Autonomic Pharmacology Part 1

Question 1

What are some of the things that occur in response to the parasympathetic activation

Answer 1

Reduced blood pressure
Reduced heart rate
Acts on M2 receptors on the heart
There is nitric oxide release leading to dilation of the blood vessels(acts on M3receptors in blood vessels)

Increased secretions(saliva and gastric juice)
Increased peristalsis
Decreased sphincter tone
Acts on M3 receptors in the Gi

Constricts bronchioles and increased secretions in the lungs
(Acts on M3 receptors)

Eye-there is miosis (eye is small) and accommodation for near vision
Eye doesn’t get wide cuz eye gets wide when you want to see far and run away from something (sympathetic)

Saliva becomes plenty and watery

Reduced sphincter tone and increased detrusor
Acts on M3 receptors on the bladder

Question 2

How does acetylcholine synthesis occur and how does botulinum toxin stops the release of Ach

Answer 2

Synthesis:
•Cholinergic neurons contain large numbers of small membrane-bound vesicles (containing ACh) concentrated near the synaptic portion of the cell membrane.
•ACh is synthesized in the cytoplasm from acetyl-CoA and choline by the catalytic action of Choline acetyltransferase (ChAT).
•Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending.
•Choline is transported from the extracellular fluid into the neuron terminal by a Na+-dependent membrane choline cotransporter (Carrier A).
•This carrier can be blocked by a group of drugs called hemicholiniums.
•The action of the choline transporter is the rate-limiting step in ACh synthesis

Choline is taken into the cell along with sodium using a transporter
It combines w Acetyl coA when it gets into the cell and the enzyme responsible is ChAt
This forms acetylcholine
This enters into the vesicle (ATP and other peptides are already in the vesicles)
When there is action potential transmission and it gets to the terminal
There is opening of a calcium channel located at the terminal allowing extra cellular calcium to enter the cell. When it enters it causes the exocytosis of the vesicle . Ach then comes out into the synaptic space
Looking for it’s receptors ( Muscarinic receptors)
Acetyl cholinesterase breaks down acetylcholine into choline and acetate
Botulinum toxin stops interaction between the SnAPs and Vamps (this interaction is caused by the release of calcium into the cell and the interaction causes exocytosis of the vesicle)

Question 3

Importance of the auto receptor which is also a muscarinic receptors

Answer 3

When there is too much of Ach there’s a negative feedback effect so it regulates further release of the Ach
So when ACh binds to it it’ll tell the vesicle not to release more Ach into the synapse

Question 4

How is Ach released and destroyed

Answer 4

Cholinergic Transmission –
Release:
•Synthesized, ACh is transported from the cytoplasm into the vesicles by an antiporter that removes protons(carrier B). This transporter can be blocked by vesamicol
•Release is dependent on extracellular Ca2+ and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca2+ ions
•The increased Ca2+ concentration “destabilizes” the storage vesicles by interacting with special proteins: the vesicular associated membrane proteins (VAMPs) and synaptosome associated protein (SNAP)
•Fusion of the vesicular membranes with the terminal membrane results in exocytotic expulsion of ACh into the synaptic cleft
•The ACh vesicle release process is blocked by botulinum toxin through the enzymatic removal of two amino acids from one or more of the fusion proteins.

After release - ACh molecules may bind to and activate an ACh receptors
•Eventually, all of the ACh released will diffuse within range of an acetylcholinesterase (AChE) molecule
•AChE splits ACh into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter.
•Most cholinergic synapses are richly supplied with AChE;
•the half-life of ACh in the synapse is therefore very short.
•AChE is also found in other tissues, eg, red blood cells.
•Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase [pseudo cholinesterase], is found in blood plasma, liver, glial, and many other tissues

Question 5

Where is M1 located and what is its effect on the locations when activated

Answer 5

Autonomic ganglion Cells, Gastric glands and Central Neurons (cortex, hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid secretion and relaxation of LES (vagal)
• Learning, memory and motor functions

So when there are diseases that bother learning and memory functions such as Dementia and Alzheimer’s you can cause the activation of M1 receptors to increase learning and memory

Question 6

Where is M2 receptors found and what is it’s effect when activated

Answer 6

M2: Cardiac Muscarinic receptors
– Mediate vagal bradycardia
– Also auto receptors in cholinergic nerve endings
– CNS – Tremor, analgesia

When activated-the G protein here is Gi in the M2 receptor
It inhibits adenylyl cyclase and decreased cyto something d and there’s k channel activation causing slowing of diastolic depolarization causing slowed contractions by receptors on SA node,

Question 7

Where is M3 receptors located and what is it’s effect when activated

Answer 7

M3: Visceral smooth muscles, glands and vascular endothelium. Also Iris and Ciliary muscles

If activated-there’s increased phospholipase C and that causes increased calcium in cytosol causing contraction of muscles or increased muscle tone

There is a protein(G couple something )that causes increased production of phospholipase C which causes the increased calcium in cytosol and increased secretions

Question 8

What is the location,function,mode of action,it’s agonists of the NN receptor (ganglion type)(nicotinic receptors) And antagonist

