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.
What are the subtypes of muscarinic receptor?
M1 - Neural
M2 - Cardiac
M3 - Exocrine and smooth muscle
(And M4 - periphery and M5 - striatal dopamine release but we dont need to know them.)
What are the subtypes of adrenoceptors, and where are these found?
Adrenoceptors are typically found at the end of sympathetic pathways.
alpha1 - vasculature
alpha2 - inhibition of presynaptic release of NA
beta1 - heart
beta2 - lungs, kidneys, vasculature
THESE ARE ALL G-PROTEIN COUPLED!!!
Which branch of the ANS regulates the vasculature?
The sympathetic nervous system by itself, as adrenoceptors cover both functions:
alpha1 - constricts
beta2 - dilates
What are the four types of drug antagonism?
Receptor blockade - antagonist binding to receptor and preventing it from binding to agonist
Physiological antagonism - drugs that act on different receptors in the same tissue but have the OPPOSITE effect. E.g. histamine (beta2) to counteract NA-mediated vasodilation.
Chemical antagonism - interactions between drugs in solution
Pharmacokinetic antagonism - A drug may reduce the absorption, increase the metabolism or increase the
excretion of another drug. Essentially a drug that reduces the concentration of another drug. E.g. being on barbiturates increases your concentration of microsomal enzymes, so if we administer another drug that is also metabolised by these microsomal enzymes it will be metabolised more quickly.
Explain use dependency in terms of ion channel receptor blockade.
An antagonist for an ion channel receptor depends on the ion channel being open, so that the antagonist has access to the inside of the channel and can block it.
Therefore, the more a receptor is being used, the more effective the antagonist is. This is the case with local anaesthesia as nociceptors fire far more rapidly than an average neurone.
List the causes of drug tolerance.
Pharmacokinetic factors - metabolism of a drug is increased (barbiturates and alcohol are good examples)
Loss of receptors - receptor downregulation is caused by overstimulation of receptor, which leads to cell endocytosing some of the receptors on the surface
Change in receptors - doesn’t involve a change in number of receptors, rather the receptors undergo a conformational change overtime and are no longer effective
Exhaustion of mediator stores - happens with amphetamines, NA is depleted and the response to a second dose will not be as much as to the first
Physiological adaptation - body undergoes homeostatic response
What are the four types of drug receptor?
Type 1 - Ionotropic
- very very fast
- e.g. nicotinic cholinoceptors and GABA receptors
- over the course of milliseconds
- 4 or 5 subunits. Has transmembrane domain (alpha helix)
Type 2 - G-protein linked receptors / Metabotropic
- has to link to a G protein, meaning they are MUCH slower
- e.g. ß1 on heart
- over the course of seconds
- 7 transmembrane domains (alpha helices)
Type 3 - Tyrosine-Kinase linked receptors
- they result in phosphorylation of intracellular proteins
- e.g. insulin receptors and Growth Factor receptors
- over the course of minutes
- 1 transmembrane domain
Type 4 - Intracellular Steroid type receptors
- stimulated by steroids or thyroid hormones
- regulates DNA transcription
- over the course of hours
- found in nucleus, there is both a binding domain and a DNA binding domain. DNA binding domain is called “zinc fingers”
What are the two divisions of pharmacology?
Pharmacokinetics - the effect of the body on the drug (e.g. absorption,
distribution, metabolism, excretion)
• Pharmacodynamics - the effect of the drug on the body (responses produced,
mechanism of action)
What are the 4 target sites of drugs?
All of the following are proteins:
Receptors - NTs and hormones bind to them. respond to agonists and antagonists
Ion channels - either voltage-sensitive or receptor-linked. Binds inside ion channel to block.
Transport systems - these are proteins that transport molecules against their concentration gradient. TCAs target the Uptake 1 proteins that sit on the presynaptic cleft, therefore increasing synaptic concentration of NA
Enzymes - can be a drug target in a few different ways: be an inhibitor e.g. anticholinesterases like neostigmine, be a false substrate e.g. antihypertensives like methyldopa or be a prodrug (the target of a prodrug is the enzyme that turns it into the final drug) e.g. chloral hydrate -> trichloroethanol for insomnia
What happens in terms of drug metabolism and paracetamol overdose?
If you saturate the liver’s microsomal enzymes (usual site of metabolism of paracetamol) with paracetamol, then another set of enzymes (P450) has to start breaking down paracetamol instead, resulting in toxic metabolites. These toxic metabolites act on the liver itself and the kidneys.
Name some exceptions to the 4-targets of drug action rule.
