Pharmacology; ANS medications

Question 1

Describe the types of neurones and neurotransmitters of the ANS

Answer 1

Sympathetic system:
1. Preganglionic:
N: Cholinergic
NT: Acetycholine

2. Postganglionic:
   N: Adrenergic
   NT: Epinephrine and Norepinephrine

Parasympathetic:
1. Preganglionic:
N: Cholinergic
NT: Acetylcholine

2. Postganglionic:
   N: Cholinergic
   NT: Acetylcholine

Question 2

Describe the anatomy and functions of the sympathetic system

Answer 2

Anatomy:
• Neurons come from lumbar and thoracic regions of spinal cord
* Short pre-ganglionic neurons

Functions:
• Dilation of pupils
• Inhibition of saliva
• Relaxed airways
• Faster heartbeat 
• Glucose release from liver
• Inhibition of digestion
* Relaxed urinary bladder

Question 3

Describe the anatomy and functions of the parasympathetic system

Answer 3

Anatomy:
• Neurons come from brain stem/ cranial region (3,7,9 and 10) and sacral regions of spinal cord
* Long pre-ganglionic neurons

Functions:
• Constriction of pupils
• Stimulation of saliva
• Constricted airways
• Slowed heart beat
• Glucose storage
• Stimulation of digestion
* Constriction of urinary bladder

Question 4

Describe the process of acteylcholine formation an and neurotransmission

Answer 4

1. Choline molecule is transported into the neuron through a sodium dependent transport system.
   Once inside the neuron, an enzyme called choline acetyltransferase enables the choline molecule to react with acetyl coenzyme (CoA) to form acetylcholine
2. Acetylcholine is packaged into a synaptic vesicle which is designed to protect it from degradation
3. When a voltage arrives, it causes the voltage gated Ca+ channels to open which allows Ca+ into the axon. As this happens, the synaptic vesicle is prompted to fuse with the membrane, resulting into the release of acetylcholine
4. Acetylcholine is then freed into the synaptic spaces, where is binds to the nicotinic or muscarinic receptors of the next neuron. This results in a cholinergic response
5. The enzyme acetylcholinesterase terminates the acetylcholine function by breaking it down into acetate and choline
6. The choline is taken up by the pre-synaptic neuron and is reused again

Question 5

Describe nicotinic receptors and its locations

Answer 5

• Ionotropic: Ion gated channels

2 types:

• Nm: found on neuromuscular joints
• Nn: CNS in the autonomic ganglia

When acetylcholine binds to nicotinic receptors, the nicotinic receptor undergoes a conformational change.
This enables Na+ to enter the cell

Question 6

Describe muscarinic receptors, its locations and the types of proteins they are coupled with.

Answer 6

• Metabotropic: G-protein coupled receptors

5 subtypes:
M1: located on neurons
M2: located on cardiac cells
M3: smooth muscles, eyes, lungs and digestive system

M1 and M3 are coupled to Gq protein; increases intracellular Ca+ levels
M2 are coupled to protein Gi; stimulates opening and exit of K+ channels

Question 7

What are the three types of cholinergic agonists?

Answer 7

• Direct acting
• Indirect acting reversible
• Indirect acting irreversible

Question 8

How do direct acting cholinergic agonists work?

What are the drugs? (4)

Answer 8

• Mimics the effects of acetylcholine by binding to nicotinic or muscarinic receptors

Types of direct acting cholinergic agonists;

Acetylcholine:

• produces a non-specific cholinergic effect, but is rapidly inactivated by cholinesterase, thus it is a short lived drug.
• Constrict pupils

Carbachol:

• Like acetylcholine but it is not very susceptible to cholinesterase, so it acts for longer
• Constrict pupil, decrease intraocular pressure

Pilocarpine:

• Used for ophthalmic preparations
• Constricts pupil, increases aqueous outflow and rapidly drops intra ocular pressure

Bethanechol:

• Stimulates urinary and GI tracts
• Can be given orally or subcutaneously

Question 9

How do indirect acting cholinergic reversible drugs work?

What are the drugs? (7)

Answer 9

• These drugs bind to acetylcholinesterase enzyme (AChE) and inactivate it
* Thus, it enables acetylcholine to work longer.

Examples are:
Edrophonium:
* reversibly binds to AChE. * short duration of action
* used to diagnose Myasthenia Gravis, a neuromuscular disease that causes muscle weakness
* When this is administered= immediate increase in muscular strength

Physostigmine:

• Stimulates both muscarinic and nicotinic receptors
• Used to treat anticholinergic drug overdoses

Pyridostigmine and Neostigmine:
* Stimulates GI tract and bladder, and reverses the effects of anaesthetics

Donepezil, Rivastigmine and Galantamine:

• Enhance cholinergic activity amongst Alzheimer’s patients and thus improves cognitive function
• Able to pass the blood the brain barrier.

