Pharma Flashcards
Identify the consequences of cholinoceptor blockade and list the main clinical uses and unwanted effects of muscarinic cholinoceptor antagonists
Clinical use: to treat hypertension
Unwanted effects: dilate pupils, constipation as gut motility is reduced, issues with emptying bladder, difficulty producing saliva.
Current use is to control blood flow during surgery.
Atropine poisoning: identify the signs and symptoms of atropine poisoning and explain how it may be treated
Signs: CNS agitation, restlessness, dry mouth, increased heartrate
Treat with anti-cholinesterase which will prevent Ach from breaking down in synapse, and Ach will build up and out-compete the atropine.
Why are nicotinic receptor agonists called ganglion blocking drugs?
Because nicotinic cholinergic receptors are present at all ganglia - both in sympathetic and parasympathetic nervous system.
What are two examples of nicotinic cholinoceptor antagonists?
Hexamethonium and trimetaphan.
What do we mean by use-dependent block?
There are two types of antagonists; true antagonists and ion channel blockers. In terms of our nicotinic cholinoceptor antagonists, trimetaphan is an ion channel blocker. This means the more open the channel is, the easier it is for the drug to enter the channel and block it. This means the more agonist is present, the more effective trimetaphan is = use-dependent block.
With hexamethonium and other true antagonists, the opposite is true; the more agonist is present the more competition there is and the less effective the antagonist is.
If a general nicotinic cholinoceptor antagonist affects both parasympathetic and sympathetic nervous system, what would be the observable effects of administering it?
Loss of function of whatever system was dominant at the time of administration.
Why do nicotinic cholinoceptor antagonists such as hexamethonium cause hypotension?
Because blood tends to be diverted away from the gut, when the sympathetic nervous system is suppressed at rest as a result of taking one of these drugs, Total Peripheral Resistance goes down and so does blood pressure. (The blood flow to the gut is under sympathetic control)
Muscarinic receptor antagonists: identify and explain the pharmacokinetic properties of muscarinic receptor antagonists
As muscarinic cholinoceptors are mostly present at parasympathetic end-organs, they are for blocking parasympathetic function.
Atropine and hyoscine: atropine no therapeutic effects at low dose but toxic at high dose, hyoscine therapeutic (sedative, probably due to higher M1 selectiveness) at low dose and toxic at high.
What is tropicamide and what is its clinical use?
It’s a muscarinic cholinoceptor antagonist that blocks parasympathetic constriction of the eye and therefore allows for observation of the back of the eye.
Identify and explain the clinical uses of muscarinic receptor antagonists
Clinical use: anaesthetic premedication: dilates airways before administration of anaesthetic.
Hyoscine patches are used for motion sickness. (Cholinergic nerve relays vision-balance mismatch to the vomiting centre)
Parkinson’s as M4 targeting antagonists because M4 receptors inhibit the little few
remaining D1 neurones in the basal ganglia, so this helps to alleviate some of the symptoms.
Asthma; rather than using salbutamol as an agonist for adrenoceptors, you can use an antagonist for muscarinic cholinoceptors.
Explain the unwanted side effects of muscarinic cholinoceptor antagonists.
Hot as hell – no sweating
Dry as bone – no secretions
Mad as a hatter – CNS disturbance
Blind as a bat – Cycloplegia (paralysis of ciliary muscle of eye therefore lack of
accommodation)
Poisoning – treat with anticholinesterases
Which receptors are adrenaline and noradrenaline selective for?
Noradrenaline is more alpha selective and adrenaline is more beta selective. However, they can both act on both receptors, they are just slightly more selective for one or the other.
Explain the clinical uses of selective and non-selective alpha and beta adrenoceptor agonists.
In epipens for anaphylactic shock. (Binds to beta2 and causes bronchodilation, beta1 and causes tachycardia and alpha1 for vasoconstriction.)
Also, for asthma and other types of bronchospasm (beta2).
Cardiogenic shock - sudden inability for heart to pump ¨ sufficient oxygen-rich blood.
For maintaining blood pressure during general anaesthesia, or keeping local anaesthesia local by restricting surrounding vessels.
Treating glaucoma (alpha2 agonist or alpha 1 agonist , as alpha2 is negative feedback receptor and alpha1 is vasoconstrictor for blood supply to ciliary bodies).
Explain the unwanted side effects of selective and non-selective alpha and beta adrenoceptor agonists.
Reduced and thickened secretions.
Not a lot of CNS effects.
Cardiovascular effects - may worsen or give arrhythmias.
What is the unusual property of an alpha2 adrenoceptor agonist?
As the alpha2 sits on the presynaptic membrane and acts as a negative feedback control, NA or an agonist binding here has a suppressive effect.
What are the examples of selective SNS agonists for alpha1, alpha2, beta1 and beta2 receptors?
alpha1: phenylephrine
alpha2: clonidine
beta1: dobutamine
beta2: salbutamol
Why might phenylephrine be used as a decongestant?
(Recap: phenylephrine is an alpha1 selective agonist)
Main effect of phenylephrine is vasoconstriction.
This will cause white blood cell build-up to leave nasal sinus
What is glaucoma?
Raised intraocular pressure due to poor drainage of aqueous humour.
Where is the aqueous humour produced?
In the ciliary bodies
How is clonidine used to treat migraines and headaches?
As it is mostly alpha2 selective (negative feedback receptor on presynaptic membrane) and inhibits NA release.
