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Flashcards in Pharmacology And Therapeutics Deck (847):

What two nervous systems make up the autonomic nervous system?



What effect does the autonomic nervous system have on pupillary constriction?

Sympathetic- pupil dilates to increase sensory info
Parasympathetic- pupil constricts


What nervous system controls the cephalic and gastric phases of gastric secretions?

Parasympathetic nervous system


At rest, which nervous system is in control or basal heart rate? How?

Parasympathetic nervous system
Baroreceptors stimulate PNS but also inhibit SNS


What is the structure of neurones in the parasympathetic nervous system?

Long preganglionic fibres and short post ganglionic fibres


What neurotransmitter is used in the parasympathetic nervous system?



What neurotransmitter is used in the sympathetic nervous system?

Noradrenaline (adrenaline) and acetylcholine


Describe the divergence of the sympathetic and parasympathetic nervous system

Sympathetic- coordinated response, very divergent, up to 1:20 pre vs post
Parasympathetic- discrete/ localised, little divergence, 1:1 pre vs post


What neurotransmitter is used in the somatic nervous system?



What receptors are found in the parasympathetic nervous system? Where are they located?

Muscarinic on the synapse and nicotinic on the effector organ


What type of receptor is the nicotinic receptor?

Type 1 ionotropic receptor (Ligand-gated ion channel)


What type of receptor is a muscarinic receptor?

G-protein coupled receptor


What neurotransmitter activates nicotinic receptors?



What neurotransmitter stimulates muscarinic receptors?



If you block nicotinic acetylcholine receptor in an individual at rest what would the effects be?

Parasympathetic nervous system is prevalent so blocks PNS activity resulting in increased heart rate and decreased gut activity


What effect would blockade of nicotinic acetylcholine receptors have on heart rate during exercise?

Sympathetic nervous system is dominant during exercise so when blocked heart rate will decrease


What are the different types of muscarinic receptor and their location?

M1- Neural (forebrain- learning & memory)
M2- Cardiac (brain- inhibitory autoreceptors)
M3- Exocrine & smooth muscle (Hypothalamus- food intake)


What receptor is the fastest? What type of receptor is this?

Nicotinic receptors which are ionotropic (type 1)


Which muscarinic receptors are stimulatory and which receptors are inhibitory?

M1 and M3 are stimulatory
M2 is inhibitory


What are the different types of adrenoceptor?

α1, α2, β1 and β2


Where are muscarinic receptors found?

Found at all effector organs innervated by postganglionic parasympathetic fibres (including sweat glands)


Where are nicotinic receptors found?

Found at all autonomic ganglia


Where are adrenoceptors found?

Found at all effector organs innervated by postganglionic sympathetic fibres


What type of receptor is an adrenoceptor?

A G-protein coupled (type 2) receptor


What neurotransmitter stimulates adrenoceptors?

Adrenaline or noradrenaline


Blockade of which receptor would induce an increased heart rate and a reduction in sweat production during exercise?

Muscarinic receptors


What enzymes facilitates the reuptake of acetylcholine in the parasympathetic nervous system?



What two components are used to produce acetylcholine?

Acetyl CoA + Choline


What is converted to DOPA to produce dopamine?



Blockade of which target would cause the most significant rise in synaptic noradrenaline concentrations?

Uptake 1 transport proteins


What is pharmacokinetics?

The effect of the body on the drug


What is pharmacodynamics?

The effect of the drug on the body


What are the different drug target sites?

1) Receptors
2) Ion channels
3) Transport Systems
4) Enzymes


Give an example of a drug which acts on a receptor?



What effect does atropine have on a receptor and which receptor does it act on?

It is a muscarine antagonist


What are the two type of ion channel which drugs act on?

1) Voltage sensitive ion channels
2) Receptor-linked ion channels


Give two examples of drugs which act on ion channels

1) Local anaesthetics
2) Calcium channel blockers


Give an example of a drug which acts on transport systems

Tricyclic antidepressants (TCAs)


How do tricyclic antidepressants work?

They slow down the transporter which elevates the amount of noradrenaline in the synapse


What are the different mechanisms by which drugs can interact with enzymes? (3)

1) Enzyme inhibitors
2) False substrates
3) Prodrugs


Give an example of an enzyme inhibitor

Anticholinesterases (e.g. neostigmine)


Give an example of a false drug. How does it work?

Methyldopa- an antihypertensive drug
It takes the place of dopa and follows the same pathway producing false product


What is a prodrug?

A drug which needs to be metabolised to produce it's active form, to allow it to work


Give an example of a prodrug

Chloral hydrate which is converted into trichloroethanol


How does plasma protein binding influence the amount of drug in the circulation?

It is not a drug binding site but it allows a free reservoir of the drug in the blood


What does the potency of a drug depend on?

The affinity and the efficacy of the drug


Give an example of a muscarinic and nicotinic antagonist

Muscarinic- Atropine
Nicotinic- Hexamethonium


What is a full agonist drug?

A drug which produces the maximal response from a cell


What is a partial agonist drug?

A drug which can be an agonist and an antagonist at some time


What is the affinity and efficacy of antagonists?

They have affinity but no efficacy


What are the two types of receptor antagonist?

1) Competitive
2) Irreversible


How do competitive antagonists work and what effect do they have on the dose-response curve?

They bind to the same site as agonists. they shift the D-R curve to the right


How do irreversible antagonists work?

They bind tightly or at different sites


A drug acting as an inhibitor at a particular drug target site prevents the removal of neurotransmitter from the synapse. What type of drug target is this drug acting on?

Transport protein


What are the different types of drug antagonism? (4)

1) Receptor blockade
2) Physiological antagonism
3) Chemical antagonism
4) Pharmacokinetic antagonsim


Give an example of physiological antagonism. How does it work?

Different receptors produce opposite effects in the same tissue.
e.g. Noradrenaline and histamine on blood pressure


How does chemical antagonism work? Give an example.

The drug reduces the concentration of an agonist by forming chemical complexes
e.g. Dimercaprol which forms heavy metal complexes (chelating agent)


How does a pharmacokinetic antagonist work? What are some possible actions of the drug? Give an example

An antagonist which decreases the concentration of active drug at the site of action. Can decrease absorption, increase metabolism, increase excretion
e.g. barbiturates


What is drug tolerance? Give an example of a drug which you become tolerant to.

The gradual decrease in responsiveness to a drug with repeated administration (days/weeks)
e.g. diazepam (benzodiazepines) for epilepsy. Stops seizures at low doses


What are the different mechanisms by which you become tolerant of a drug? (5)

1) Pharmacokinetic factors
2) Loss of receptors
3) Change in receptors
4) Exhaustion of mediated stores
5) Physiological adaptation


How do pharmacokinetic factors contribute to drug tolerance? Give an example

Causes increased rate of metabolism of the drug
e.g. barbiturates: alcohol


How does a loss of receptors contribute to drug tolerance? Give an example

Receptors are down-regulated by membrane endocytosis
e.g. β-adrenoceptors


How does a change in receptors contribute to drug tolerance? Give an example

Receptor desensitisation from a conformational change in the receptor
e.g. nicotinic ACh receptor at the neuromuscular junction


Give an example of a drug which leads to tolerance by exhaustion of mediated stores

Enters the brain and is taken up into the presynaptic neurone and increases release of noradrenaline in the brain


How does physiological adaptation cause drug tolerance?

It is homeostatic response where tolerance to the drug side effects occurs, e.g. you lose drowsiness or nausea


What are the four types of receptor families?

1) Ion-channel linked receptors
2) G-protein coupled receptors
3) Kinase-linked type
4) Intracellular steroid type receptors


Which receptor family initiates the fastest response?

Type 1 ion-channel linked receptors


Which receptor family is the most useful for therapeutically useful drugs?

Type 2 G-protein coupled receptors


What type of antagonism is utilised by anti-venom?

Chemical antagonism


Which form of tolerance would not involve any changes in the cells that mediate the euphoric effects of drugs of abuse (heroin and cocaine)?

Increased metabolic degradation


What is the journey of a drug through the body?



What are the different methods of administration of a drug? (4)



What is the most rapid and effective way to administer a drug?



How do drug molecules move around the body?

1) Bulk flow transfer (i.e. in the bloodstream)
2) Diffusional transfer (i.e. molecule by molecule over short distances)


Drugs have to traverse both aqueous and lipid environments in the body. How do they cross these barriers?

1) Diffusing through lipid
2) Diffusing through aqueous pores in the lipid
3) Carrier molecules
4) Pinocytosis


What is the polarity of substances that can freely penetrate lipid membranes?



What is ion-trapping?

Where ions become trapped in the blood due to pH. Ionised and unionised form of the drug is in a dynamic equilibrium which causes slow release of the drug.


What factors influence drug distribution?

1) Regional blood flow
2) Extracellular binding
3) Capillary permeability
4) Localisation in tissues


How does regional blood flow affect the distribution of a drug?