Question 10

How do indirect acting cholinergic reversible drugs work?

What are the drugs? (2)

Answer 10

• Very toxic as they don’t let go of their binding with acetylcholinesterase

Drugs:
• Sarin gas: nerve agents
* Echthiophate:
* Forms a covalent bond with acetylcholinesterase leading to a very strong cholinergic stimulation

Question 11

What are the adverse effects of cholinergic drugs?

Answer 11

DUMB BELS

• Diarrhoea
• Urination
• Miosis (pupil constriction), muscle weakness
• Bronchorrhea (water mucous from lungs discharged via coughing)
• Bradycardia (slow heart rate)
• Emesis (vomiting)
• Lacrimation (crying.. Lol my life)
* Salivation, sweating

Question 12

How do anticholinergic agents work?

Answer 12

Bind to muscarinic receptors and inhibit muscarinic function

Question 13

Describe the types of anticholinergics (8)

Answer 13

• Cyclopentolate and tropicamide:
* Preferred over atropine because while it causes pupil dilation, it only lasts for a few hours

• Scopolamine:
prevents motion sickness/ post operative nausea and vomiting. It is longer lasting and more effective than atropine

• Ipratropium and Tiotropium:
Block all types of muscarinic receptors. This results in decreased contractility of smooth muscles in lungs/ enhance bronchodilation = reduction of mucous secretion/ Inhaled for treatment of bronchospasms

Tiotropium lasts longer than ipratropium. Ipratropium is also used as nasal sprays to treat runny noses

• Oxybutynin, trospium: treat overactive bladder by blocking M3 receptors which is the main receptor involved in bladder function

Atropine:
• Causes relaxation of eye muscles and thus dilation of pupils, inability to visually focus and unresponsiveness to light
* Lasts too long
• Atropine blocks the M3 receptors of the GI tract which reduces gut motility and delays gastric emptying
• At higher doses it blocks M2 receptors within the cardiac muscles, causing tachycardia (rapid heartbeat)

Question 14

What are the corresponding negative effects of anticholinergics?

Answer 14

ABCDS
• Agitation
• Blurred vision
• Constipation and confusion
• Dry mouth
* Stasis and sweating

Question 15

Describe ganglionic blockers (nicotine)

Answer 15

• Nicotine is both a cholinergic agonist and antagonist as it can activate and block cholinergic function
• Acts on nicotinic receptors of sympathetic and parasympathetic ganglia
• It results in the increased release of dopamine, serotonin and norepinephrine
• Causes addiction as it stimulates the CNS
• It is non-selective. At low levels, it stimulates the nervous system, but in high doses, it blocks the receptors in the nervous system.

For example, in high doses it can stimulate adrenal medulla and increase blood pressure/ heart rate. At higher doses, it will depress the adrenal medulla and cause bp to fall
• Increases motility which can lead to nausea and vomiting

Question 16

How does neuromuscular transmission work?

Answer 16

• When acetylcholine binds to a nicotinic receptor on a muscle, it sends a message to Na+ channels to open up
• A large amount of Na+ enters the cell and the change of voltage causes Ca+ to be released from sarcoplasmic reticulum, a reservoir for Ca+ in the muscle
* This increase in Ca+ enables the contraction of the muscle

Question 17

What are neuromuscular blocker and what are the 2 types?

Answer 17

• Block cholinergic transmission between nerve endings and nicotinic receptors on skeletal muscles
* There are two types; non-depolarizing and depolarizing

Question 18

How do non- depolarising neuromuscular blockers work?

Answer 18

• They are competitive antagonists
• The bind to acetylcholine receptors and block ion channel opening
• Thus, they prevent depolarisation of the membrane
* Must be given intravenously
* They are used to promote muscle relaxation so less general anaesthesia needs to be use
• They paralyse small contracting muscles first and big muscles last. The effect wears off in the reverse i.e, big muscles recover before small muscles
* Eyes, face, hands, arm/neck muscles and diaphragm

Question 19

Describe the types of non- depolarising neuromuscular blockers and their duration. (5)

Answer 19

• Duration refers to when the drug was first administered to when the patient regains 25% of muscle strength
• Atracurium
• 40 mins
• Causes histamine release, low bp and bronchoconstriction.
• It releases toxic metabolite laudanosine which causes seizures

• Rocuronium and Vecuronium:

• 40 mins
• Metabolised by liver, so their action is prolonged in people with kidney/liver dysfunction

• Cisatracurium:

• 90 mins
• Doesn’t rely on kidney and liver (hepatic) function, thus it is used in instances of organ failure

Pancuronium:

• 90 mins
• excreted unchanged in urine

Question 20

How do depolarising neuromuscular blockers work?

