PHAR232 exam prep Flashcards
Nicotine can increase blood pressure and heart rate. Given what you know about the autonomic nervous system and the location of receptors within that system, explain how nicotine can accomplish this, being sure to include information on intracellular signalling events. HINT: in one location in the periphery, nAChRs control vesicle mobilisation and therefore you need to remember how vesicles are mobilised
1ST activation of Sympathetic Ganglia
= Activate nAChRs
= Incease Influx of Na+ ions
= depolarization & AP
= Increase in NA alpha 1 and beta 1 Rs
= Activate PLC
= increase IP3 & DAG
= increase Ca2+ from SR
= Increase Ca++
= Constriction of blood vessels
= Increase BP, HR and contraction force
2nd = stimulate nAChRs on Adrenal Glands
- Influx of Na+ - depolarize to threshold = AP
- Open voltage gated Ca2+ channels
- Mobilise ACh vesicles
- Release Adrenalin
- Activate beta-1 receptors in the heart
- Activate adenylate cyclase
= Increase cAMP + PKA - = Increase voltage gated Ca2+ activity
- = Increase Ca2+
- = Increase HR, contraction force
It is well established that the sympathetic nervous system controls sweating and flushing of the skin. However, acetylcholinesterase inhibitors can increase the amount of sweat that is produced. In light of what you know about the autonomic nervous system, explain how this is possible.
= AchE inhibitors = reduced ACh breakdown
= Increased ACh
= Increased SNS
= SNS uses ACh as the NT at the skin, sweat glands and superficial skin
= Increasesd ACh = increase sweating and flushing
= Increases goosebumps
Even if Ach is predominantly associated with PNS **
Organophosphate pesticides are acetylcholinesterase inhibitors. Explain the type of symptoms you would expect from organophosphate pesticide poisoning in a person and the extent to which a muscarinic acetylcholine receptor antagonist would work as an antidote. Using resources available on the web, is there anything else that can be used as an antidote? If so, what is the name of this drug and what is its role in the management of organophosphate pesticide poisoning.
Blocking AChE = Increases ACh
= Significantly Increased PNS
= Shallow breathing,
= Slowed HR
= hypotension, unconsciousness,
= Skin: flushing, heavy sweating
= Increased saliva,
= diarrhoea, incontinence, blurry vision (constricted pupils)
= Muscle twitching
= Tear production
Drug to counteract = atropine
= mAChR antagonist (competitive)
= competitive binding on mAChRs
= Reduced ACh binding
= Reduces PNS overstimulation
You have found a drug that binds to the receptors on the pre-synaptic cell that act as the “eyes” of the synapse (i.e. the autoreceptors). If this drug is able to increase the amount of neurotransmitter released, what must its action be at this receptor? Explain your answer.
- Alpha-2 receptors upon activation, INHIBIT NT release
- = negative feedback mechanism
- Needs to be an antagonist of autoreceptors to INCREASE NT release
Cocaine blocks the neuronal noradrenaline transporter (NET, also known as uptake 1) in the adrenergic synapse. What is the effect on the activity of the noradrenergic synapse in the presence of cocaine? NOTE: please focus on the synapse, not a particular target tissue.
- NET = acts like VACCUUM removing NA
= Cocaine blocks NET (noradrenaline transporter)
= Decreased re-uptake of NA
= NA synaptic cleft accumulation
= Prolonged NA availability
= Increased HR
= Increased SNS
Monoamine oxidase inhibitors are used to treat depression. If you block this enzyme, what happens to signalling at the adrenergic synapse? NOTE: please focus on the synapse, not a particular target tissue.
MOAs = breakdown of NT to metabolites
- MOA inhibitors = Increased MOI
- = decrease breakdown of serotonin, dopamine and NA
- = Increased NT in presynaptic neuron
- = Increased vesicle storage
- = Increase NT availability
- = Increased NT release into synaptic cleft
- = Prolonged NT availability in synaptic cleft
You are involved with a team trying to manage a patient who has been administered a drug that blocks beta-2 adrenergic receptors. Explain the effect of these drugs directly on blood vessels. Speculate on the effect on overall blood pressure if these drugs only acted directly on blood vessels.
- Beta-2 receptor on BV usually = vasodilation
- Blocking Beta-2 receptor = vasoconstriction
- = Increased vascular resistance
- = Increase BP
A young man decides to end his life when his relationship breaks up. He purchases a number of bottles of eye drops containing pilocarpine, a muscarinic agonist normally used to treat glaucoma, and drinks the contents in rapid succession. His friends find him shortly thereafter and take him to the Emergency Department of the local hospital. Provide an overview of the symptoms that he will be experiencing upon arrival at the hospital and explain why they occur.