Answer 8

Location-in autonomic ganglion of all types (sympathetic,para,adrenal medulla)

In the ganglion Ach had to activate a nicotinic receptor and when activated it causes the release of the neurotransmitters depending on the type of system either para or sympa or adrenal medulla(causes production of 80 percent adrenaline and 20 percent noradrenaline)

Function-depolarization and post ganglionic impulse,stimulates all autonomic ganglion,adrenal medulla,catecholamines release

Mode of action- sodium ,potassium,calcium channels opening

Agonists-acetylcholine,carbachol(CCh),nicotine

Selective stimulation of NN receptors
Dimethyl phenyl piperazinium (DMPP)

Antagonist-Trimethaphan,Mecamylamine,hexamethonium

Question 9

What is the location,function,mode of action,it’s agonists of the NM receptor (muscle type)(nicotinic receptors) And antagonist

Answer 9

Location- skeletal muscle end plates

Function- stimulate skeletal muscle contraction

Mode of action-postsynaptic and excitatory (opening of actions potassium,sodium)

Agonists-acetylcholine,carbachol,suxamethonium

Selective stimulation by phenyl trimethyl anmonium(PTMA)

Antagonist-tubocurarine ,atracurium,vecuronium,pancuronium

Question 10

Name two muscarinic agonists

Answer 10

Pilocarpine
Bethanechol

Acetylcholine is not used clinically cuz it has a short action

Question 11

Name some Nicotinic receptor agonists

Answer 11

Succinylcholine
Nicotine
Anticholinesterase

Question 12

Nome some anti cholinesterase to prevent the degradation of the acetylcholine to let it stay long

Answer 12

Edrophonium
Neostigmine
Distigmine
Pyridostigmine(organophosphate compounds)

Question 13

Name some ganglion blockers

Answer 13

Trimetaphan (not ever used clinically) cuz it leads to the collapse of the cardiovascular system

Excess nicotine
(Depolarizing block)
At high doses nicotine causes block of the ganglion

Question 14

Name some muscarinic antagonist

Answer 14

Atropine
Hyoscine
Ipratropium
Tropicamide
Benzatrophine

Question 15

Name the types of cholinergic agonists and two main targets of these drugs actions

Answer 15

Acrtylcholine (ACh) is too rapidly hydrolyzed and inactivated by acetycholinesterases to be of any therapeutic use.
Its action can be replicated by other substances namely:

1. Direct cholinergic agonists
2. Indirect Cholinomimetics (cholinesterase inhibitors).

Two main targets of drug action:

1. The postsynaptic receptor and
2. The acetylcholinesterase enzyme, which breaks down acetylcholine.

NB: Some drugs are specific for the muscarinic receptor; others are specific for the nicotinic receptor

Question 16

Name the two classes of direct cholinergic agents and give examples of each class and the side effects of these drugs

Answer 16

Esters: - structurally related to acetylcholine, e.g.
•Bethanechol (used in the treatment of urinary retention)
•Carbachol (The choline ester of carbamic acid, used in the treatment of glaucoma)
Esters form stronger bonds making it hard for acetylcholinesterase to break it
These are long acting as compared to acetylcholine

2. Alkaloids: pilocarpine; muscarine(it’s a mushroom, it activates muscarinic receptors.it’s a poison. Not used clinically); arecoline

• The effects of all of these agents are exclusive muscarinic.
• Of this group, only pilocarpine enjoys therapeutic use, which is almost exclusively by local application to the eye in glaucoma
• Side effects often listed for these drugs include sweating (increased secretion), salivation, GI distress, and cramps (due to increased motility).

Question 17

What are pseudo cholinesterases and where are they abundant in the body

Answer 17

Pseudocholinesterases

There are other cholinesterases that also metabolize Ach and drugs with related structures.

These other cholinesterases are sometimes called pseudocholinesterases or nonspecific cholinesterases, and they are abundant in the liver.

Question 18

Which drug is a direct agonist at nicotinic receptors and how is nicotine used therapeutically

Answer 18

Nicotine is a direct agonist at nicotinic receptors. nicotine is used therapeutically to help patients stop smoking.
How?
If person tries to stop smoking completely it’ll cause withdrawal syndrome
So you give the person a nicotine patch so nicotine is released small small so person doesn’t have withdrawal syndrome

Question 19

What is the use of bethanechol,carbachol,cemiveline,pilocarpine

Answer 19

Bethanechol-non obstructive urine retention

Carbachol-glaucoma

Cemiveline-dry mouth from Sjögren’s syndrome

Pilocarpine-glaucoma

Question 20

During surgery apart from a local anaesthetic what is given to cause muscle relaxation

Answer 20

Nicotinic antagonist (muscle type not ganglion type)

Question 21

Name the classes under indirect cholinesterase inhibitors and give examples

Answer 21

They could be
Reversible (water soluble e.g. Physostigmine, Neostigmine) and Irreversible inhibitors (lipid soluble e.g. organophosphates-very poisonous so aren’t used therpaeuticaly so are used as biological weapons)

Question 22

What do indirect cholinesterase inhibitors do

Answer 22

They act by blocking the metabolism of Ach by cholinesterases.
They effectively increase the concentration of Ach at all cholinergic synapses.