Answer 20

• Acetylcholine receptor agonists; they mimic the function of acetylcholine but they are much more resistant to acetylcholinesterase and thus they produce constant depolarisation (Phase I block)
• Eventually the nicotinic receptors become desensitised to the binding of succinylcholine, and so they don’t open anymore/ prevent formation of action potential (Phase II block)

Question 21

Describe a depolarising neuromuscular blocker, including the issues associated with it.

Answer 21

• Succinylcholine is the only depolarising agent still used in clinics
* It is hydrolysed by Pseudocholinesterase
* They bind to nicotinic receptors and open Na+ channels = depolarisation
• Patients lacking Pseudocholinesterase will experience prolonged apnoea in the presence of succinylcholine
• Due to prolonged depolarisation, there is an influx of K+ in extracellular fluid which leads to hyperkalaemia
• Hyperkalaemia becomes an issue in people with high K+ levels and can cause heart problems
* In genetically susceptible patients, it can trigger malignant hyperthermia

Question 22

Describe the process of adrenergic synthesis and neurotransmission

Answer 22

1. It begins with the uptake of an amino acid called Tyrosine into the neurone. This is achieved by sodium linked carriers.
   Once inside the neurone, tyrosine is hydroxylated by tyrosine hydroxylase into L-DOPA.
   Amino acid DOPA decarboxylase then converts this L-DOPA into dopamine
2. Dopamine is transported into a synaptic vesicle where an enzyme called dopamine beta-hydroxylase converts it into Norepinephrine
3. When an action potential occurs, it opens Ca+ channels and thus they enter the neurone
   The increased Ca+ levels causes the synaptic vesicle to fuse with the membrane and prompt endocytosis of Norepinephrine
4. Norepinephrine binds with post-synaptic receptors on effector organs = intracellular response
   It may also bind with pre-synaptic receptors which results in the decrease of Norepinephrine
5. Norepinephrine is diffused from the synaptic space into systemic circulation. It is deactivated by an enzyme called COMT.

Question 23

What are the two types of adrenergic receptors?

Answer 23

• α receptors

* β receptors

Question 24

List the locations of α receptors.

Answer 24

α1 receptors:

• Smooth muscles of veins and bladder = vasoconstriction
• Muscles of eye: dilate pupils
• Liver: increases glycogen breakdown
• Kidney: inhibits renin release = low bp

α2 receptors:

• Pancreas: decreases insulin release
• pre-synaptic nerve endings, so when stimulated, they will decrease the production of cAMP which inhibits the further release of Norepinephrine

Question 25

List the locations of β receptors.

Answer 25

β1: * Heart: increase HR and contractions * Kidney: renin release = high bp β2: * LunGs/ bronchial smooth muscle: bronchodilation * Smooth muscles and arteries of smooth muscles: vaxoodilation * Pancreas: insulin release * Smooth muscles of GI tract: lowered gut motility β3: * Adipose tissue = lipolysis * Urinary bladder: relaxed bladder (no urination)

Question 26

How do adrenergic antagonists work? | What are the types of adrenergic antagonists?

Answer 26

• Antagonists block receptors and therefore neurotransmissions * Non-selective α blockers * Selective α blockers

Question 27

List and describe the types of Non-selective α blockers (2)

Answer 27

• Non-selective agents can work on α1 blockers and α2 blockers • Phentolamine and Phenoxybenzamine: * treat hypertension caused by a tumor of the adrenal glands that secrete Norepinephrine • α 1 receptor binding = vasodilation • α 2 receptor binding = pre-synaptic binding inhibits further norepinephrine release Phenoxybenzamine is an irreversible antagonist. The only way the body can overcome its effect is by making new adrenergic receptors Phentolamine is a reversible antagonist, hence its effect only lasts a few hours

Question 28

List and describe the types of selective α blockers (7) • Suffix Osin = α1 selective blocker

Answer 28

* These agents selectively and reversibly block α1 receptors located in vascular smooth muscles * They block receptors in smooth muscles of bladder and prostate gland = muscles relax which leads to the relief of urinary difficulty * Prazosin, Doxazosin, Terazosin: lower bp * Tasulosin, Alfuzosin and Silodozin: are effective in relieving systems associated with enlarged prostate as they are very selective to the α1 receptors in the prostate. They can cause headaches and congestion α2 receptors don’t have clinical applications in humans Yohimbine is the only α2 receptor using in veterinary medicine to reverse the sedative effect of α agonists

Question 29

What are 1st generation β blockers? Provide examples. (2)

Answer 29

* Non- selective. Block both β1 and β2 receptors * They block β receptors in heart = decreased heart rate and reduced contractility and thus demand placed on the heart * Propranolol a lipophilic β receptor, is able to pass the blood brain barrier and treat migraines * Timolol reduces intra ocular pressure = treat glaucoma β2 receptors are found in the lungs. When blocked, it will lead to vasoconstriction. Not good for asthma

Question 30

What are 2nd generation β blockers?