Amount of blood flowing to different tissues varies when at rest compared to during strenuous exercise
e.g. when exercising more blood (and drug) will be delivered to the muscles


How does extracellular binding affect the distribution of a drug?

If a drug is heavily bound to plasma proteins you would have to administer higher doses of the drug to have an effect. Ionised drugs can move through the H₂O filled gap junctions


How does capillary permeability affect the distribution of a drug?

Capillary permeability is dependent upon the organ in question


What are the two main organs involved in excretion of a drug?

Kidneys and Liver


Where are drugs secreted and reabsorbed in the kidneys?

In the proximal tubule acids and bases are actively secreted
In the proximal and distal tubules lipid soluble drugs are reabsorbed


How are drugs excreted through the liver?

Biliary excretion- large molecular weight molecules can concentrate
Active transport systems- into bile (bile acids and glucuronides)
Drugs become trapped in bile and are deposited in the intestines to be excreted in the faeces, or they are reabsorbed into the blood and excreted in the urine


What is enterohepatic cycling?

Drugs (or metabolites) are excreted into the gut (via bile) then reabsorbed and taken to the liver and excreted again (via bile). This leads to drug persistence


What is bioavailability?

The proportion of the administered drug that is available within the body to exert it's pharmacological effect
The amount of drug that appears in the circulation after it has left the liver


What is a biological half-life?

The time taken for the concentration of drug in the blood/plasma to fall to half of it's original value


What is clearance?

The blood clearance is the volume of blood (plasma) cleared of a drug in a unit of time


Which of the following drugs would be least likely to penetrate lipid membranes?
a) Ionised drug
b) Non-ionised drug
c) Protein-bound drug
d) Lipophilic drug
e) Hypophilic drug

a) Ionised drug


What is first-order kinetics?

The rate of elimination of a drug where the amount of drug decreases at a rate that is proportional to the concentration of the drug remaining in the body. It applies to most drugs in clinical use


What is zero-order kinetics?

The rate of elimination of a drug where you get rid of the same amount of drug per unit time. Implies a saturable (usually enzymic) metabolic process which applies to very few drugs. Half life does not apply


What is hepatic first pass metabolism?

The degradation and alteration of a drug by the liver, before it enters the systemic circulation


What are the phase I metabolic changes that are made to a drug? (3)



What are the phase II metabolic changes that are made to a drug? (6)

Amino acid conjugation
Glutathione conjugation


Where is cytochrome P450 found? What is it's role in drug metabolism?

Embedded on the smooth endoplasmic reticulum in the liver. It is an important enzyme in phase I oxidising reactions and it is involved in the metabolism of the majority of drugs


What is the most common cytochrome P450 reaction?



What is the effect of metabolism of pentobarbitone?

Pentobarbitone makes you sleep but the metabolised form is inactive


What is the effect of metabolism of acetanilide?

Acetanilide is a prodrug. It is toxic, but it is metabolised to form paracetamol.


What enzyme is needed to metabolise alcohol?

Alcohol dehydrogenase


What kind of kinetics does alcohol dehydrogenase have?

Zero order kinetics- it is saturable


What does cytochrome P450 use as a cofactor?



What is the purpose of phase I metabolism?

Prepares a drug for phase II metabolism by introducing a functional group such as -OH, -NH₂, -SH or -COOH


What is the most common phase II metabolic reaction?

Glucuronidation reactions


What occurs in a glucuronidation reaction?

A sugar is added to the drug to produce a soluble molecule which can be excreted (often in bile)


What is the second most common phase II metabolic reaction?

Acetylation reactions


What occurs in an acetylation reaction?

Acetyl CoA acts as a donor compound; an acetyl group is transferred to an electron-rich atom (N, O or S)


What occurs in a methylation reaction?

Methyl group is transferred to an electron-rich atom (N, O or S)


What type of reactions are phase II reactions? What functional groups do they utilise?

Conjugation reactions. They utilise -OH, -NH₂, -SH and -COOH


What are cholinomimetics?

Drugs which mimic the action of acetylcholine, mainly in the peripheral nervous system


What enzyme is required to produce acetylcholine?

Choline acetyltransferase


What receptor does acetylcholine induce effects in?

Muscarinic receptors; will also generate a response in nicotinic responses but requires higher doses of acetylcholine


What nerve stimulates M2 receptors?

Vagus nerve


What subunits make up the nicotinic receptor? What do these determine?

α, β, γ, δ and ε
Subunit combination determines the ligand binding properties of the receptor


What are the muscarinic effects of cholinomimetics in the eye?

Contraction of the ciliary muscle: accomodation for near vision
Contraction of the sphincter pupillae: Constricts pupil (miosis) and improves drainage of intraocular fluid via the canals of Schlemm
Lacrimation (tears)


What is the muscarinic effect of cholinomimetics in the heart?

Binds to M2 acetylcholine receptors in atria and nodes of the heart. decreases cAMP:
1) Decreased Ca²⁺ entry = decreased cardiac output
2) Increased K⁺ effect = decreased heart rate


What is the muscarinic effects of cholinomimetics in the vasculature?

Most blood vessels do not have parasympathetic innervation
ACh acts on vascular endothelial cells to stimulate NO release via M3 acetylcholine receptors
NO induces vascular smooth muscle relaxation
Results in a decrease in TPR


What are the muscarinic effect of cholinomimetics on the cardiovascular system?

Decreased heart rate
Decreased cardiac output (due to decreased atrial contraction)
Vasodilation (stimulation of NO production)
All of these combine to produce a sharp drop in blood pressure


What are the muscarinic effects of cholinomimetics in non-vascular smooth muscle?

Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle- it has an excitatory effect
Lung: bronchoconstriction
Gut: Increased peristalsis
Bladder: Increased bladder emptying


What are the muscarinic effects of cholinomimetics in exocrine glands?

Increased bronchial secretions
Increased gastrointestinal secretions (including gastric HCl production)
Increased sweating (SNS mediated)


Give two examples of directly acting cholinomimetic drugs

1) Choline esters (bethanechol)
2) Alkaloids (pilocarpine)
Both drugs have very similar structures to acetylcholine


What is pilocarpine? What are it's main uses and side effects?

A non-selective muscarinic agonist with good lipid solubility. Particularly useful in ophthalmology as a local treatment for glaucoma
Side effects: blurred vision, sweating, gastrointestinal disturbance and pain, hypotension, respiratory distress


What is bethanechol? What are it's main uses and side effects?

A selective M3 acetylcholine receptor agonist. Mainly used to assist bladder emptying and to enhance gastric motility.
Side effects: sweating, impaired vision, nausea, bradycardia, hypotension, respiratory difficulty


How do indirectly acting cholinomimetic drugs work? What are the two different types? (Give examples)

Increase the effect of normal parasympathetic nerve stimulation by slowing down the action of acetyl cholinesterase
1) Reversible anticholinesterases (e.g. physostigmine, neostigmine, donepezil)
2) Irreversible anticholinesterases (e.g. ecothiopate, dyflos, sarin)


What is the action of cholinesterase enzymes? What are the two different types?

Metabolise acetylcholine to choline and acetate
1) Acetylcholinesterase
2) Butyrylcholinesterase


Where is acetylcholinesterase found? Describe it's action

Found in all cholinergic synapses (peripheral and central)
Very rapid action and highly selective for acetylcholine


Where is butyrylcholinesterase found? Describe it's action

Found in plasma and most tissues but not in cholinergic synapses with broad substrate specificity. It is the principal reason for low plasma acetylcholine. Shows genetic variation


What is the effect of a low dose of cholinesterase inhibitors?

Enhanced muscarinic activity


What is the effect of a moderate dose of cholinesterase inhibitors?

Further enhancement of muscarinic activity. Increased transmission at all autonomic ganglia


What is the effect of a high (toxic) dose of cholinesterase inhibitors?

Depolarising block at autonomic ganglia and neuromuscular junction


What is the mechanism of action of reversible anticholinesterase drugs? Give examples

Competes with acetylcholine for active site on the cholinesterase enzyme.
Donates a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding.
Carbamyl is removed by slow hydrolysis.
Increases the duration of acetylcholine activity in the synapse
e.g. physostigmine, neostigmine


Where does physostigmine act? What is it used for?

Primarily acts at the postganglionic parasympathetic synapse.
It is a reversible anticholinesterase drug. Used to treat glaucoma, aiding intraocular fluid drainage. Also used to treat atropine poisoning, particularly in children


What is the mechanism of action of irreversible anticholinesterase drugs? Give examples

Rapidly react with the enzyme active site, leaving a large blocking group. This is stable and resistant to hydrolysis, so recovery may require production of new enzymes
e.g. ecothiopate


What is ecothiopate? What is it used to treat? What are the side effects?