- Knew muscarinic receptors would slow HR
- To lower HR enough for death
mAChRs activation = Increase PNS
= Decrease HR, contraction force and CO
= Vasodilation
= Increase GI = Increase diarrhoea
= Increased glandular secretions = increased tears, sweating, salivation, flushing
= Increased dizziness
= Hypotension
= Blurred vision (decreased intraocular pressure)
Explanation of Symptoms:
mAChRs = Increase PNS
Pilocarpine = muscarinic agonist, or parasympathomimetic
= Increase mAChRs activity
Overstimulation PNS, leading to what’s sometimes termed a “SLUDGE” syndrome (Salivation, Lacrimation, Urination, Diarrhea, Gastrointestinal cramps, Emesis).
Catechol-O-methyltransferase (COMT) is a metabolic enzyme used by adrenergic neurons. Mutations of these enzymes have been identified in a small subset of people with schizophrenia. You work for a large research lab that is trying to develop COMT inhibitors. Describe the role of this enzyme in adrenergic neurons and the impact on adrenergic signalling if this enzyme were inhibited.
Catechol-O-methyltransferase (COMT) – back up enzyme to destroy NA, serotonin and dopamine
= transfers methyl group to catecholamines
= Primary deactivation and breakdown of NA, 5-HT and DA
COMT inhibition
= Increase catecholamines
= Increased serotonin, NA, DA
= Increase NT availability
= Increased cognition
= Prolonged availability for neurotransmission
Potential side effects:
= Adrenergic R overstimulation
= Increased SNS
= Increased HR, BP
Mutations = changed availability of NTs
Inhibit COMT = increases NA
Clonidine is used in the management of hypertension. Given that it is an agonist and that receptors are associated with vasoconstriction, explain how this drug could reduce blood pressure.
Alpha-2 receptors = autoreceptors = turn off NA release
= Decrease neuronal excitation
Alpha-2 = Auto receptor for the adrenergic system
- Presynaptic Location: α2 autoreceptors
- Inhibition of Release: When activated by NA, α2 auto-receptors inhibit release of NA.
- = negative feedback mechanism,
- = limits NA released into synaptic cleft.
Identify ONE (1) condition or disease or disorder the alpha-1 agonist drug is used to treat AND 1 key side effect.
Nasal congestion
side effect: Hypertension
(A1 = VASOCONSTRICTION)
Identify ONE (1) condition or disease or disorder the alpha-2 agonist drug is used to treat AND 1 key side effect.
Hypertension
side effect: Dry mouth
(A2 = INHIBITS NA
= INCREASED PNS )
Identify ONE (1) condition or disease or disorder the Betea-1 agonist drug is used to treat AND 1 key side effect.
Heart failure (to increase CO)
Side effect: Tachycardia
(beta 1 = increase HR, Increase force of contraction)
Identify ONE (1) condition or disease or disorder the beta-2 agonist drug is used to treat AND 1 key side effect.
Asthma to increase bronchodilation
Side effect: Muscle tremors
Think: beta-2 = 2 lungs = increase SNS = want more air
= bronchodilation
Identify ONE (1) condition or disease or disorder the muscarinic agonist drug is used to treat AND 1 key side effect.
- Glaucoma (to reduce intraocular pressure)
Diarrhoea
(muscarinic = increased PNS)
what is a Nicotinic ACh receptor antagonist drug that increases HR?
Curare
What is a Non-specific adrenergic antagonist drug to Reduce HR?
Propranolol
Would an Acetyl-Cholinesterase inhibitor increase or decrease HR?
Decrease HR
Would an Alpha & beta agonist increase or decrease HR?
Increase HR
Would a Muscarinic agonist increase or decrease HR?
Reduce HR
Would a Muscarinic antagonist increase or decrease HR?
Increase HR
Is dilation of skeletal muscle blood vessels activation of cholinergic or adrenergic signalling?
Adrenergic
= increase SNS
promotion ejaculation of cholinergic or adrenergic signalling?
Adrenergic
= increase SNS
promote amylase secretion NOT saliva cholinergic or adrenergic signalling?
Adrenergic = dry mouth
SNS – provides amylase
PNS – provides saliva
contract radial muscle and dilate pupil is it cholinergic or adrenergic signalling?
Adrenergic
= Increase SNS
relax non-pregnant uterus is it cholinergic or adrenergic signalling?
Adrenergic – beta 2 receptors
- Changes over menstrual cycle
- Different receptors at different times
increase sweating is it cholinergic or adrenergic signalling?
Cholinergic
- Controlled by SNS but is CHOLINERGIC
- Skin = always cholinergic (less priority = mAChRs)
reduce vaginal muscle contraction is it cholinergic or adrenergic signalling?
Cholinergic
= Increase PNS
= Increase relaxation
dilate GI sphincters is it cholinergic or adrenergic signalling?
