGY OF BETA BLOCKERS

• Effects of Beta Blockade: -

• Membrane Stabilizing action: -

• Intrinsic Sympathomimetic action: -

• Effects of CNS: -

• Metabolic effects; -

• Intraocular pressure: -
PHARMACOLOGY OF BETA BLOCKERS
• ADME: -
• ADRs: -
• Therapeutic Uses: -
NONSELECTIVE ALPHA AND BETA BLOCKERS

• Labetalol

• Carvedilol

• Bisoprolol
DRUG RECEPTOR INTERACTION…

• https://www.youtube.com/watch?v=u49k72rUdyc
• https://www.youtube.com/watch?v=w3d37cAL7VU
• https://www.youtube.com/watch?v=pQ2zpn0K6XQ

• https://www.youtube.com/watch?v=D96mSg2_h0c

• https://www.youtube.com/watch?v=B5pHcg2XwE0