A potent inhibitor of acetylcholinesterase. Slow reactivation of the enzyme by hydrolysis takes several days.
Used as eye drops to treat glaucoma.
Side effects: sweating, blurred vision, GI pain, bradycardia, hypotension and respiratory difficulty


What type of anticholinesterase drugs can access the brain? What is the effect of low and high doses?

Non-polar anticholinesterase drugs can cross the blood-brain barrier
Low doses: Excitation with possible convulsions
High doses: Unconsciousness, respiratory depression, death


What anticholinesterase drugs are used to treat Alzheimer's disease?

Donepezil and tacrine. Acetylcholine is important in learning and memory.
Potentiation of central cholinergic transmission relieves Alzheimer's symptoms but does not effect degeneration


What are the effects of organophosphate poisoning? How is it treated?

Organophosphate is an insecticide or nerve agent which causes severe toxicity (increased muscarinic activity, CNS excitation and depolarising neuromuscular block)
Treatment: IV atropine, artificial respiration, IV pralidoxime (must be given within a couple of hours)


Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system?

Pre- and post-ganglionic parasympathetic synapses


What is the target site of heroin?

μ opioid receptors


What is the route of heroin from injection to binding to it's receptor?

Injected into venous system → heart → pulmonary circulation → aorta → systemic circulation → brain → brain capillaries →diffuses across blood-brain barrier (lipophilic) → binds opioid receptors


How does alcohol tolerance occur?

Pharmacokinetic tolerance means you produce more alcohol dehydrogenase so you have to drink larger quantities of alcohol to achieve the same results


Fentanyl has a left shift on the dose response graph compared to heroin. What does that mean?

The effects of fentanyl occur at a lower dose than heroin


What is drug affinity?

Where the drug binds the receptor more readily, meaning the drug-receptor complex is formed for longer periods


What is drug efficacy?

A drug's ability to activate the receptor to produce a response


How does naloxone work?

It is a competitive opioid receptor antagonist


What is the structure-affinity relationship?

Where drugs have a very similar structure, but the very small changes between them change the activity of the drug
e.g. codeine, morphine and heroin


How would a partial agonist curve differ from a full agonist on a dose-response graph?

A partial agonist would not have as much of a response on the curve (it would have ∼ half the height)


What is drug potency?

ED50 (effective dose where you see 50% response)
Potency ≈ affinity + efficacy
Clinically efficacy is not relevant than potency


What are the different types of formulation that can be used to deliver a drug orally?

Soluble (effervescent) tablets
Enteric-coated tablets


Why are excipients added to a drug formulation?

To alter bioavailability of a drug
To improve the flavour of the drug
To reduce the rate at which the drug is released into the blood


How does the ionisation of a drug and pH affect the bioavailability?

Ionisation affects whether the drug can be absorbed through the membrane. pH affects whether the drug is ionised or non-ionised.


Why would it be advantageous to take soluble aspirin?

When it needs to be absorbed quickly, for example for a headache so it works more quickly


When would it be advantageous to take enteric-coated aspirin?

When slow release of the drug is required, for example for long lasting pain relief in arthritis


Why is bioequivalence important when prescribing generic versions of a drug?

To ensure the effects of the drug are similar to the original form of the drug and to minimise side effects of the new drug


What is a narrow therapeutic index?

A narrow range between a harmful effect and the desired therapeutic effect


How can good bioavailability be achieved for drugs that undergo extensive first-pass metabolism?

Intravenous administration
Use prodrugs
Drug could work at very low doses or administered in high doses


What kind of illness could affect the bioavailability of drugs?

Liver disease
Gastrointestinal diseases which affect absorption


What is the efficacy of antagonists?

They have no efficacy as they do not cause a response


Which of the following drugs has efficacy for the muscadine can acetylcholine receptor?
1) Acetylcholine
2) Atropine
3) Acetyl-cholinesterase
4) Adrenaline
5) Acetate

1) Acetylcholine

2) Atropine (antagonist)
3) Acetyl-cholinesterase (enzyme in the synapse)
4) Adrenaline (adrenergic receptor)
5) Acetate (breakdown product)


What are of the autonomic nervous system is influenced by nicotinic receptors?

All of the autonomic nervous system


What is a ganglion blocking drug?

A nicotinic receptor antagonist


What is the mechanism of nicotinic receptor antagonists? Give two examples of these drugs

1) Bind to and block the nicotinic receptor
2) Enter the ion channel and block passage through the channel
Use dependent block: the more ACh present (the more active the channel) the more effective the antagonist
Partial blockade: slows the ion channel down
e.g. Hexamethonium and Trimetaphan


What effect will blocking the nicotinic receptor have on the body?

The effect will depend upon which arm of the autonomic nervous system is active. If parasympathetic is active it will block parasympathetic actions (e.g. Decrease gut motility, increase heart rate etc)


Which of the following effects would be observed at rest after treatment with a ganglion blocking drug?
1) Increased heart rate
2) Pupil constriction
3) Bronchodilation
4) Detrusor contraction
5) Increased gut motility

1) Increased heart rate
3) Bronchodilation


Why would a nicotinic receptor antagonist cause hypotension?

It would inhibit blood vessel constriction and reduce renin secretion which would decrease blood pressure


Give two examples of nicotinic receptor antagonists.



Hexamethonium and Trimetaphan are two examples of nicotinic receptor antagonists. One is primarily a receptor antagonist and one is primarily an ion channel blocker. Which is which?

Hexamethonium is primarily an ion channel blocker
Trimetaphan is primarily a receptor antagonist
But both drugs can have both actions


What is the difference between toxins and drugs?

Drugs predominantly only target the autonomic nervous system.
Toxins bind irreversibly to receptors, and target both the autonomic nervous system and the skeletal muscle, causing paralysis


Why are muscarinic receptors better targets for drugs?

They are only found on the post-synaptic neurones in the parasympathetic nervous system, and sweat glands, so they produce a much more specific effect


Give examples of muscarinic receptor antagonists. (3)



What is the difference between Atropine and Hyoscine in terms of effect on the CNS?

These drugs are very similar with the exception of the CNS:
Normal dose- Atropine has little effect on the CNS, but Hyoscine induces sedation and amnesia
Toxic dose- Atropine induces mild restlessness and agitation whilst Hyoscine induces CNS depression or paradoxical CNS excitation associated with pain


Atropine and Hyoscine are both lipid soluble and therefore are both able to cross the BBB and access the brain. Which drug has greater permeation into the CNS?

Atropine is less M1 selective


Why do muscarinic receptor antagonists make good anaesthetic premedications?

They block:
Trachea and bronchiole constriction
Salivary gland watery secretions
Decrease in heart rate and contractility

Plus they induce sedation


How are muscarinic receptor antagonists used in Parkinson's disease?

The cholinergic system inhibits the dopaminergic system in Parkinson's disease
(The loss of dopaminergic neurones = less dopamine = less D1 receptor activation)
M4 receptors also inhibit D1, amplifying the response
Muscarinic receptor antagonists dampen down these effects


Why is Ipratropium Bromide specially designed for it's use? What is this drug used for?

Used for asthma. Inhaled to produce effects.
It is a similar structure to atropine, but it is a larger molecule, so it cannot cross the membrane to produce side effects


How can muscarinic receptor antagonists be used to treat irritable bowel syndrome?

Parasympathetic nervous system increases GI motility and tone and increases secretions
Muscarinic receptor antagonists block these effects, reducing the symptoms of IBS


What is cyclopegia?

Inability to focus on near objects


Which of the following drugs would you administer to treat an atropine overdose?
1) Bethanechol
2) Ecothiopate
3) Hyoscine
4) Physostigmine
5) Pralidoxime

Answer: 4 (and 1)

2 and 4 are anticholinesterases (increase amount of ACh in the synapse)
5 can reverse anticholinesterase poisoning
4 is reversible
1 is a muscarine agonist


What is Botulinum toxin? How does it induce it's effects?

Prevents ACh vesicles from docking with the membrane and exocytosing. Injected directly into the skeletal muscle it causes paralysis of the muscle


What is the selectivity for noradrenaline of the adrenoceptors?

α1 = α2 > β1 = β2


What is the selectivity for adrenaline of the adrenoceptors?

β1 = β2 > α1 = α2


What adrenoceptor is found on the presynaptic adrenergic neurone? What is the function of this receptor?

α2 receptor provides negative feedback to the neurone, to inhibit more noradrenaline release


Give examples of directly acting SNS agonists and the receptor they selectively bind?

Adrenaline (non-selective)
Phenylephrine (α1)
Clonidine (α2)
Dobutamine (β1)
Salbutamol (β2)
Higher concentrations of drugs will start to lose selectivity and effect other receptors


Why is adrenaline administered during anaphylactic shock?

Adrenaline works on β-receptors (preferably to α-receptors) causing:
- bronchodilation (β2)
- tachycardia (β1)
- ↑ vasoconstriction (α1)
It will have a small effect on breathing and heart rate


Give examples of pulmonary conditions where adrenaline would be administered. Why?