The enzyme that is specific for Ach is called acetylcholinesterase, and it is found on both the pre- and postsynaptic membranes.

Question 23

Acetylcholine has more affinity ormuscarinic receptors as compared to nicotinic but acts on both of em
Anti cholinesterase has some effect on nicotinic receptors but prefers miscarinic receptors to nicotinic receptors true or false. Give an example of this

Answer 23

True

When you give acetylcholine low dose it’ll cause Bradycardia
But when you give a drug that blocks muscarinic receptors examples atropine and you give more acetylcholine it’ll cause increased heart rate and blood pressure
Cuz the acetylcholine at low dose acted on the muscarinic receptors but once those receptors are blocked and you add more acetylcholine it’ll act on nicotinic receptors in the ganglion leading to productions of norepinephrine and Acetylcholine since the muscarinic receptors are blocked norepinephrine action will be seen instead of acetylcholine action causing high bp and increased heart rate

Question 24

Name some examples of carbamates and how reversible inhibitors works

Answer 24

They include the quaternary amines and the carbamates.
They compete with acetylcholine for the active site on the cholinesterase enzyme.
This group includes the drugs with names ending in “-stigmine” and “-nium.”

Chemically, these agents include esters of
•Carbamic acid (carbamates such as physostigmine, neostigmine)

The reversible cholinestrease (AchE) inhibitors
They have similar actions and side effects as the direct acting drugs (muscarinic).

In addition, because they increase the concentration of Ach, they have effects at the neuromuscular junction (nicotinic).

These drugs cause similar side effects as the direct cholinergic agonists.

They also affect nicotinic receptors, primarily at the neuromuscular junction.

Reversible cholinestrease inhibitors can have effects on the cholinergic system in the CNS, if the drug can cross the blood-brain barrier.

The effects range from tremor, anxiety, and restlessness to coma.

Question 25

How is AchE(reversible cholinesterase inhibitors) used in myasthenia gravis

Answer 25

Myasthenia gravis Myasthenia gravis is an immune disease in which there is loss of acetylcholine receptors at the neuromuscular junction, resulting in weakness and fatigability of skeletal muscle. Ach receptors are bound by immune agents in the end plates of skeletal muscles so Ach can’t act on those muscles so the patient gets skeletal muscle weakness The AchE increases the Ach and the Ach will compete w the immune agents and surmount those agents More common in women 20 to 40 with possible line to thymus gland tumors. Begins with double vision & swallowing difficulties & progresses to paralysis of respiratory muscles The quaternary carbamates (Neostigmine, Pyridostigmine) are used to overcome the relative ACh deficiency at the motor end plate in Myasthenia gravis Additionally, steroids are used to reduce antibodies that bind to ACh receptors

Question 26

How is AchE(reversible cholinesterase inhibitors) used in Alzheimer’s

Answer 26

In the early stages of Alzheimer disease, administration of centrally acting AchE inhibitors can bring about transient improvement in cognitive function or slow down deterioration in some patients. •Suitable drugs include rivastigmine, donepezil, and galantamlne, which require slowly increasing dosage these cross bbb and inhibit acetylcholinesterase from destroying the little Ach produced by the remaining cholinergic neurons. Physostigmine and the other stigmines don’t cross the bbb so can’t be used in Alzheimer’s •Peripheral side effects (inhibition of ACh breakdown) limit therapy. •Donepezil and galantamine are not esters of carbamic acid and act by a different molecular action. •Galantamine is also thought to promote the action of ACh at nicotinic cholinoceptors by an allosteric mechanism. There is destruction of cholinergic neurons so there’s low production of Ach So AchE helps in more Ach being there

Question 27

How is AchE(reversible cholinesterase inhibitors) used in Other treatments

Answer 27

Uses of reversible AchE inhibitors are in the treatment of •open-angle glaucoma and •the reversal of nondepolarizing neuromuscular blockade after surgery (e.g. tubocurarine but not succinylcholine). •Paralytic ileus or bladder atony (Neostigmine preferred)

Question 28

What are the uses of these indirect acting cholinergic agents

Answer 28

Ambenonium- Myasthenia gravis Edrophonium-diagnosis of myasthenia gravis (cuz it’s short acting as compared to ambenonium ) Neostigmine- myasthenia gravis,urine retention Pyridostigmine- myasthenia gravis Tacrine- Alzheimer’s disease

Question 29

The irreversible inhibitors phosphorylate the enzyme and inactivate it. Chemically, these agents include esters of Phosphoric acid (very important while reversible inhibitors are esters of carbamic acid) (organophosphates such as paraoxon, and nitrostigmine or parathion). These cholinesterase inhibitors are widely used as insecticides. Because the organophosphates are lipid soluble, they rapidly cross all membranes, including skin and the blood-brain barrier. True or false And what drugs treat organophosphate poisoning

Answer 29

Pralidoxime (2-PAM) and Atropine are used to treat poisoning with organophosphates