General anaesthesia - don’t interact directly with any receptor or transport system, but dampen synaptic transmission
Antacids - neutralise gastric acid
Osmotic purgatives - stimulate voiding of gut contents by drawing water into gut lumen
Explain what a competitive antagonist is and what it does to the dose-response curve.
It binds to the same site as the agonist, and therefore the response is SURMOUNTABLE with a higher concentration of agonist. It shifts the dose-response curve to the right.
Examples: atropine (competitive nicotinic cholinoceptor antagonist) and propanolol (competitive beta blocker)
List the major routes by which drugs may be administered and their
advantages and disadvantages.
Either systemic or local (part of the body only).
Can also be classified as either enteral or parenteral (enteral is anything into the GI tract, parenteral is anything that isn’t the GI tract)
IV - rapid systemic exposure but requires training
Intraperitoneal - not really used in humans, rodents mostly
Ingestion
Inhalation
Intramuscular
Subcutaenous
Dermal
Be able to describe the factors that effect the passage of drugs across
membranes.
Drugs have to traverse both LIPID and AQUEOUS environments • So if the drug is a lipid molecule, then the aqueous environment is a barrier and vice versa
Compartments are aqueous e.g. blood, lymph, ECF
• Barriers are lipid e.g. cell membranes
• Methods of crossing these barriers:
o Diffusing through lipid (if they are of suitable nature)
o Diffusing through aqueous pores in the lipid (if they are polar)
o Carrier molecules
o Pinocytosis - the cell engulfs the molecule and takes it in
• REMEMBER: non-polar substances can freely dissolve in non-polar solvents i.e.
can penetrate lipid membranes easily
IMPORTANT: most drugs are either WEAK ACIDS or WEAK BASES
• Therefore, drugs exist in ionised (polar) or non-ionised (non-polar) forms
• The drug will be in dynamic equilibrium with the ionised and unionised form
• The ratio of ionised to non-ionised depends on the pH of the environment and
the pKa of the molecules
Be able to describe the factors that determine drug distribution.
Factors influencing drug distribution:
o Regional blood flow (well perfused tissues will be exposed to a higher concentration of drug. there might be factors affecting perfusion - like activity in skeletal muscle)
o Extracellular binding (plasma protein binding) - if plasma protein bound then drug is no longer available for absorption. albumin can bind both ionised and unionised forms of drugs
o Capillary permeability - fenestrated, continuous or discontinuous
o Localisation in tissues - e.g. fat isn’t well perfused and is therefore a highly lipophilic environment, lipophilic molecules tend to localise there, fatty tissue e.g. brain, testes
What’s the journey of a drug through the body? (there’s a mnemonic for this)
ADME Absorption Distribution Metabolism Excretion
What’s the pH partition hypothesis?
Let’s take the example of aspirin:
Aspirin is a weak base and has a pKa of 3.4
The stomach has a pH of 1
Stomach pH < Aspirin pKa
this forces aspirin to be non-ionised in stomach, so can readily diffuse across border
As aspirin enters small intestine, which is much more basic, it will become ionised. This means there is a much slower absorption of aspirin in the small intestine than in the stomach.
Once aspirin is absorbed it goes through the portal system and into the blood and is now in an aqueous environment -> ionised form. It is therefore essentially trapped.
• Be able to describe the principle routes of drug metabolism and excretion
Two main routes of excretion - liver or kidneys
- many drugs excreted by kidneys as they are converted into a water-soluble form. this is mainly through active secretion in the PCT rather than ultrafiltration as drugs are often too big to be ultrafiltrated. Lipid-soluble drugs might be reabsorbed in the DCT or CD.
- liver deals differently - drugs concentrated in bile and secreted into intestines, mostly large molecular weight drugs and lipophilic drugs.
Why might treatment with I.V. sodium bicarbonate increase aspirin excretion?
I.V. Sodium Bicarbonate increases urine pH
o Increase in urine pH ionises the aspirin
o This makes it less lipid soluble
o Less aspirin is reabsorbed in the proximal and distal tubules
o Increase in the rate of excretion of aspirin
Remember aspirin has pKa of 3.5. At pH <3.5 it is unionised.
What is meant by drug persistence?
That a drug can stay in the system for longer due to enterohepatic recycling. It is excreted in bile into the intestines but then reabsorbed into the portal vein.
What is the definition of bioavailability?
Proportion of the administered drug that is available within the body to
exert its pharmacological effect
Explain what first order kinetics are.
the rate of elimination of a drug where the amount of drug
decreases at a rate that is proportional to the concentration of drug remaining
in the body
Most drugs on the market follow first order kinetics.
Graph: x axis is half life and y axis log of drug concentration
How is volume of distribution for a drug calculated?