Asthma emergencies
Acute bronchospasm associated with chronic bronchitis or emphysema
β2 receptor causes bronchodilation
Suppression of mediator release


Why is adrenaline administered in glaucoma?

Glaucoma = increased intraocular pressure due to poor drainage of the aqueous humour
Adrenalin causes decreased production of aqueous humour due to vasoconstriction of the ciliary body blood vessels


Why would local anaesthetics contain adrenaline?

Adrenaline causes vasoconstriction which reduces blood supply and prevents removal of the local anaesthetic. This prolongs the action of the drug
Act on the α1 receptor


What are the unwanted actions of adrenaline? (5)

1) Secretions
Reduced and thickened mucous
2) CNS
3) CVS effects
- tachycardia, palpitations, arrhythmias
- cold extremities, hypertension
- overdose
- cerebral haemorrhage, pulmonary oedema
4) GIT
5) Skeletal muscle


What are the clinical uses of Phenylephrine? What receptor is it most selective for?

It is chemically related to adrenaline but it id resistant to degradation by the COMT gene (but not MAO)
- Vasoconstriction
- Mydriatic
- Nasal decongestant
Most selective for α1 > α2 > β1/2


What are the clinical uses of Clonidine? What receptor is it most selective for?

Found on adrenergic presynaptic neurones
Decreases release of NA and decrease synaptic drive
Most selective for α2 > α1 > β1/2


What is Clonidine used to treat? How does it achieve this?

Treatment of hypertension and migraine
Reduces sympathetic tone- inhibition of NA release = decrease in Renin-Angiotensin-Aldosterone-System which causes ↓ heart rate and ↓ vasoconstriction


Why is Isoprenaline preferable to adrenaline? What receptor is it most selective for?

It is chemically similar to adrenaline but it is less susceptible to uptake 1 and MAO breakdown. It has a plasma half-life of 2 hours
Most selective for β1 = β2 > α1/2


What are the clinical uses of Isoprenaline? What must you be cautious of using this drug?

- Cardiogenic shock
- Acute heart failure
- Myocardial infarction
Non-selective for β1 and β2. β2 activity causes a fall in venous blood pressure which results in a reflex tachycardia via the stimulation of baroreceptors


What are the clinical uses of Dobutamine? What receptor is it most selective for?

Used in cardiogenic shock- does not result in reflex tachycardia like Isoprenaline, but it is rapidly metabolised by COMT
Most selective for β1 > β2 > α1/2


What are the clinical uses of Salbutamol? What receptor is it most selective for?

Used in the treatment of asthma (β2-relaxation of bronchial smooth muscle) and in treatment of threatened premature labour (β2-relaxation of uterine smooth muscle)
Most selective for β2 > β1 > α1/2


What are the side effects associated with salbutamol?

Reflex tachycardia
Blood sugar dysregulation


What are the effects of cocaine on the CNS?

Low Doses- euphoria, excitement, increased motor activity
High Doses- activation of CTZ, CNS depression, respiratory failure, convulsions and death


What are the effects of cocaine on the CVS?

Low Doses- tachycardia, vasoconstriction, raised blood pressure
High Doses- ventricular fibrillation and cardiac arrest


What is tyramine? Where is it found?

A dietary amino acid
Found naturally in cheese, red wine and soy sauce


When does ingestion of tyramine cause problems?

When taking MAO inhibitors tyramine competes with MAO which is required for the breakdown of NA
Causes hypertensive crisis


What is the role of the α2-receptor on the presynaptic neuron?

Involved in receptor-mediated negative feedback of noradrenaline release


What are the different types of adrenoceptor and their action?

α1: Vasoconstriction, relaxation of GIT
α2: Inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions
β1: Increased cardac rate and force, relaxation of GIT, renin release from kidney
β2: Bronchodilation, vasoconstriction, relaxation of visceral smooth muscle, hepatic glycogenolysis
β3: Lipolysis


What are the adrenoceptor antagonists that act on the different adrenoceptors?

Non-selective (α1 + β1): Labetalol
α1 + α2: Phentolamine
α1: Prazosin
β1 + β2: Propranolol
β1: Atenolol


What are the clinical uses of SNS antagonists?

Cardiac arrhythmias


What are the tissue targets for antihypertensives?

1) Sympathetic nerves that release the vasoconstrictor noradrenaline
2) Kidney- blood volume/ vasoconstriction
3) Heart
4) Arterioles- determine peripheral resistance
5) CNS- determines blood pressure set point and regulates some systems involved in blood pressure control and autonomic nervous system


What action do β1-adrenoceptor antagonists have?

1) Acts in CNS to reduce sympathetic tone
2) Heart: reduces heart rate and cardiac output but this effect disappears in chronic treatment
3) Kidney: reduces renin production. Common long-term feature in their anti-hypertensive action is a reduction in peripheral resistance


What is the role of the β1-receptor on the presynaptic neuron?

Involved in receptor-mediated positive feedback of noradrenaline


What are the unwanted effects of β-antagonists?

Cardiac failure
Cold extremities
Bad dreams


Why do β-antagonists cause bronchoconstriction? Who is particularly susceptible?

Activation of β2 receptors cause bronchodilation so non-selective β-antagonists cause bronchoconstriction,
In asthmatic patients this can be dramatic and life-threatening. Also clinically important in patients with obstructive lung disease (e.g. bronchitis)


Why do β-antagonists cause cardiac failure? Who is particularly susceptible?

Patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output, and removal of this by blocking β-receptors will produce a degree of cardiac failure


Why do β-antagonists cause hypoglycaemia?

Use of β-antagonists mask the symptoms of hypoglycaemia (sweating, palpitations, tremor). Non-selective β-antagonists will also block the β2-receptor driven breakdown of glycogen


Why do β-antagonists cause fatigue?

Due to reduced cardiac output and reduced muscle perfusion


Why do β-antagonists cause cold extremities?

Loss of β-receptor mediated vasodilation in cutaneous vessels


What is the mechanism of action of propanolol? What effect does it have once taken?

β1 and β2 (non-selective) adrenoceptor antagonist
In a subject at rest propanolol causes very little change in heart rate, cardiac output or arterial pressure, but reduces the effect of exercise or stress on these variables


What is the mechanism of action of atenolol? What effect does it have once taken?

"Cardio-selective drugs"
β1-selective: antagonises the effects of noradrenaline on the heart but will affect any tissue with β1 receptors (e.g. kidney)
Less effect on the airways than non-selective drugs, but still not safe with asthmatic patients. Selectivity is concentration dependent


What is the mechanism of action of labetalol? What effect does it have once taken?

Dual acting β1 and α1 antagonist, higher ratio of β1 to α1 (4:1)
This drug lowers blood pressure via a reduction in peripheral resistance
Like β-blockers, labetalol induces a change in heart rate or cardiac output but this effect wanes with chronic use


What action do α-adrenoceptor antagonists have?

1) Fall in arterial pressure
2) Postural hypotension
3) Cardiac output/ heart rate increases- reflex response to fall in arterial pressure (β-receptors)
4) Blood flow through cutaneous and splanchnic vascular beds increased, but effects on vascular smooth muscle are slight


What is the mechanism of action of phentolamine? What effect does it have once taken?

Non-selective α-antagonist
Causes vasodilation and a fall in blood pressure due to blockade of α1-receptors
Blockade of α2-receptors tends to increase noradrenaline release (takes away negative feedback), enhances the reflex tachycardia that occurs with any blood pressure lowering agent
Increased GIT motility, diarrhoea a common problem


What is the mechanism of action of prazosin? What effect does it have once taken?

Highly selective α1-antagonist
Causes vasodilation and a fall in arterial pressure
Less tachycardia than non-selective antagonists since they do not increase noradrenaline release from nerve terminals (no α2 actions)
Cardiac output decreases, due to fall in venous pressure as a result of dilation of capitance vessels
Hypotensive effect is dramatic


What is the mechanism of action of methyldopa?

An antihypertensive agent taken up by noradrenergic neurons.
Decarboxylated and hydroxylated to form false transmitter α-methyl-noradrenaline
Not deaminated within neuron by MAO (Mono Amine Oxidase) and therefore tends to accumulate in larger quantities than noradrenaline, and displaces noradrenaline from synaptic vesicles


How does methyldopa differ from noradrenaline?

False transmitter released in the same way as noradrenaline but
1) Less active than noradrenaline on α1-receptors, less effective in causing vasoconstriction
2) More active on presynaptic (α2) receptors, auto-inhibitory feedback mechanism operates more strongly, reduces transmitter release below normal levels
Some CNS effects; stimulates vasopressor centre in the brain stem to inhibit sympathetic outflow


What are the benefits of methyldopa that allow it to be used in patients with other conditions?

Renal and CNS blood flow are well maintained, so widely used in hypertensive patients with renal insufficiency or cerebrovascular disease
Recommended in hypertensive pregnant women, has no adverse effects on foetus despite crossing the blood-placenta barrier


What are the adverse effects of methyldopa?