Answer 30

* They are cardio-selective β1 receptor blockers * Suitable for patients with chronic lung diseases * In high doses, the selectivity of 2nd gen β blockers to β1 receptors will be lost and so they may block β2 receptors

Question 31

What are 3rd generation β blockers? (6)

Answer 31

* Includes both selective and non-selective β blockers * They act on blood vessels and thus cause vasodilation = good for hypertension • Carvedilol and Labetalol: produce vasodilation by block β and α1 receptors • Nebivolol: β1 selective. Produces vasodilation. Has anti-oxidant properties= good for heart failure * Betaxolol: β1 selective. Vasodilation by blocking Ca+ channels, and decrease intra occular pressure * Pindolol and Acebutolol: can block but also stimulate β1 and β2 receptors which doesn't drastically affect heart rate. Used for patients with very slow heart rates

Question 32

What are the two classes of adrenergic agonists?

Answer 32

* Catecholamine and | * Non- catecholamine

Question 33

Describe catecholamine and non- catecholamine agonists.

Answer 33

``` Catecholamine • Has two hydroxyl side groups • Has an ethyl chain • Has a terminal amine group • Metabolized by catechol- O- methyltransferase and monoamine oxidase • Rapidly Metabolised • Polar: cannot pass blood brain barrier • Injected ``` ``` Non-catecholamine • No hydroxyl side groups • Has an ethyl chain • Has a terminal amine group • Metabolized by monoamine oxidase • Metabolised very slowly = longer acting • Not very polar: can pass blood brain barrier • Orally given ```

Question 34

What are the types of adrenergic agonists?

Answer 34

* Non- selective Direct acting agonists * Selective Direct acting agonists * Indirect acting agonists * Mixed action agonists

Question 35

Describe the types of adrenergic agonists?

Answer 35

Non- selective Direct acting agonists • Bind to either α or β receptors • Mimic effects of epinephrine, norepinephrine and dopamine * Are catecholamines, thus they need to be injected Selective Direct acting agonists • Bind to specific receptors • Mimic effects of epinephrine, norepinephrine and dopamine Indirect acting agonists * Don’t act on receptors, but instead enhance the effect or Norepinephrine or epinephrine * The enhance their effect by blocking their re-uptake or inhibition of their degradation Mixed action agonists * Cause activation of adrenergic receptors by both direct binding as well as release of endogenously-stored norepinephrine from presynaptic terminals.

Question 36

Describe the types of adrenergic Non- selective Direct acting agonists (3)

Answer 36

• Epinephrine: Activates all adrenergic receptors. Leads to vasoconstriction, bronchodilation and increases bp. EpiPen • When β1 receptors are activated, it results in increased cardiac output. When β2 receptors are activated = bronchodilation • Norepinephrine: only stimulates α1 receptors = vasoconstriction and increased bp. Otherwise, not much clinical use compared to epinephrine • Dopamine: * At low doses stimulates dopamine receptors * At high doses, stimulates β1 receptors * Even higher doses, stimulates α1 receptors. Used for hypotensive shock and acute heart failure

Question 37

Describe the types of adrenergic selective direct acting agonists (6)

Answer 37

α1: • Phenylephrine used to treat nasal congestion. Increases bp, good for hypotensive patients • Oxymetazoline also used for nasal congestion and eye redness α2: • Chlonadine: treats ADHD and withdrawal symptoms from alcohol and opioids β1 • Dobutamine increases cardiac rate and cardiac output β2 • Albuterol and terbutaline are short acting bronchodilators • Salmeterol and formoterol are long acting bronchodilators β2 Mirabegron: stimulates receptors in the bladder, causing relaxation and thus easing the symptoms of an overactive bladder

Question 38

Describe the types of adrenergic selective indirect acting agonists (2)

Answer 38

* Cocaine and Amphetamine: block re-uptake of norepinephrine as well as Dopamine, particularly in the region of the brain which controls the rewards system. They stimulate α1 and β1 receptors that lead to a rise in bp and increase heart rate

Question 39

Describe the types of adrenergic mixed action agonists (2)

Answer 39

* Ephedrine and pseudoephedrine: cause activation of adrenergic receptors by direct binding and releasing stored epinephrine. Long duration * Ephedrine, rarely used clinically due to side effects *Pseudoephedrine vasoconstrict and relax bronchial smooth muscles, however it strongly activates receptors in nasal passages by constricting blood vessels = less mucous releas