Autonomic Pharmacology Part 1 Flashcards
What are some of the things that occur in response to the parasympathetic activation
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
How does acetylcholine synthesis occur and how does botulinum toxin stops the release of Ach
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)
Importance of the auto receptor which is also a muscarinic receptors
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
How is Ach released and destroyed
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
Where is M1 located and what is its effect on the locations when activated
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
Where is M2 receptors found and what is it’s effect when activated
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,
Where is M3 receptors located and what is it’s effect when activated
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
What is the location,function,mode of action,it’s agonists of the NN receptor (ganglion type)(nicotinic receptors) And antagonist
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
What is the location,function,mode of action,it’s agonists of the NM receptor (muscle type)(nicotinic receptors) And antagonist
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
Name two muscarinic agonists
Pilocarpine
Bethanechol
Acetylcholine is not used clinically cuz it has a short action
Name some Nicotinic receptor agonists
Succinylcholine
Nicotine
Anticholinesterase
Nome some anti cholinesterase to prevent the degradation of the acetylcholine to let it stay long
Edrophonium
Neostigmine
Distigmine
Pyridostigmine(organophosphate compounds)
Name some ganglion blockers
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
Name some muscarinic antagonist
Atropine Hyoscine Ipratropium Tropicamide Benzatrophine
Name the types of cholinergic agonists and two main targets of these drugs actions
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:
- Direct cholinergic agonists
- Indirect Cholinomimetics (cholinesterase inhibitors).
Two main targets of drug action:
- The postsynaptic receptor and
- The acetylcholinesterase enzyme, which breaks down acetylcholine.
NB: Some drugs are specific for the muscarinic receptor; others are specific for the nicotinic receptor
Name the two classes of direct cholinergic agents and give examples of each class and the side effects of these drugs
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
- 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).
What are pseudo cholinesterases and where are they abundant in the body
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.
Which drug is a direct agonist at nicotinic receptors and how is nicotine used therapeutically
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
What is the use of bethanechol,carbachol,cemiveline,pilocarpine
Bethanechol-non obstructive urine retention
Carbachol-glaucoma
Cemiveline-dry mouth from Sjögren’s syndrome
Pilocarpine-glaucoma
During surgery apart from a local anaesthetic what is given to cause muscle relaxation
Nicotinic antagonist (muscle type not ganglion type)
Name the classes under indirect cholinesterase inhibitors and give examples
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)
What do indirect cholinesterase inhibitors do
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.
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
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
Name some examples of carbamates and how reversible inhibitors works
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.
How is AchE(reversible cholinesterase inhibitors) used in myasthenia gravis
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
How is AchE(reversible cholinesterase inhibitors) used in Alzheimer’s
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
How is AchE(reversible cholinesterase inhibitors) used in Other treatments
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)
What are the uses of these indirect acting cholinergic agents
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
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
Pralidoxime (2-PAM) and Atropine are used to treat poisoning with organophosphates
Give examples of nerve gases (chemical warfare) and insecticides
Cholinesterase inhibitors are designed to be deadly = “NERVE GAS” (Military)
e.g., soman, sarin, tabun, VX
- Insecticides
e. g., diazinon (SPECTRACIDE), chlorpyrifos (DURSBAN), parathion, malathion
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
True
How do organophosphates work
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
Name the classes of cholinergic antagonists
1.Muscarinic Antagonist
Selective
Non selective
- Antinicotinic
I.Ganglion Blockers (Nn)
II.Neuromuscular Blockers (Nm)
What are muscarinic antagonists and give examples
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)
What is the effect of muscarinic antagonists on the cardiovascularsystem,exocrine ,the eye,
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).
-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
True
Name some clinical uses of muscarinic antagonists and the specific drugs used
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)
How are muscarinic anatagonists used to treat urinary incontinence and drugs used
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
How are muscarinic anatagonists used to treat COPD and drugs used
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
How are muscarinic anatagonists used to treat Parkinson’s and drugs used
Parkinsons disease
–Trihexiphenidyl and benztropine
–Used for treatment of Parkinson’s disease
–Management of extrapyramidal symptoms in psychosis treatment.