Dry mouth
Orthostatic hypotension
Male sexual dysfunction


What effect does increased sympathetic drive have on arrhythmias? What drug is used to treat them?

Increase in sympathetic drive to the heart via β1 can precipitate or aggrivate arrhythmias. Particularly after myocardial infarction there is an increase in sympathetic tone
AV conductance depends critically on sympathetic activity. β-adrenoceptor antagonists increase the refractory period of the AV node, interfering wth AV conduction in atrial tachycardias, and slowng ventricular rate


What class II antiarrhythmic is used particularly for arrythmias that occur during exercise or stress?

Propanolol- a non-selective β-antagonist; effects mainly attributed to β1-antagonism


What are the different types of angina?

Stable: pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels (e.g. atheroma)
Unstable: pain with less and less exertion, culminating with pain at rest. Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel. Risk of infarction
Variable: occurs at rest, caused by coronary artery spasm, associated with atheromatous disease


What is the treatment for angina? Give an example of a drug.

Decrease heart rate
Decrease systolic blood pressure
Decrease cardiac contractile activity
At low doses β1-selective agents (e.g. metoprolol) reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle
Reduce the oxygen demand whilst maintaining the same degree or effort


What are the side effects of β-adrenoceptor antagonists used to treat angina? In what cases should the use of these drugs be avoided?

Side effects: fatigue, insomnia, dizziness, sexual dysfunction, bronchospasm, bradycardia, heart block, hypotension, decreased myocardial contractility
NOT USED: bradycardia (<55bpm), bronchospasm, hypotension (systolic <90mmHg), AV block or severe congestive heart failure


What drugs are used to treat glaucoma? Give examples. How do they work?

Non selective β1 and β2 antagonists
e.g. carteolol hydrochloride, levobunolol hydrochloride, timolol maleate
Reduce the rate of aqueous humour formation by blocking the receptors on ciliary body
Selective β1 antagonists betaxolol hydrochloride also shown to be effective


What are some other uses of β-antagonists?

Anxiety states- to control somatic symptoms associated with sympathetic over-reactivity, such as palpitations and tremor
Migraine prophylaxis
Benign essential tremor


What is the effect of pilocarpine on pupil size, accommodation and the light reflex? What is this drug used for? Why has it been superceded by other agents?

Causes decreased pupil size as it enhances parasympathetic nervous system response which causes more contraction of sphincter pupilae muscle.
Increased accommodation for near vision due to enhanced PNS leading to increased lens bulging and constriction of ciliary muscles.
Loss of light reflex due to PNS causing maximal constriction.
Used to treat glaucoma as it causes contraction of the sphincter pupilae which allows the canal of Schlemm to open and the intraocular fluid to drain. Has side effects so more selective drugs are used.


What are the effects of tropicamide on pupil size, accommodation and the light reflex? How may the effects of tropicamide be used in the clinical setting?

Causes increased pupil size due to inhibition of the PNS (antagonist) causing less constriction of the sphincter pupilae.
Decreased accommodation for near vision due to decreased contraction of the ciliary muscles.
Loss of light reflex due to loss of ability to constrict.
Clinically tropicamide is used to allow visualisation of the retina


How does the sympathetic nervous system influence ocular function? (3)

1) α2-receptors on dilator pupilae which means radial muscle constricts which dilates the pupil
2) Activity on β1-receptors on ciliary body which means aqueous humour production generated
3) Activity on α1-receptors on blood vessels which means vasoconstriction occurs


Why can a sympathomimetic drug (dipivefrine) and a β-blocker (timolol) both be used to treat glaucoma?

Dipivetrine causes vasoconstriction (main effect outweighs other sympathetic effects)
Timolol also reduces blood flow


What are some of the problems associated with drugs (e.g. dipivetrine and timolol) applied topically to the eye, in terms of local and systemic bioavailability? How might you reduce these adverse effects?

Eye is heavily vascularised- more gets into the blood vessels than into the eye (need a higher dose). If this is chronic treatment, over time it will leak into the systemic circulation
With eye drops some of the drug is lost
Use more selective drug to have less systemic effects
Timolol is a β-blocker = more selective as an antagonist than dipivetrine as an agonist (prodrug for adrenaline)- acts on both α and β


A toxic dose of heroin produces a similar effect on the eye to organophosphates. What is this effect and how does the mechanism differ between the two drugs? What happens to the eyes if toxicity continues and asphyxia occurs?

Organophosphate and heroin both affect the PNS.
Opiate receptors on GABA interneurones; respond to heroin which causes disinhibition. Heroin causes massive stimulation of cranial nerve 3 (the occulomotor nerve), which leads to pathognomic pupil constriction if given a toxic dose. If toxicity continues and asphyxia occurs loss of oxygen causes nerve damage and further dilation
Organophosphate is an anticholinesterase so it causes increased ACh in the synapse


Why are prostaglandin analogues commonly utilised in the treatment of glaucoma? Give an example

End result the same as pilocarpine. Gets into venous drainage channels (main action to break down collagen). Clear path within venous drainage channel means there is less resistance to flow and therefore improved drainage
e.g. latanoprost


Why are carbonic anhydrase inhibitors commonly utilised in the treatment of glaucoma? Give an example.

Ciliary body β- receptors are coupled to carbonic anhydrase (which generates bicarbonate).
Inhibiting carbonic anhydrase means less bicarbonate is generated so not enough Na and bicarbonate are available to create aqueous humour.


What type of activation is required in action potentials and end-plate potentials?

Action potential is all or nothing (threshold to activate)
End-plates have a graded potential


What receptors are found on the end-plate of the neuromuscular junction?

Nicotinic (pentameric) receptors


What subunit of the nicotinic receptor does the ACh bind to? What effect does this have on stimulation of the receptor?

It binds to the α-subunit. This means you need more than one ACh to stimulate the receptor


Give examples of drugs that drugs which act on the central processes? How do they work?

e.g. Diazepam, baclofen
They reduce the action potential propagation and reduce muscle contraction of skeletal muscle


What drugs target the conduction of nerve action potential in motor neurones?

Local anaesthetics
Inhibit the influx of sodium by blocking the voltage-sensitive sodium channels, which reduces the generation of propagation of action potentials.
Can also effect the motor neurones so avoid injecting near to motor neurones


What drugs target the release of ACh?

Hemicholinium (Inhibits/slows down reuptake of choline so leads to depletion of ACh)
Ca²⁺ entry blockers (interact with presynpatic Ca²⁺ channels to dampen down Ca²⁺ influx)
Neurotoxins (e.g. cobra venoms and bacterial toxins. Inhibits release of ACh)


What drugs target the depolarisation of the motor end-plate which causes initiation of an action potential?



What drugs target the propagation of an action potential along the muscle fibre and muscle contraction?

e.g. Dantrolene
Works by inhibiting the release of Ca²⁺ ions from the sarcoplasmic reticulum in skeletal muscle fibres


What part of the synapse do neuromuscular blocking drugs target?

Postsynaptic action


Give an example of a non-depolarising neuromuscular blocking drug.



Give an example of a depolarising neuromuscular blocking drug.



What is the mechanism of action of suxamethonium? What happens when it is administered?

Induces an extended end plate depolarisation which causes a depolarisation block (over stimulating the receptors)
It is broken down much slower than ACh so they switch off due to overstimulation
Phase 1 (depolarisation) block
Causes fasciculations then flaccid paralysis


What is the route of administration of suxamethonium? What is it's duration of action? How is it metabolised?

Administered intravenously
Causes ∼5 minute paralysis
Metabolised by pseudocholinesterase in liver and plasma


What are the uses of suxamethonium?

- Endotracheal intubation
- Muscle relaxant for electroconvulsive therapy (used to treat severe clinical depression- last resort)


What are the unwanted effects of suxamethonium?

1) Post-operative muscle pains (from fasciculations)
2) Bradycardia
- direct muscarinic action on heart (can be blocked with atropine premeds)
3) Hyperkalaemia
- soft tissue injury or burns damage cholinergic fibres so upregulates nicotinic receptors on surface (denervation super sensitivity) = exaggerated response to drug; ventricular arrhythmias / cardiac arrest
4) Increased intraocular pressure
- avoid for eye injuries, glaucoma


What is the mechanism of action of tubocurarine? What happens when it is administered?

A competitive nicotinic ACh antagonist
70-80% block necessary (to bring down the graded potential)
Tubocurarine causes flaccid paralysis
Administration causes paralysis of:
1) extrinsic eye muscles (double vision)
2) small muscles of the face, limbs, pharynx
3) Respiratory muscles
(unblocked in reverse order)


What are the uses of tubocurarine?

1) Relaxation of skeletal muscles during surgical operations- particularly abdominal muscles (= less anaesthetic)
2) Permits artificial ventilation- causes relaxation of respiratory muscles


How do you reverse the actions of a non-depolarising neuromuscular blocker? Give an example of a drug that would be used.