Dose / initial concentration of blood in plasma (C0)
However, you can never really determine the initial concentration of the drug in the
plasma because instantaneously the drug will start being removed from the
body. So you extrapolate the line backwards to see where it crosses the y axis
Explain what zero order kinetics are.
- a constant amount of drug is
removed per unit time
Alcohol follows zero-order kinetics
because you eliminate alcohol at a constant rate
With zero-order kinetics it is basically saying that something is going on that is
saturating the system (usually an enzyme e.g. alcohol dehydrogenase)
Graph: x axis is time and y axis is drug concentration
Why do we need drug metabolism?
Because most drugs are lipophilic and therefore cannot easily be excreted in urine.
Metabolism also tends to reduce pharmacological and toxicological activity of the drug
What is referred to by Hepatic First Pass metabolism?
A drug tends to be converted into something different before it even enters systemic circulation, as it has to pass through the liver first.
First pass metabolism can be pre-hepatic - intestines, stomach, oesophagus
and buccal cavity have a small amount of metabolism capacity
• If a drug undergoes extensive first pass metabolism giving it a low
bioavailability then an option is to give it intravenously (but this is invasive)
What are the types of Phase I reactions?
Oxidation, reduction and hydrolysis.
Phase I is all about releasing/exposing functional groups.
Oxidation/reduction creates new functional groups
Hydrolysis exposes existing functional groups.
These functional groups will serve as a point of attachment for Phase II drugs.
Phase I reactions often inactivate drugs, but sometimes they activate drugs such as prodrugs.
You introduce a functional group but if the drug was lipophilic when it started
then it’ll still be pretty lipophilic
What are the types of Phase II reactions?
Glucuronidation, acetylation, amino acid conjugation, sulphation, methylation, glutathione conjugation
What’s cytochrome P450?
An enzyme system in the liver, consisting of 57 enzymes.
This system has the capacity to metabolise loads of different xenobiotics. It is also involved in the metabolism of endogenous molecules like steroids and oestrogens.
Outline the oxidation of a drug by CYP450.
CYP450 works in a cyclic manner.
Drug binds to active site on CYP450. All CYP450 enzymes have a porphyrin ring and a ferric iron (Fe3+) in the middle of the active/catalytic site. Drug binds to this iron, and then electron is transferred FROM NADPH.
Electron taken up by CYP450 complex, transferred to iron which becomes ferrous (3+ -> 2+)
Then molecular oxygen binds and CYP450 complex now has oxygen and Fe2+ bound to it (and drug bound to Fe2+)
Fe2+ loses an electron TO THE OXYGEN. Nothing happens to drug, but oxygen becomes unstable.
Then NADPH donates a SECOND electron, reduces Fe3+ -> Fe2+ again. Then Fe2+ donates electron to oxygen WHICH NOW BECOMES VERY UNSTABLE. Drug still unchanged.
Then we get a conversion of the drug to its hydroxylated derivative and we get a conversion of the remaining oxygen to water, by adding two protons.
The drug is released and the CYP450 has iron in its ferric state again, ready to undergo next reaction.
Oxidation reactions involves a hydroxylation step catalysed by P450.
Give examples of oxidative (Phase I) reactions involving aliphatic and aromatic compounds.
Aliphatic: Pentobarbitone -> oxygen added to a carbon in the chain, makes it no longer pharmacologically active.
Aromatic: Acetanilide -> oxygen attacks carbon in aromatic ring, -> paracetamol
This is an example of a prodrug being turned into the active compound
Give examples of oxidative (Phase I) reactions involving N-demethylation and O-demethylation.
Many drugs have amine function (80-90%), so this is a very effective way of removing pharmacological activity.
N-demethylation is the oxidation of a methyl group that is in a nitrous environment (bound to N). In imipramine there’s a tertiary nitrogen, one of the methyl groups gets oxidised and leaves as formaldehyde.
O-demethylation: similar to n-demethylation, but instead is done by P450, on a methyl group attached to an oxygen atom. For example, with codeine; This converts oxygen to the hydroxyl group and we release formaldehyde and generate morphine (from codeine)
Give examples of oxidative (Phase I) reactions involving N-oxidation and alcohol oxidation.
N-oxidation is oxidation of nitrogen itself. It involves an oxygen atom being added to a tertiary amine.
The two lone electrons on a nitrogen, after binding to three methyl groups, can sometimes be donated to another atom, usually oxygen, to form a dative bond.
This is not done by P450, it is done by Flavin
containing monooxygenase.
What is flavin containing monooxygenase deficiency?
Flavin containing monooxygenase is needed to oxidise certain compounds containing teriary amines.