Question 30

Give examples of nerve gases (chemical warfare) and insecticides

Answer 30

Cholinesterase inhibitors are designed to be deadly = “NERVE GAS” (Military) e.g., soman, sarin, tabun, VX 2. Insecticides e. g., diazinon (SPECTRACIDE), chlorpyrifos (DURSBAN), parathion, malathion

Question 31

Accumulation of ACh at cholinergic receptors when using nerve gases produces effects reflecting stimulation of cardiac muscle, smooth muscles and glands. Such effects would be identical to those caused by muscarine poisoning. •Bradycardia and hypotension occurs. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia. True or false

Answer 31

True

Question 32

How do organophosphates work

Answer 32

Organophosphates As Nerve Gas Agents In Chemical Warfare •Irreversible inhibition of acetylcholinesterase by these agents produces accumulation of ACh at the end plate of skeletal muscle fibers. •This in turn leads to depolarizing blockade of the NM nicotinic receptor. •Skeletal muscle paralysis occurs. •Movement is impossible. •The diaphragm is also paralyzed. •The individual eventually dies due to respiratory paralysis. –Persian gulf war syndrome

Question 33

Name the classes of cholinergic antagonists

Answer 33

1.Muscarinic Antagonist Selective Non selective 2. Antinicotinic I.Ganglion Blockers (Nn) II.Neuromuscular Blockers (Nm)

Question 34

What are muscarinic antagonists and give examples

Answer 34

They block muscarinic receptors competitively, causing inhibition of all muscarinic functions •They are effective in several clinical situations unlike cholinergic agonists Drugs belonging to this group a- Atropine & Hyoscine (scopolamine) (natural alkaloids) b- Homatropine (synthetic comp.) c- Atropine methonitrate (quaternary comp.) d- Ipratropium (quaternary comp.) e- Pirenzepine (selective M1 antagonist) f- Cyclopentolate and tropicamide (tertiary amines developed for ophthalmic use)

Question 35

What is the effect of muscarinic antagonists on the cardiovascularsystem,exocrine ,the eye,

Answer 35

Cardiovascular effect: •Heart: Small dose of atropine (bradycardia by blocking M1 receptors on presynaptic neuronal junctions thereby causing more release of Ach) •Higher doses of atropine can cause a progressive increase in heart rate by blocking M2 receptors on the sinoatrial node. •Exocrine glands: •At low dose, it inhibits salivary, lachrymal, bronchial & sweat glands •Inhibition of secretions by sweat glands can cause elevated body temp •It produces uncomfortable dry mouth & skin •Gastric secretion is only slightly reduced The Eye: - Iris: Passive mydriasis (dilation of the pupil) & the eye becomes unresponsive to light - Ciliary Muscle: Paralysis of accommodation (cycloplegia i.e inability to focus for near objects) - These permit the measurement of refractive errors without interference by the accommodative capacity of the eye. - Shorter-acting antimuscarinics (cyclopentolate and tropicamide) have largely replaced atropine due to prolonged mydriasis observed with atropine (7 to 14 days vs. 6 to 24 hours with other agents).

Question 36

-In patient with narrow angel glaucoma, Intraocular pressure may rise dangerously, so short acting antimuscarinic tropicamide or α agonist phenylephrine are more preferred in ophthalmic examination True or false

Answer 36

True

Question 37

Name some clinical uses of muscarinic antagonists and the specific drugs used

Answer 37

Cardiovascular: •Treatment of heart block (atropine) * Neurological: * Prevention of motion sickness (scopolamine) * Reduce involuntary movement & rigidity in case of Parkinsonism (benztropine) * Nocturnal enuresis (TCA is more preferred) •Eye –Tropicamide and cyclopentolate are used to produce mydriasis and cycloplegia Respiratory: •Treatment of asthma & COPD(in asthma there’s is increased secretion and constriction of bronchioles)(ipratropium) •To dry secretions & prevent reflex bronchconstriction during anesthesia (atropine or hyoscine) •GIT: •Antispasmodic action & suppress gastric acid secretion •Hyoscine is used in case of endoscopy & pirenzepine in case of peptic ulcer (H2 antagonists are more preferred)

Question 38

How are muscarinic anatagonists used to treat urinary incontinence and drugs used

Answer 38

Treatment of Urinary Incontinence –Occurs as a result of overactive detrusor muscles in the bladder preventing it from containing urine –Act by competitively blocking muscarinic (M3) receptors in the bladder which results in •Decreased intravesical pressure, •Increased bladder capacity, •Reduced frequency of bladder contractions. –e.g. solfenacin, darifenacin, oxybutynin, fesoterodine, tolterodine, trospium Muscarinic agonists for treatment of urinary retention and antagonists for incontinence

Question 39

How are muscarinic anatagonists used to treat COPD and drugs used

Answer 39

Chronic obstructive pulmonary disease (COPD) and Asthma –Aclidinium, glycopyrrolate, ipratropium, (short acting) and tiotropium(long acting) –are approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). –ipratropium, and tiotropium are used in treatment of asthma

Question 40

How are muscarinic anatagonists used to treat Parkinson’s and drugs used

Answer 40

Parkinsons disease –Trihexiphenidyl and benztropine –Used for treatment of Parkinson’s disease –Management of extrapyramidal symptoms in psychosis treatment.