Administer anticholinesterases
Increases the amount of ACh in the synaptic cleft
e.g. Neostigmine (and atropine to reduce stimulation of muscarinic receptors (combined IV injection)


Describe the pharmacokinetics of tubocurarine. How is it administered? What is the duration of paralysis?

Administered intravenously (highly charged)
Induces paralysis for 40-60 mins (long duration)
Does not cross the BBB or placenta
Is not metabolised
Excreted: 70% urine; 30% bile


What drug would be used in a patient who has impaired renal or hepatic function? Why?

Has a 15 minute duration of action so is less dependent on rapid excretion.


What are the unwanted effects of tubocurarine?

Caused by ganglion block; histamine release
- Ganglion blockade = decreased TPR
- Histamine release from mast cells
2) Tachycardia (can lead to arrhythmias)
- reflex
- blockade of vagal ganglia (reduces the firing rate of the heart)
4) Excessive secretions (bronchial and salivary)
5) Apnoea (always assist respiration)


The clinical use of neuromuscular blocking drugs will most likely involve interference with which of the following physiological processes?
1) Kidney function
2) Consciousness
3) Body temperature regulation
4) Pain sensation
5) Respiration

5) Respiration


Which of the following effects would be observed with a non-depolarising neuromuscular block?
1) Initial muscle fasciculations
2) Irreversible nAChR blockade
3) The block would be enhanced by anti-cholinesterase drugs
4) A flaccid paralysis
5) Increased arterial pressure

4) A flaccid paralysis


Give an example of a β-blocker that exerts it's maximum effect during exercise or stress.



Which of the following pharmacodynamic properties is a competitive receptor antagonist most likely to display?
a) High efficacy and zero affinity
b) High potency and moderate affinity
c) Zero efficacy and moderate affinity
d) Zero potency and zero affinity
e) Moderate efficacy and moderate affinity

C) Zero efficacy and moderate affinity

Only agonists possess efficacy


How does adrenaline reduce the effects of mast cell derived histamine during an anaphylactic response?

Physiological antagonism


Give an example of a drug that works by pharmacokinetic antagonism.



What type of drug can never induce a maximal response?

A partial agonist
e.g. clonidine


Why does reducing the lipid solubility of drugs make them easier to excrete?

It reduces reabsorption in the kidney


Which one of the following effects can be attributed to anti-cholinesterase poisoning?
a) Bronchodilation
b) Reduced gut motility
c) Increased secretions
d) Tachycardia
e) Mydriasis

c) Increased secretions

Blocks the action of acetylcholinesterase which causes a build up of ACh in the synapse and increases the action


How do muscarinic receptor antagonists influence function within the striatum and thus improve the symptoms of Parkinson's?

They increase dopamine receptor activation


Neuromuscular blockade by tubocurarine is used as an adjunct to anaesthesia in surgery. How does tubocurarine bring about it's effects at the motor end plate?

Antagonism of the actions of acetylcholine at nicotinic receptors


What is the mechanism for regulating contractility in the heart?

Electrical excitation of the cell from action potentials arises from the sino-atrial node which induces membrane depolarisation that promotes If (funny channels) to open and cause a small release of Ca²⁺ into the cytoplasm.
The small Ca²⁺ current induces a release of Ca²⁺ from the SR (Ca-induced Ca-release) through It (transient) and Il (Long lasting) ryanodine receptors


How do β-blockers affect channels involved in maintaining heart rate?

Decrease If and and Ica which contractility


How do calcium antagonists affect channels involved in maintaining heart rate?

Decrease Ica


What are the two different classes of calcium antagonist? Which type have higher selectivity on the heart?

1) Rate slowing (Cardiac and smooth muscle actions)
- Phenylalkylamines (e.g. Verapamil)
- Bencothiazepines (e.g. Diltiazem)
2) Non-rate slowing (smooth muscle actions - more potent)
- Dihydropyridines (e.g. amlodipine)

Rate slowing have higher selectivity on the heart. Non-rate slowing have higher selectivity on the vasculature


What drugs influence myocardial oxygen supply/demand? How do they work?

Organic nitrates (directly supply NO) and potassium channel openers (tend to lead to hyperpolarisation)

Both dilate coronary vessels and improve oxygen to the heart
↑ coronary blood flow
Vasodilation = ↓ afterload
Venodilation = ↓ preload


What does Ivabradine do?

Increases heart rate


What is the treatment for angina?

β-blocker or calcium antagonist as background anti-angina treatment
Ivabradine is a newer treatment
Nitrate as symptomatic treatment (short acting)- taken pre-exercise
Other agents (e.g. potassium channel opener) if intolerant to other drugs


What are the unwanted side effects of β-blockers?

- Worsening of cardiac failure (CO reduction)
- Bradycardia (heart block) (due to less conduction through AV node)
- Bronchoconstriction (blockade of β2 in airways)
- Hypoglycaemia (in diabetics on insulin) (decreased glycogenolysis/gluconeogenesis)
- Cold extremities and worsening of peripheral arterial disease (blockade of β2 in skeletal muscle vessels)
- Fatigue
- Impotence (sexual dysfunction)
- Depression
- CNS effects (lipophilic agents) e.g. nightmares


What are the side effects of calcium channel blockers?

- Bradycardia and AV block
- Constipation (25%)

Dihydropyridines- 10-20% patients
- Ankle oedema
- Headache/flushing
- Palpitations


What are the aims of treatment of cardiac rhythm disturbances?

- Reduce sudden death
- Prevent stroke
- Alleviate symptoms


What are the different types of arrhythmias?

- Supraventricular arrhythmias (e.g. amiodarone, verapamil)
- Ventricular arrhythmias (e.g. flecainide, lidocaine)
- Complex (supraventricular and ventricular arrhythmias) (e.g. disopyramide)


What is the Vaughan Williams classification of anti-arrhythmic drugs?

Class Mechanism of Action
I Sodium channel blockade
II β adrenergic blockade
III Prolongation of repolarisation
('Membrane stabilisation' mainly due to potassium channel blockade)
IV Calcium channel blockade


What are the uses of adenosine (anti-arrythmic)?

Used intravenously to terminate supraventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil
Used for acute arrhythmias
Couples with G causing reduced cAMP


What are the uses of verapamil (anti-arrythmic)? How does it work?

Used for reduction of ventricular responsiveness to atrial arrhythmias
Depresses SA automatically and subsequent AV node conduction


What are the uses of amiodarone (anti-arrythmic)? How does it work? What are the side effects?

Used for superventricular and ventricular tachyarrhythmias- often due to reentry
Has complex action probably involving multiple ion channel block

Amiodarone accumulates in the body (half life- 10-100 days)
Has a number of important adverse effects including:
- photosensitive skin rashes
- hypo- or hyper- thyroidism
- pulmonary fibrosis


What effect does digoxin have on inotropy?

Causes inhibition of Na/K/ATPase which results in increased intracellular Ca²⁺ exchange= Positive inotropic effect
Central vagal stimulation causes increased refractory period and reduced rate of conduction through AV node


What are the uses and side effects of digoxin?

- Atrial fibrillation and flutter lead to a rapid entricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output
- Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV nodes. Fewer impulses reach the ventricles and ventricular rate falls
Adverse effects:
- Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity


What effect does hypokalaemia have on digoxin toxicity?

It lowers the threshold for toxicity.
Digoxin prevents K⁺ uptake into cells, so more K⁺ outside of cells. If you have lower K⁺ the effect of digoxin is enhanced because you have lower K⁺


What do most antihypertensive drugs target?

Total peripheral resistance


What effect does arteriole contraction and relaxation have on vessel radius, resistance and flow?

↓ radius
↑ resistance
↓ flow

↑ radius
↓ resistance
↑ flow


What does a patients blood pressure need to be over to be classes as hypertensive?

140/90 mmHg


What conditions are liked to hypertension?

- Stroke (50% of ischaemic strokes)
- ~25% of heart failure cases (70% in elderly)
Major risk factor for myocardial infarction and chronic kidney disease


What would be the first line of treatment for an individual under 55 with hypertension?

ACE inhibitor or angiotensin receptor blocker


What would be the first line of treatment for an individual over 55 or an afro caribbean of any age?

Calcium channel blocker or thiazide-type diuretic


What is the second line of treatment for hypertension?

ACE inhibitor and calcium channel blocker
ACE inhibitor and thiazide type diuretic


What is the third line of treatment for hypertension?

ACE inhibitor and calcium channel blocker and thiazide type diuretic


What treatment is given following the third line of treatment for resistant hypertension?

Consider low dose spironolactone
Consider β-blocker or α-blocker


How do ACE inhibitors treat hypertension? What side effect does this cause?

Prevents the conversion of angiotensin I to angiotensin II
Also prevents the conversion of bradykinin to inactive metabolytes- this causes a cough


What drugs end in -pril?

ACE inhibitors


What are the uses of ACE inhibitors? Give an example of the drug.