How are muscarinic anatagonists used to treat cholinergic agonist poisoning
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
Adverse effects of Muscarinic antagonists
Dry mouth & blurred vision
–Tachycardia
–Restlessness, confusion, hallucination & delirium
What are ganglion blockers
They block nicotinic receptors of autonomic ganglia, therefore they are rarely used therapeutically (experimental tools in pharmacology)
How do neuromuscular blockers work
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
How do neuromuscular blockers interfere w postsynaptic action of Ach
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
- 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
What are the clinical uses of neuromuscular blockers
Used by anaesthetists to relax skeletal muscles during surgical operations and
•Used to prevent muscle contractions during electroconvulsive therapy (ECT)
How do aminoglycosides which are also antibiotics cause neuromuscular blockade
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.
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
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)
How is epinephrine synthesize and released
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
Physostigmine helps in atropine poisoning true or false
True
What does nor mean
One methyl group less
How does carbidopa work
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
How does fusaric acid work and why isn’t it really therapeutically used
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
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
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
Adrenocepter antagonists are alpha blockers and beta blockers
Name the classes under them with examples
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
Full meaning of VMA and what it’s used for
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.
When alpha 1 receptors are activated what things occur
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
When alpha 2 receptors are activated what things occur
inhibition of NE release
•inhibition of ganglionic transmission
•vasoconstriction
•(quanitatively less important than a1)
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
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
What are the therapeutic uses of alpha and beta receptors
vascular smooth muscle contraction a1 inhibition of transmitter release a2 cardiac stimulation b1 vascular smooth muscle relaxation b2 bronchiolar smooth muscle relaxation b2
Name the types of adrenergic agonists and give examples of each and classes under each
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
How does epinephrine work and it’s effects
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.
How does clonidine work and it’s effects and name other selective alpha 2 agonists
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
How does dobutamine work ,it’s effects and it’s uses
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
How does terbutaline work ,it’s effects and uses
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
How does ephedrine work ,it’s effects and it’s uses
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
How does amphetamine work ,it’s effects and uses
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
How does dopamine work ,it’s effects and uses
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
How does fenoldopam work ,it’s effects and uses
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
Name the uses of sympathomimetics on the cardiovascular system
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.
Name the uses of sympathomimetics on the anaphylaxis system
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)
Name the uses of sympathomimetics on the respiratory system
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
What is the end effect of activation of alpha 2 receptor
The long term effect is It’ll decrease bp by inhibiting the further release of norepinephrine
But acutely it can raise the bp
Name three other uses of sympathomimetics
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
Name the classes of adrenergic antagonists
Alpha and beta blockers
Types of alpha and beta blockers,alpha selective ,non selective ,beta selective and non selective with examples
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
Name some non selective beta blockers that are third generation and beta 1 selective that are third generation
Carvedilol
Labetalol
Carteolol
Bucinodolol
Betaxolol
Celiprolol
Nebivolol
Labetalol as a beta adrenergic antagonist acts on alpha 1 and beta receptors true or false
True
Name some anti adrenergic agents
guanethidine – adrenergic neuron blocker
- reserpine – depletes storage sites
- alpha methyl-dopa –false transmitter?
- alpha methyl-p-tyrosine –false transmitter?
What are ergot derivatives
•ergot derivatives (e.g. ergotamine, dihydroergotamine). This group of compounds has many actions in addition to α-adrenoceptor block
Name some clinical uses of alpha adrenoreceptor antagonists
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
Name the places with beta receptors that beta blockers block
Beta-adrenoceptor blocking drugs (beta-blockers) block the beta-adrenoreceptors in –the heart, –peripheral vasculature, –bronchi, –pancreas, and –liver
What is Intrinsic Sympathomimetic activity (ISA) with examples
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
Name the beta blockers that are more water soluble and the importance of them being water soluble
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
What is the use of decreases in the following: rate, contractility, cardiac output, conduction velocity, automaticity.
Applications: Antiarrhythmic and Anti-Anginal
Name the clinical uses of beta adrenoreceptor antagonists ,contraindications,side effects and route of administration
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