Question 41

How are muscarinic anatagonists used to treat cholinergic agonist poisoning

Answer 41

Atropine is used for the treatment of overdoses of cholinesterase inhibitors such as: •physostigmine & organophosphate insecticides •Mushrooms (muscarine) •The ability of atropine to enter CNS is of particularly importance

Question 42

Adverse effects of Muscarinic antagonists

Answer 42

Dry mouth & blurred vision –Tachycardia –Restlessness, confusion, hallucination & delirium

Question 43

What are ganglion blockers

Answer 43

They block nicotinic receptors of autonomic ganglia, therefore they are rarely used therapeutically (experimental tools in pharmacology)

Question 44

How do neuromuscular blockers work

Answer 44

Drugs can block neuromuscular transmission in three main ways: •By inhibiting Ach synthesis e.g. hemicholinum & triethylcholine •By inhibiting Ach release e.g. botulinum toxins, excess Mg, aminoglycosides antibiotics By interfering with the postsynaptic action of Ach

Question 45

How do neuromuscular blockers interfere w postsynaptic action of Ach

Answer 45

By interfering with the postsynaptic action of Ach: a- Depolarizing Blocking Agents (DNMB) or non competitive or irreversible blocking agents •Produce initial stimulation followed by failure of transmission •Depolarizing blockers also act on acetylcholine receptors, but trigger the opening of the ion channels. So contractions occur but after sometime the contractions stop causing paralysis or desensitization can occur by too much sodium getting inside so when sodium comes kraa it won’t be felt causing paralysis •They are not reversed by anticholinesterases. •Suxamethonium is the only drug of this type used clinically. •e.g. succinylcholine & decamethonium 3. By interfering with the postsynaptic action of Ach: b- Competitive Blocking Agents (CNMB) •These drugs compete with acetylcholine for the receptor but do not initiate ion channel opening so that sodium won’t enter for calcium to come and cause contractions causing flaccid paralysis) •They reduce the endplate depo They reduce the endplate depolarizations produced by acetylcholine to a size that is below the threshold for muscle action potential generation and so cause a flaccid paralysis. •e.g. curare, gallamine, tubocurarine

Question 46

What are the clinical uses of neuromuscular blockers

Answer 46

Used by anaesthetists to relax skeletal muscles during surgical operations and •Used to prevent muscle contractions during electroconvulsive therapy (ECT)

Question 47

How do aminoglycosides which are also antibiotics cause neuromuscular blockade

Answer 47

The mechanism by which aminoglycoside antibiotics and verapamil produce neuromuscular blockade must be the same. Both classes of drugs interfere with calcium ions movements through the calcium channels of the membrane of the motor nerve-endings inhibiting acetylcholine release at the synaptic cleft.

Question 48

``` What are some of the things that occur in response to sympathetic activation In the heart Kidney Eye Skeletal muscle GIt Skin Liver Bladder Blood vessels Respiration(bronchi) Fat tissues Saliva ``` And the receptors that will be activated

Answer 48

``` Eye-pupillary dilation(alpha 1receptors) Saliva-little and viscous(copious is in parasympathetic)(alpha 1) Dilation of bronchi(beta 2) Increased heart rate(beta 1 and beta 2) Increased force Increased bp ``` In the fat tissues lipolysis increases and fatty acid liberation increases (beta 1,2,3) In the skin perspiration increases (its cholinergic cuz release of acetylcholine causes this )(M3 receptors) Constriction of blood vessels(alpha 1 and 2) Dilation of blood vessels (beta 2) Increased secretion of renin(beta 1) Renin activated angiotensinongen to angiotensin 1 Angiotensin 1 to angiotensin 2 by angiotensin converting enzyme And angiotensin 2 activates angiotensin receptors causing increased bp and constriction of vessels Glycogenolysis and glucose release in the liver increases (Beta 2) Reduced peristalsis (beta 2) Sphincter tone increases(alpha) Decreased blood flow to GI (alpha 1) (So pee won’t come)Increased sphincter tone(alpha 1) Detrusor muscle tone decreases (so you won’t feel like peeing ) (beta 2) Increased glycogenolysis in skeletal muscles (beta 2)

Question 49

How is epinephrine synthesize and released

Answer 49

Epinephrine is synthesized from NE within the adrenal medulla: small glands associated with the kidneys. 2. Preganglionic fibers of the sympathetic nervous system synapse within the adrenals. 3. Activation of these preganglionic fibers releases acetylcholine, which binds to postjunctional nicotinic receptors in the tissue. 4. This leads to stimulation of NE synthesis within adenomedullary cells, but unlike sympathetic neurons, there is an additional enzyme (phenylethanolamine-N-methyltransferase) that adds a methyl group to the NE molecule to form epinephrine. 5. The epinephrine is released into the blood perfusing the glands and carried throughout the body. 7