Cholinergic
= Increase PNS
= Increase GI secretions and GIT
You are provided with a list of drug groups used in therapeutic management. For each of the conditions mentioned below, identify ONE (1) drug group from the list that is used routinely to treat that condition. Please note that the drug groups might be used once, more than once or not at all.
(4 marks)
a. beta-1 agonist
b. alpha-1 agonist
c. beta-2 agonist
d. alpha-2 agonist
e. Beta antagonist
f. Alpha antagonist
g. mAChR agonist
h. mAChR antagonist
i. nAChR agonist
j. nAChR antagonist
CONDITIONS:
i. asthma
ii. hypertension
iii. hypotension
iv. glaucoma
v. nasal congestion
vi. urinary retention
vii. emesis
viii. incontinence
i. asthma ____beta 2 agonist _
as Beta 2 is primary over mAChR antagonist (MORE Beta 2 receptors in lungs)
ii. hypertension ____beta antagonist
iii. hypotension ___beta1 agonist
(always about vasoconstriction) or alpha 1 agonist
iv. glaucoma _____ mAChR agonist
v. nasal congestion ___alpha-1 agonist
- Constricts BV and out competes histamine dilation
vi. urinary retention _____ mAChR agonist
= Increase PNS to relax sphincter to urinate
vii. emesis _____ mAChR antagonist
= Want to stop GI
= Reduce parastalsis
viii. incontinence ______ mAChR antagonist
Nicotine can increase blood pressure and heart rate. Keeping in mind what you know about the autonomic nervous system and the location of receptors within that system, explain how nicotine can accomplish this, being sure to include basic information about how this happens. NOTE: you are not required to write out all the steps of the mechanism; this is about an overview of what is happening.
SNS = increased HR and BP
nAChRs = pre-ganglionic for both PNS and SNS
Post-ganglionic NA are predominantly SNS
= NA activates beta 1 receptors in the heart
= NA activates alpha 1 receptors in the heart
= Beta-1 adrenergic receptors in heart
= Increased contraction force, increased vasoconstriction
= increased BP
= NA activates alpha-1 receptors and increases adrenalin synthesis from adrenal medulla
= Increased adrenalin
Beta-1 Receptors in kidneys
= Increase renin
= Increased baroreceptor feedback
= Increased angiotensin I and angiotensin II
= Angiotensin II = major vasoconstrictor
= Increased aldosterone
= Increase Na+ and H20 retention
= Increased Blood volume
= Increased BP
Beta-1 Receptors on Adrenal medulla
= Increased adrenalin
= adrenalin targets beta-1 receptors on heart
= Increased cortisol
= increase HR, increased force of contraction and BP
Adrenalin also targets alpha-1 receptors on blood vessels
Alpha-1 adrenergic Receptors on blood vessels
= Primary role: vasoconstriction
You have received a grant from Mongo Pharma to investigate potential new treatments for Alzheimer’s disease, with a focus on the acetylcholine neurons that are degenerating in this condition. The current treatment is acetylcholinesterase inhibitors, and the company does not want to target acetylcholine receptors.
Choose FOUR (4) other protein targets at the cholinergic synapse that could be used in drug discovery and development, and provide the following information for each target:
- identify whether the drug would activate or inhibit the target;
- explain how this action would improve cholinergic signalling; and
- identify what, if any, effect each proposed drug would be expected to have on non-cholinergic synapses.
GOAL: INCREASE ACh
- Increase NT synthesis
Action = Activate target
= Increase CAT (choline acetyltransferase) enzyme activity
= Increase ACh production
= Increased conversion of choline and Acetyl-CoA to ACh
= Increase NT availability in cytosol
Non-cholinergic: Minimal = CAT specific to ACh
- Increase ACh packaging
Action: Activate
= Increase Vesicular ACh Transporter (VAChT)
= Increased ACh packaging
= Increased ACh availability
= Increased ACh available for release upon AP
Non-cholinergic: minimal effect = specific to ACh synapses
- Increase choline re-uptake
= Activate choline uptake transporter (CHT)
= Increase re-uptake of choline
= Increased choline precursor for ACh
= Increased ACh synthesis
Non-cholinergic: minimal effect = specific to ACh synapses
- Inhibit ACh MUSCARINIC ACH receptors
Action: Inhibition
(Autoreceptors when activated = decrease of ACh)
= Inhibit presynaptic ACh auto-receptor negative feedback
= Reduce negative feedback signalling
= Increase ACh release
= Increased ACh release into synaptic cleft
= Increase AP
NOT: Acetylcholinesterase’s and NOT nAChRs
DRUG EXPECTATION ON NON-CHOLINERGIC SYNAPSES:
* INCREASED ACh = skin, sweat glands and BV of skin would be DILATED
* = Increase sweating, piloerection, BV dilation to release heat