Humans generate trimethylamine in their GI tract (product of protein metabolism)
o Trimethylamine smells terrible
o In the liver, flavin containing monooxygenase converts trimethylamine
into trimethylamine N-oxide which is odourless and polar so it can be
readily excreted in the urine
o A small subset of the population has defective flavin containing
monooxygenase so they produce trimethylamine but they can’t metabolise and excrete it so they sweat and breathe it out
o This is also called fish odour syndrome
Where in the cell are both flavin containing monooxygenase and P450 found?
Endoplasmic reticulum.
Outline a Phase I reduction reaction.
Reduction reactions are far less common than oxidation reactions. However, the GI tract is a low oxygen environment so reduction can work effectively.
Most reductases are bacterial enzymes in the gut.
Prontosil is split into two amines
Outline a Phase I hydrolysis reaction.
Procainamide is a local anaesthetic and it is metabolised around the amine
function to generate a carboxylic acid and an amine
• This is catalysed by hydrolysis enzymes:
o Esterases - hydrolysis of an ester
o Amidase - hydrolysis of an amide
What is a conjugating agent?
A large, polar, endogenous chemical needed for Phase II reactions. They target specific functional groups.
Outline glucuronidation
- Most common Phase II reaction
- Addition of sugar to foreign compound
- E.g. ibuprofen is glucuronidated
- By glucuronyl transferase. UDP-glucuronic acid is the conjugating agent.
- Results in large, polar molecule. Because of size often excreted in bile.
ROH + UDPGA -> RO-D-glucuronide
Outline acetylation
- By acetyl transferase. Conjugating agent is Acetyl CoA
- Acetyl CoA acts as donor compound
- Acetyl group transferred to electron rich atom (N, O or S)
RNH2 + CH3COSCoA -> RNHCOCH3 CoASH
Outline methylation
- By methyl transferase. Cojugating agent is S-adenosyl methionine.
- Methylation DECREASES polarity
- E.g. noradrenaline: methyl group attached to S on s-adenosyl methionine is transferred onto noradrenaline to form adrenaline
RZH + S-adenosyl methionine -> RZ-CH3 + S-adenosyl-homocysteine
where Z = N, S or O
Outline sulphation
- By sulphotransferases. Conjugating agent is 3’phosphoadenosine-5’phosphosulfate (PAPS)
- The xenobiotic gets sulfated to produce the sulfuric acid derivative of the molecule
• This derivative is very polar and water soluble
ROH + PAPS -> ROS O3- + PAP
Outline glutathione conjugation
- By glutathione transferase
- Glutathione conjugation is one of the most important processes toxicologically
• Glutathione reacts with electrophiles - these are damaging species that are often generated during metabolism. These can damage DNA and proteins. - The body has a lot of glutathione. Glutathione is a tripeptide: glycine + glutamine + cysteine
- The important part is the cysteine, which has the thiol group which is the one that reacts
R-X + GSH -> R-SG + XH
X in this case can be e.g. Cl
What other word can be used to describe cholinomimetic drugs?
Parasympathomimetic drugs, as the parasympathetic nervous system is fully cholinergic.
What type of receptors are M1, M2, M3, M4 and M5 receptors?
All are muscarinic.
M1, M3 and M5 are Gq protein linked receptors, they stimulate PLC to increase production of IP3 and DAG. These are all excitatory.
M2 and M4 are Gi protein linked receptors. They reduce the production of cAMP. M2 receptors (heart) are inhibitory.
What are the two main locations for nicotinic receptor and of what subunits do they consist?
Muscle = 2 alpha + beta + delta + epsilon
• Ganglion = 2 alpha + 3 beta
Outline the muscarinic effects on the eye.
There’s three:
- Contraction of ciliary muscle - for near vision
- Contraction of sphincter pupillae (circular muscle of the iris). This increases drainage of intraocular fluid (and constricts pupil).
- Lacrimation (tears)
Outline the flow of aqueous humour
Aqueous humour is produced by the ciliary bodies behind the lens. It then travels to the anterior chamber of the eye, supplying nutrients and oxygen to the lens and cornea (which don’t have a blood supply).
It diffuses across lens, and then drains at the canals of Schlemm on both sides of the lens. It then returns to the venous system.
How could a muscarinic agent help someone with Angle-Closure glaucoma?
In angle-closure glaucoma, the angle between the iris and the cornea becomes reduced/narrowed. This reduces the flow of aqueous humour through the canals of Schlemm.
A muscarinic agent causes contraction of the iris, and an opening up of the angle between the iris and the cornea, allowing for drainage of intraocular fluid.