Question 50

Physostigmine helps in atropine poisoning true or false

Answer 50

True

Question 51

What does nor mean

Answer 51

One methyl group less

Question 52

How does carbidopa work

Answer 52

It is given in conjunction w levodopa It inhibits dopa decarboxylase And is used to treat Parkinson’s disease You can’t give dopamine directly cus it can’t cross the bbb Levodopa can cross the bbb and is converted to dopamine by dopa decarboxylase in the brain but the dopa decarboxylase is also available in the peripheral tissues so when you give levodopa it can be converted to dopamine in the peripheral tissues and won’t get to the brain but carbidopa doesn’t cross the bbb so it guides levodopa so dopa decarboxylase will be inhibited by carbidopa while levodopa goes to the bbb

Question 53

How does fusaric acid work and why isn’t it really therapeutically used

Answer 53

It is an experimental drug not a clinical drug It’s a dopamine beta hydroxylase inhibitor preventing the production of norepinephrine But then dopamine has action on beta and alpha receptors and too much of dopamine in the body isn’t good cuz it can cause psychosis due to the euphoria

Question 54

Name the two classes of drugs under sympathomimetics (mimic sympathetic system) And give examples Name the two classes under direct acting drugs and give examples

Answer 54

``` Indirectly acting: Ephedrine Amphetamine Tyramine Cocaine ``` Directly acting: Alpha agonists- Alpha 1 and alpha2-norepinephrine and epinephrine Alpha 2 selective- Clonidine Alpha methyl norepinephrine Alpha 1 selective- Phenylephrine Metaraminol Beta agonists- Beta 1 and beta 2- Epinephrine Isoprenaline Beta 1 selective-norepinephrine Dobutamine Beta 2 selective(selective that it prefers one receptor to the other but has little effect on the one it doesn’t prefer) Salbutamol Terbutaline

Question 55

Adrenocepter antagonists are alpha blockers and beta blockers Name the classes under them with examples

Answer 55

Alpha blockers Alpha 1 and 2 Phenoxybenzamine -irreversible (treatment of pheochromocytoma check) Phentolamine -reversible (diagnosis) Alpha 1 selective-prazosin Doxazosin Tamulosin ``` Beta blockers Beta 1 and beta 2 Propanolol Nadolol (least lipid soluble) Timolol Oxprenolol Pindolol Carvedilol ``` Beta 1 blocker(cardioselective) Metoprolol Atenolol (least lipid soluble) Acebutolol The rest are very lipid soluble (the beta blockers) except acebutolol and pindolol which are partial agonists

Question 56

Full meaning of VMA and what it’s used for

Answer 56

Vanillylmandelic acid Used in the diagnosis of pheochromocytoma This final product, along with its precursors normetanephrine and metanephrine, is measured in urine and plasma in the diagnosis of pheochromocytoma, which can cause severe hypertension and cardiac arrhythmias.

Question 57

When alpha 1 receptors are activated what things occur

Answer 57

arterial and arteriolar constriction (cutaneous, visceral, skeletal & pulmonary) • venous constriction •uterine contraction( so it’s activated during labor) •pupillary dilation (contraction of radial smooth muscle of iris) (circular muscle which is the opposite of the radial smooth muscle has Muscarinic receptors on it? •contraction of ureter •contraction of spleen •contraction of pilomotor muscles

Question 58

When alpha 2 receptors are activated what things occur

Answer 58

inhibition of NE release •inhibition of ganglionic transmission •vasoconstriction •(quanitatively less important than a1)

Question 59

When beta 1 and beta 2 receptors are activated what occurs and why wouldn’t we want to give a non selective beta blocker to a diabetic who’s hypertensive

Answer 59

cardiac stimulation (chronotropic, inotropic, dromotropic) * stimulation of lipolysis (b3) * stimulation of renin secretion Beta 2 arteriolar dilation (skeletal muscle, coronary visceral beds) •intestinal relaxation •bronchiolar relaxation •uterine relaxation(activated during premature labor to prevent premature labor) •bladder body relaxation •stimulation of insulin release •skeletal muscle tremor(if someone has diabetes and hypertension don’t give person a non selective beta blocker cuz blocking beta 2 stops the tremors and these tremors occur during hypoglycemia so if it’s blocked the person won’t realize he’s going hypo cuz the tremors aren’t coming ) •stimulation of glycogenolysis

Question 60

What are the therapeutic uses of alpha and beta receptors

Answer 60

``` vascular smooth muscle contraction a1 inhibition of transmitter release a2 cardiac stimulation b1 vascular smooth muscle relaxation b2 bronchiolar smooth muscle relaxation b2 ```

Question 61

Name the types of adrenergic agonists and give examples of each and classes under each

Answer 61

Direct-selective -alpha 1(phenylephrine,methoxamine), alpha 2(clonidine) ,beta 1(dobutamine) ,beta 2(terbutaline,salbutamol) non selective -oxymetazoline(acts on both alpha receptors),isoproterenol or isoprenaline(acts on both beta receptors),epinephrine (acts on both alpha and beta),norepinephrine (acts on alpha receptors and beta 1 receptors) Mixed acting-ephedrine (alpha and beta receptors and is a releasing agent) Indirect -releasing agents (amphetamine) uptake inhibitors(cocaine) ,COMT or MAO inhibitors

Question 62

How does epinephrine work and it’s effects

Answer 62

very potent vasoconstrictor and cardiac stimulant •Increases systolic BP by –its positive inotropic and chronotropic actions on the heart (predominantly β1) –and the vasoconstriction induced in many vascular beds ( α) •Also activates β2 receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation. •Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is sometimes seen with epinephrine injection. •Activation of these 2 receptors in skeletal muscle contributes to increased blood flow during exercise.