Also a bit alpha1 selective so will vasoconstrict (and migraine associated with vasodilation). Although the vasoconstriction does not occur in the brain, vasoconstriction in the brain is mostly b2 controlled rather than alpha1.
What is the possible complication related to using isoprenaline for cardiovascular problems such as heart failure or cardiogenic shock? And how is this overcome clinically?
Although isoprenaline is beta1 selective and will have an effect on the heart (increase cardiac output), it is equally selective for beta2 which in turn causes vasodilation and hypotension.
So, instead we use dobutamine which is far more beta1 selective.
What is the main pharmacological difference between adrenaline and salbutamol?
Salbutamol is more resistant to MAO, and therefore has a longer half-life.
What is the equation for a drug getting oxidised by Cytochrome P450?
RH + NADPH + O2 + H+ ——–> ROH + NADP+ + H2O
Î___ Cytochrome P450
Outline the Phase 1 reactions that can occur.
A hydroxyl group can be added (oxidation): paracetamol is activated by having a OH group added to the aromatic ring itself.
Methyl group removed (oxidation): codeine (prodrug) is activated into morphine by having methyl group removed.
Nitrogen can become oxidised: second carbon in ethanol has oxygen added to it to become acetylaldehyde.
Reduction and hydrolysis are far less common than oxidation. They both break the molecule in two.
Name the conjugating agents and the target functional groups for the following phase 2 reactions: Glucuronidation Acetylation Methylation Sulphation Glutathione conjugation
Glucuronidation: UDP-glucuronic acid, OH, COOH, NH2, SH
Acetylation: Acetyl CoA, OH, NH2
Methylation: S-adenosyl-methionine, OH, NH2
Sulphation: 3’-phosphoadenosine-5’-phosphosulphate, OH, NH2
Glutathione conjugation: glutathiones, electrophiles
Adrenoceptor antagonists: List the clinical uses, principal pharmacological features, mechanism of action and unwanted effects of selective and non-selective α and β adrenoceptor antagonists and compare the pharmacology of selective and non-selective adrenoceptor antagonists.
a1 – Vasoconstriction, relaxation of GIT.
a2 – Inhibition of NT release, contraction of VSMC, CNS.
b1 – Cardiac stimulation, relaxation of GIT, renin release.
b2 – Bronchodilation, vasodilation, relaxation of VSMC, hepatic glycogenolysis.
b3 – Lipolysis.
Non-selective (a1 + b1) – Labetalol.
§ a1 + b2 – Phentolamine.
§ a1 – Prazosin.
§ b1 + b2 – Propranolol.
§ b1 – Atenolol.
List the clinical uses of adrenoceptor antagonists
Hypertension - ß1 blockers targetting presynaptic membrane lead to suppressed release of NE
What are the unwanted effects of beta-blockers?
- Bronchoconstriction – of little importance unless the patient has an airway disease.
- Cardiac failure – in patients with heart disease this may be a problem.
- Hypoglycaemia - b-blockers may mask symptoms (tremors etc.) and non-selective b-blockers will also block hepatic glycogenolysis (b2).
- Fatigue – reduced CO.
- Cold extremities – loss of b-receptor mediated vasodilation.
- Bad dreams.
Identify the principal target organs of (a) the sympathetic nervous system and
(b) the parasympathetic nervous system and describe how each responds to
autonomic stimulation.
There is always a balance between the sympathetic and the parasympathetic NS in tissues, however, in some tissues one is predominant
a. Liver is largely sympathetic, arterioles under only sympathetic innervation, sweat glands
b. Eyes and lungs are largely parasympathetic. Heart is largely under parasympathetic innervation at rest, baroreceptor firing activates parasympathetic stimulation and sympathetic inhibition (however: no parasympathetic innervation of arterioles)
Summarise the processes involved in the biosynthesis, release and metabolism
of acetylcholine and identify potential targets for pharmacological
manipulation of cholinergic transmission.
Acetyl CoA + Choline (both from diet) -> Ach + CoA by Choline Acetyl transferase.
Ach packed into vesicles and released as stimulated by action potential.
Ach broken down into Choline and Acetate by Acetylcholinesterase
Summarise the processes involved in the biosynthesis, release and metabolism
of noradrenaline (norepinephrine) and adrenaline (epinephrine) and identify
potential targets for pharmacological manipulation of adrenergic transmission.
Tyrosine -> DOPA by tyrosine hydroxylase.
DOPA -> dopamine by DOPA decarboxylase
dopamine -> noradrenaline by dopamine ß hydroxylase (this takes place inside vesicles)
vesicles of NA released.
Uptake 1: NA taken back up into presynaptic neurone and broken down into its metabolites by MAO (monoamine oxidase)
Uptake 2: NA can be taken up into extraneuronal tissue, and in that case it is broken down into metabolites by Catechol-O-Methyl Transferase (COMT)
Classify the cholinoceptors located in the ANS into two main classes and state
(a) where each type is found and (b) the signalling systems they each employ.
Nicotinic and muscarinic
NICOTINIC - found in ALL autonomic ganglia (SNS and PNS). They are ion-channel-linked receptors (ionotropic). Stimulated by acetylcholine.
MUSCARINIC - found in any tissue innervated by post-ganglionic PARASYMPATHETIC fibres AND ALSO SWEAT GLANDS (sympathetic). They are G-protein-coupled. Stimulated by muscarine, EXCEPT sweat glands stimulated by acetylcholine.