Question 63

How does clonidine work and it’s effects and name other selective alpha 2 agonists

Answer 63

Selective α 2-agonists •used primarily for the treatment of systemic hypertension •IV infusion of clonidine causes an acute rise in BP due to activation of postsynaptic α 2 receptors in vascular smooth muscle (The long term effect is It’ll decrease bp by inhibiting the further release of norepinephrine But acutely it can raise the bp) •Other selective α 2 agonist include: –Apraclonidine, Brimonidine, Guanfacine, Guanabenz, Methyldopa

Question 64

How does dobutamine work ,it’s effects and it’s uses

Answer 64

Mechanism: –Selective for b1-receptors •Pharmacological Effects: –Cardiac stimulation - force increases more than rate, consequently CO (cardiac output)increases without a dramatic increase in heart rate •Therapeutic Uses: Congestive heart failure

Question 65

How does terbutaline work ,it’s effects and uses

Answer 65

Mechanism: Selective for b2-receptors •Pharmacological Effects: Smooth muscle relaxation, esp. airway smooth muscle •Therapeutic Uses: Reversible bronchospasm (major use) To delay premature labor (minor use) Orcipprenaline (metaproterenol), salbutamol (albuterol), ritodrine, Pirbuterol, isoetharine, bitolterol, fenoterol, formoterol procaterol

Question 66

How does ephedrine work ,it’s effects and it’s uses

Answer 66

Mechanism: indirectly acting with possibly some direct effects on a and b receptors Indirectly causes the release of norepinephrine ``` • Pharmacological Effects: –vasoconstriction, –positive inotropic effect, –relaxation of bronchiolar smooth muscle, –mydriasis, –CNS stimulation 7/30/2021 65 Ephedrine contd •Therapeutic Uses: bronchospasm, nasal decongestant, mydriatic, narcolepsy (major uses). Relief of pain of of dysmenorrhea (minor) ``` • Additional Comments: Orally effective, crosses the blood-brain barrier. Tachyphylaxis develops to some of its actions

Question 67

How does amphetamine work ,it’s effects and uses

Answer 67

Mechanism: indirectly acting • Pharmacological Effects: –Systemic - vasoconstriction, cardiac stimulation –Central - in general, stimulatory. Acts in medulla, cortex, cerebrospinal axis. Anorexigenic ``` •Therapeutic Uses: –narcolepsy –hyperkinetic syndrome –obesity –fatigue ```

Question 68

How does dopamine work ,it’s effects and uses

Answer 68

Mechanism: –Complex mixture of α and β effects (with no particular selectivity), indirect sympathomimetic actions(by being converted to norepinephrine)and direct action on dopamine receptors. • Pharmacological Effects: –Vasodilatation in renal and mesenteric beds, mediated by dopamine receptors at low doses – D1 –Cardiac Stimulation - increase in rate, force, cardiac output, mediated by b1-receptors at medium concentrations –Vasoconstriction - at high concentrations, mediated by a1 receptors –Also increases norepinephrine levels • Therapeutic Uses: Shock/Chronic Refractory Congestive Failure

Question 69

How does fenoldopam work ,it’s effects and uses

Answer 69

It is a D1 receptor agonist that selectively leads to peripheral vasodilation in some vascular beds •The primary indication for fenoldopam is as an intravenously administered drug for the treatment of severe hypertension •Continuous infusions of the drug have prompt effects on blood pressure

Question 70

Name the uses of sympathomimetics on the cardiovascular system

Answer 70

Cardiac arrest: adrenaline intravenously, or sometimes via an endotracheal tube •Cardiogenic shock ; dobutamine (b1-agonist) by intravenous infusion for its positive inotropic effect; low-dose dopamine to increase renal perfusion (via dopamine receptors in renal vasculature) and maintain glomerular filtration • Heart block: symptomatic heart block is treated by electrical pacing; b-agonists (isoprenaline) can be used temporarily while this is being arranged.

Question 71

Name the uses of sympathomimetics on the anaphylaxis system

Answer 71

``` Acute anaphylactic (or type I hyper-sensitivity) reactions—sudden and sometimes life-threatening immunological reactions , usually caused by bee stings or by hypersensitivity reactions to drugs (especially penicillin). • Adrenaline is the first-line treatment, usually injected intramuscularly; intravenous infusion requires close monitoring, usually in an intensive care unit. ``` The only time you’ll use adrenaline is in anaphylactic shock (hypotension and brocho constriction) In anaphylaxis mast cells release histamine This causes release of inflammatory agents that will occlude the bronchioles causing occlusion and constriction of the bronchioles)

Question 72

Name the uses of sympathomimetics on the respiratory system

Answer 72

Asthma: selective b2-receptor agonists (salbutamol, terbutaline, salmeterol) by inhalation; salbutamol by intravenous infusion in severe attacks. •Nasal decongestion: drops containing oxymetazoline or ephedrine for short-term use

Question 73

What is the end effect of activation of alpha 2 receptor

Answer 73

The long term effect is It’ll decrease bp by inhibiting the further release of norepinephrine But acutely it can raise the bp

Question 74

Name three other uses of sympathomimetics

Answer 74

Prolongation of local anaesthetic action : vasoconstrictor agents such as adrenaline can be injected with the local anaesthetic solution; it must not be injected into digits because of the risk of gangrene * inhibition of premature labour (salbutamol) * Miscellaneous indications for a2-agonists (e.g. clonidine) include hypertension, menopausal flushing, migraine prophylaxis; efficacy is limited

Question 75

Name the classes of adrenergic antagonists

Answer 75

Alpha and beta blockers

Question 76

Types of alpha and beta blockers,alpha selective ,non selective ,beta selective and non selective with examples

Answer 76

Alpha-alpha 1 selective -prazosin,Terazosin,Doxazosin,Urapidil,Tamsulosin ,alpha 2 selective-Yohimbine ,idazoxan and non selective phenoxybenzamine,phentolamine (reversible and irreversible) Ergot derivatives (example ergotamine) Beta-selective beta1(second generation)-atenolol,bisoprolol,acebutolol,metoprolol,alprenolol and non selective (first generation)-nadolol,Timolol,propanolol,penbutolol

Question 77

Name some non selective beta blockers that are third generation and beta 1 selective that are third generation

Answer 77

Carvedilol Labetalol Carteolol Bucinodolol Betaxolol Celiprolol Nebivolol

Question 78

Labetalol as a beta adrenergic antagonist acts on alpha 1 and beta receptors true or false

Answer 78

True

Question 79

Name some anti adrenergic agents

Answer 79

guanethidine – adrenergic neuron blocker * reserpine – depletes storage sites * alpha methyl-dopa –false transmitter? * alpha methyl-p-tyrosine –false transmitter?

Question 80

What are ergot derivatives

Answer 80

•ergot derivatives (e.g. ergotamine, dihydroergotamine). This group of compounds has many actions in addition to α-adrenoceptor block

Question 81

Name some clinical uses of alpha adrenoreceptor antagonists

Answer 81

Hypertension : α1-selective antagonists. Prazosin is short-acting. Preferred drugs are longer-acting (e.g. doxazosin, terazosin), used either alone in mild hypertension, or in combination with other drugs * Benign prostatic hypertrophy (especially tamsulosin, a selective α1A-receptor antagonist) * Phaeochromocytoma: phenoxybenzamine used in conjunction with β -receptor antagonist in preparation for surgery 7/30/2021

Question 82

Name the places with beta receptors that beta blockers block

Answer 82

``` Beta-adrenoceptor blocking drugs (beta-blockers) block the beta-adrenoreceptors in –the heart, –peripheral vasculature, –bronchi, –pancreas, and –liver ```

Question 83

What is Intrinsic Sympathomimetic activity (ISA) with examples

Answer 83

ISA, partial agonist activity represents the capacity of beta-blockers to stimulate as well as to block adrenergic receptors * partial agonists inhibit the activation of receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists * E.g. Oxprenolol, pindolol, acebutolol and celiprolol * they tend to cause less bradycardia than the other beta-blockers and may also cause less coldness of the extremities 7/30/2021 83

Question 84

Name the beta blockers that are more water soluble and the importance of them being water soluble

Answer 84

Some beta-blockers are lipid soluble and some are water soluble * E.g. Atenolol, celiprolol, nadolol, and sotalol are the most water-soluble * they are less likely to enter the brain, and may therefore cause less sleep disturbance and nightmares

Question 85

What is the use of decreases in the following: rate, contractility, cardiac output, conduction velocity, automaticity.

Answer 85

Applications: Antiarrhythmic and Anti-Anginal

Question 86

Name the clinical uses of beta adrenoreceptor antagonists ,contraindications,side effects and route of administration

Answer 86

``` Cardiovascular system –hypertension –angina pectoris –following myocardial infarction (protection against dysrhythmias and repeated infarction) –cardiac dysrhythmias ``` •Clinically stable cardiac failure (prolong survival) •Other uses –glaucoma, e.g. timolol eye drops –Thyrotoxicosis, as adjunct to definitive treatment (e.g. properatively) –anxiety states, to control somatic symptoms associated with sympathetic overactivity, such as palpitations and tremor –migraine prophylaxis –benign essential tremor (a familial disorder). 7/30/2021 87 •Contra-Indications: asthma, cardiac conduction disturbances, hypoglycemia • Side Effects: Tiredness, vivid dr Side Effects: Tiredness, vivid dreams, insomnia, hallucinations •Route of Administration -All of the b-blockers available for oral administration –Propranolol available for IV and in a long-acting oral tablet –Timolol and Betaxolol available as an opthalmic solution