- hypertension
- heart failure
- post-myocardial infarction
- diabetic nephropathy
- progressive renal insufficiency
- patients at high risk of cardiovascular disease
e.g. Enalapril


What law states that increased venous return leads to increased cardiac contractility?

Starling's law


What are angiotensin receptor blockers? What are their uses?

Antagonists or type I (AT₁) receptors for Ang II, preventing the renal and vascular actions of Ang II
Uses: hypertension and heart failure


Which drug is preferable: ACe inhibitors or angiotensin receptor blockers? Why?

ACE inhibitors as there is lower incidence of stroke


What are the different types of calcium channel blocker? Which is more likely to have an effect on the heart?

Dihydropyridines (DHPs)
- More selective for blood vessels
- Amlodipine: does not cause any negative inotropy
- Also licensed for prophylaxis or angina
Non-DHPs (aka rate-limiting)
- Verapamil: large negative inotropic effect (more likely to have an effect on the heart)


Which calcium channel blocker would you use to treat hypertension?



How do dihydropyridines treat hypertension?

DHPs inhibit Ca²⁺ entry into vascular smooth muscle cells
↓TPR = ↓BP


Why are ACE inhibitors and angiotensin receptor blockers used as the first line of treatment?

Because they have a less severe side effect profile so patients are more likely to continue taking them


Why are afro caribbeans advised to take calcium channel blockers or thiazide type diuretics as the first line of treatment?

They have a low plasma renin activity. Need to utilise dual therapy with this ethnic group


Why would α₁-adrenoceptor antagonists be used to treat hypertension?

α₁ causes vasoconstriction and are found on blood vessels so blocking these will prevent this.
This will prevent IP₃ production which means no Ca²⁺
Reduced vasoconstriction but α₂ receptors are negative feedback (particularly in the brain) so you get an enhanced sympathetic response


What sort of drug is bendrofluazide? How does it act to lower blood pressure?

Thiazide diuretic
Increases salt excretion and therefore water causing blood pressure to decrease. It blocks water moving from lumen to blood; blood volume decreases; preload decreases (venous return decreases)


What class of drug is ramipril? Why is this the best choice for a second line treatment?

ACE inhibitor which blocks production of angiotensin II- a vasoconstrictor which also causes aldosterone secretion. Causes vasoconstriction and reduces fluid volume.
Used as second line treatment as first diuretic will cause compensatory activation of RAAS, which is then targeted by the ACE inhibitor


Why is digoxin prescribed to a patient with atrial fibrillation? What is the mechanism of action?

It slows down the heart rate and increases contractility
Heart rate is reduced because the Na/K pump is blocked- sodium then builds up inside the cell- calcium cannot therefore be removed from the cardiac muscle- this will impact contractility


What is the difference between stable and unstable angina?

Stable angina occurs after exercise; unstable angina can occur at any time


What is the mechanism of action of warfarin? Which clotting factors are affected?

Blocks vitamin K reductase which prevents the production of clotting factors
It prevents the carboxylate the glutamic acid which resides in the clotting factors which allows clotting
Factors II, VII, IX, X


What is GTN spray?

Nitric oxide donor. Causes vasodilation (cyclic GMP- interferes with smooth muscle contraction causing vessel relaxation


How does simvastatin lower cholesterol?

It is a HMG-CoA reductase inhibitor which is a rate limiting step in cholesterol synthesis


Aspirin is an anti-coagulant. How does it work?

It is a cyclooxygenase inhibitor on platelets which prevents thromboxane synthesis.
Thromboxane normally activates platelets and causes vasoconstriction


What is congestive heart failure?

When the heart does not work efficiently to meet tissue demand
Congestive means there is a backlog of blood (pooling) in the venous system


What is furosemide? How does it work?

A loop diuretic. It blocks the Na/K/Cl cotransporter in the ascending limb, so water is not absorbed in the descending limb


Why are recreational drugs abused?

They target the reward pathway in the brain.
Dopinergic neurons have cell bodies in the ventral tegmental area which project to the nucleus accumbens


What are the different routes of administration of recreational drugs?

- Intranasal
- Oral
- Inhalation
- Intravenous


What is the fastest route of administration of recreational drugs?

Drug diffuses across alveoli and enters the pulmonary circulation. It then returns to the heart and immediately into the systemic circulation (to the brain)


What are the different classifications of drugs of abuse?

- Narcotics/painkillers - opiate like drugs
e.g. heroin
- Depressants - 'downers'
e.g. alcohol, benzodiazepines (valium), barbiturates
- Stimulants - 'uppers'
e.g. cocaine, amphetamine ('speed'), caffeine, metamphetamine ('crystal meth')
e.g. Cannabis, Ecstasy (MDMA)


In what order does cannabis accumulate in the tissues?

1) Blood
2) Brain
3) High perfusion tissues
4) Low perfusion tissues
5) Fat


How long after smoking cannabis will the effects persist in the body? Where is it detected?

For 30 days in fat


What is the relationship between plasma cannabinoid concentration and degree of intoxification?

There is a poor correlation


What is cannabis converted to in the liver? How does this compound compare to cannabis?

Converted to 11-hydroxy-THC
This is more potent


What are the pharmacokinetics of cannabis?

Liver → 11-hydroxy-THC
GIT → 65%
Bile → enterohepatic recycling
Urine → 25%


What receptors does cannabis act on?

CB₁ and CB₂ receptors


Where are CB₁ receptors?

In the brain
- Hippocampus
- Cerebellum
- Cerebral cortex
- Basal ganglia


Where are CB₂ receptors found?

Immune cells


What is the mechanism of action of cannabis stimulating euphoria?

Cannabis binds to CB₁ receptors which decreases GABA firing to the ventral tegmental area. This then increases dopamine release to the nucleus accumbens (disinhibition)


How does cannabis cause psychosis?

The Anterior Cingulate Cortex has a major role in performance monitoring with behavioural adjustment in order to avoid losses (e.g. stop talking when driving requires more concentration)
Heavy cannabis user experience hypoactivity in the ACC


How does cannabis influence food intake?

1. Presynaptic inhibition of GABA (by cannabis binding to CB₁) increases MCH (melanin concentrating hormone) neuronal activity
2. Increased orexin production
MHC and orexin stimulation makes you hungry


What effect does cannabis have on immunity?

CB₂ receptors are found on immune cells
- B cells
- T cells
- NK cells
- Macrophages
- Mast cells


What effect does cannabis have on memory?

Causes memory loss
- Limbic regions
(Amnestic effects / ↓ BDNF)
BDNF = Brain derived neurotrophic factor


What effect does cannabis have on the medulla?

Low CB₁ receptor expression in the medulla which means it is very difficult (impossible) to fatally overdose on cannabis- no effect on CVS


What are the pharmaceutical properties of cannabis?

Multiple sclerosis / pain / stroke - regulatory
Fertility / obesity - pathology
Up-regulation of CB₁ receptors in the adipose tissue of the genetically obese compared with lean mice


What is Dronabinol? What is it used for?

Cannabis based drug
Used to treat nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type os nausea without good results.
Used to treat loss of appetite and weight loss in people who have AIDS


What types of cocaine can you take intravenously, orally or intranasally?

Paste → 80% cocaine
Cocaine HCl → dissolve in acidic solution


What types of cocaine can be taken by inhalation?

Crack → precipitate with alkaline solution (e.g. baking soda)
Freebase → dissolve in non-polar solvent )e.g. ammonia + ether)


Why does oral cocaine have slow absorption?

pKa = 8.7
Ionized in the GIT so it is absorbed slowly


How and where is cocaine metabolised?

Metabolised by cholinesterase in the liver and in the blood plasma


How do the pharmacokinetics of cocaine contribute to the addictive potential of the drug?

T½ = 20-90 minutes
- Very quick breakdown means it will be taken again and again.
- Very fast speed of onset which makes it more addiactive.
- Inhaled
- Cleared from the body very quickly


What is the effect of high dose cocaine?

Local anaesthetic effect by blocking sodium channels


At low levels how does cocaine cause euphoria?

Cocaine is a monoamine reuptake inhibitor or neurotransmitters (e.g. seratonin, dopamine etc)


What effect does cocaine have on dopamine's affinity and efficacy for the dopamine receptor?

Cocaine has no effect on the affinity or efficacy of dopamine for the receptor. It causes a build up of dopamine in the synapse of the nucleus accumbens


What are the positive effects of dopamine?

- Mood amplifications (euphoria and dysphoria)
- Heightened energy
- Sleep disturbance
- Motor excitement (restlessness)
- Talkativeness
- Increased sexual interest
- Anger, verbal aggression
- Mild to moderate anorexia


What are the negative effects of cocaine?

- Irritability, hostility, anxiety, fear, withdrawal
- Extreme energy or exhaustion
- Total insomnia
- Compulsion
- Rambling, incoherent speech
- Decreased sexual interest
- Possible extreme violence
- Total anorexia
- Delusions of grandiosity


How does cocaine cause myocardial infarction?

- Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating sympathetic outflow and increasing the sensitivity of adrenergic nerve endings to noradrenaline.
- Also acts like a class I antiarrhythmic agent (local anaesthetic) by blocking sodium and potassium channels which depresses cardiovascular parametres
- Stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principle vasodilator produced by endothelial cells
- Activates platelets, increasing platelet aggregation promoting thrombosis


What are the volatile substances in cigarettes?

- Nitrogen
- Carbon monoxide/dioxide
- Benzene
- Hydrogen cyanide


What are particulates in cigarettes?

- Alkaloids
- Tar


What are the different ways of administering nicotine and the associated doses? How much of each type of each administration is absorbed?

Nicotine spray- 1mg (20-50%)
Nicotine gum- 2-4mg (50-70%)
Cigarettes- 9-17mg (20%)
Nicotine patch- 15-22mg/day (70%)


Where is nicotine absorbed?

pKa of nicotine is 7.9 but cigarette smoke is acidic so it is not absorbed in the buccal cavity
Absorption in alveoli independent of pH


How is nicotine metabolised?

70-80% is converted to Cotinine by Hepatic CYP2A6


What is the half life of nicotine?

T½ = 1-4 hours


What are the pharmacodynamics of nicotine?

Nicotine is an agonist on nicotinic receptors so has a profound effect on the nervous system
- Nicotine binds to nicotinic ACh receptors on cell bodies in the ventral tegmental area
- Stimulates release of dopamine in the nucleus accumbens


What are the effects of nicotine on the cardiovascular system?

↑ sympathetic stimulation (CNS and adrenals)
↑ Heart rate and systolic volume
Vasodilation of skeletal muscle arterioles
↑ lipolysis, FFA, VLDL
↑ TXA₂ (platelet activation)
↓ NO
No effect on lung function (only effect is due to components of smoke)


What effect does nicotine have on the metabolism and weight?

↑ metabolic rate
Nicotine is an appetite suppressant so reduces smokers weight


What effect does nicotine have on neurodegenerative disorders?

Nicotine is protective against neurodegenerative disorders


How does nicotine prevent Parkinson's disease?

Nicotine increases brain CYPs which metabolise neurotoxins which cause Parkinson's disease


How does nicotine prevent Alzheimer's disease?

↓ β-amyloid toxicity
↓ amyloid precursor protein


How does caffeine affect the reward pathway?

Caffeine is an adenosine (A1) receptor antagonist so it can induce euphoria by blocking the effects of adenosine
- Caffeine increases dopamine release
- Adenosine binds to A1 receptors- decreases the release of dopamine and decreases D1 receptor function


How do you calculate the number of units in an alcoholic drink?

Units = [%ABV x volume(ml)] / 1000


What is the recommended safe level of alcohol to consume per week?

Men and women ≤ 14 units / week


How many units of alcohol consumed in one sitting is classed as binge drinking?

>8 units


What is the legal driving limit blood alcohol level? How many drinks is this?

1 drink


What effect does drinking on a full stomach have on your blood alcohol level?

Speed of onset ∝ Gastric emptying
Drinking on a full stomach slows the speed of gastric emptying so the speed of onset of the alcohol is slower
If you drink on a full stomach the alcohol is retained in the stomach for longer and it is not absorbed
Fluid stimulates gastric emptying so on an empty stomach it would go straight into the duodenum and be absorbed


Where is alcohol metabolised to acetaldehyde? What enzymes are involved?

Alcohol → acetaldehyde (toxic)
1) 85% in the liver (first pass hepatic metabolism)
- Alcohol dehydrogenase (75%)
- Mixed function oxidase (25%)
2) 15% in the GIT
- Alcohol dehydrogenase


What does a breath test measure?

Unmetabolised alcohol in your breath


What enzyme is responsible for increased alcohol tolerance?

Mixed function oxidase
It is upregulated in heavy alcohol consumption


What is the difference between blood alcohol levels in men and women who consume the same amount of alcohol?

♀ body water: 50%
♂ body water: 59%

Alcohol is fairly water soluble. Men have more body water and women have more adipose tissue so alcohol is better distributed and dissolved in men

Women also have less alcohol dehydrogenase


What is acetaldehyde converted to? What enzyme is involved?

Acetaldehyde → Acetic acid
- Aldehyde dehydrogenase


What causes asian flush?

A polymorphism in aldehyde dehydrogenase


What drug is used is alcohol aversion therapy? How does it work?

Causes acetaldehyde from breaking down acetaldehyde which is toxic, and therefore produces unwanted negative effects to be experienced


What is the primary effect of alcohol? What is this dependent on?

Depressant effect
Degree of CNS excitability
↙︎ ↘︎
Environment Personality
↙︎ ↘︎
Non-social Social
setting setting


What are the acute effects of alcohol on the CNS?

1. GABAa receptor: positive effect on function by post-synaptic and pre-synaptic influence- increases production of steroid (allopregnenolone)
2. NMDA firing rate is reduced (enhances an excitatory transmitter)
3. Reduces neurotransmitter exocytosis (decrease Ca²⁺ channels)


What is the potency and selectivity of ethanol?

Low potency
Low selectivity
Alcohol is a small straight forward molecule which binds to a lot of targets and influences a lot of symptoms (if large amount in the system) so it has large effects very easily


How does alcohol have an effect in the limbic system?

Minds to μ-receptors which decreases GABA firing. Not a selective agonist like opiates so does not have as powerful an effect as heroin


How does alcohol cause cutaneous vasodilation?

↓ Ca²⁺ entry
↑ Prostaglandins
Though to be the effect of acetaldehyde


How does chronic alcohol consumption cause increased blood pressure?

- Centrally mediated decrease in baroreceptor sensitivity leads to an acute increase in heart rate.
- Alcohol diminishes the brains control of arteriole baroreceptors


How does alcohol cause diuresis (polyuria)?

Acetaldehyde has an effect on the posterior pituitary by preventing vasopressin secretion
Less vasopressin (ADH) means more water excretion


A deficiency in what is the reason for disorders associated with the CNS resultant from chronic alcohol consumption?



What CNS conditions are associated with chronic alcohol abuse? Briefly explain.

1) Dementia
Cortical atrophy / ↓ volume cerebral white matter
2) Ataxia
Cerebellar cortex degeneration
3) Wernicke-Korsakoff syndrome
Thiamine deficiency
4) Wernicke's encephalopathy
3rd ventricle and aqueduct
5) Korsakoff's psychosis
Dorsomedial thalamus


What is Wernicke's encephalopathy?

Neuropsychiatric condition characterised by the triad ophthalmoplegia, ataxia and confusion (only 10% experience all three)
Caused by overwhelming metabolic demands on brain cells that have depleted intracellular thiamine (vit B1)


What is Korsakoff's psychosis?

Associated with polyneuritis
Characterised by an impaired ability to acquire new information and substantial, irregular memory loss


How does chronic alcohol consumption result in a fatty liver?

Metabolism of alcohol uses NAD⁺ to produce NADH. This disrupts the dehydrogenase-related reactions in the cytoplasm and mitochondria (TCA and β-oxidation of fatty acids) thereby suppressing energy supply and fatty acid oxidation
This also diverts NAD⁺ from normal functions such as glycolysis to alcohol metabolism. Acetyl CoA (unable to enter the citric acid cycle) are transformed to ketones


How does hepatitis result from chronic alcohol abuse?

Mixed function oxidase enzyme generates free radicals. These free radicals generate an inflammatory stimulus, which if prolonged, releases cytokines
This is reversible


How does cirrhosis result from chronic alcohol abuse?

After hepatitis is the alcohol consumption is prolonged the liver will get cirrhosis
- Decreased hepatocyte regeneration
- Increased fibroblasts
- Decreased active liver tissue


What are the benefits of low dose alcohol consumption?

↓ Mortality from coronary artery disese
↑ HDLs
↑ tPA levels / ↓ platelet aggregation

Some evidence that it is specifically wine


What are the effects of chronic alcohol consumption of the GIT?

Damage to gastric mucosa ∝ dose
Acetaldehyde could be carcinogenic


What are the effects of chronic alcohol consumption on the endocrine system?

↑ ACTH secretion
↓ Testosterone secretion
Effects sex steroid function


What causes a hangover after drinking alcohol?

Negative symptoms occur when blood alcohol reaches 0
- Nausea:
Irritant → Vagus → Vomiting centre
- Headache
- Fatigue
Rebound excitation = poor sleep quality
- Restlessness and muscle tremors
- Polyuria and polydipsia
↓ ADH secretion


What are the different procoagulants in the blood?

- Prothrombin
- Factors V, VII-XIII
- Fibrinogen


What are the different anticoagulants in the blood?

- Plasminogen
- TFPI (Tissue factor pathway inhibitor)
- Proteins C & S
- Antithrombin


What type of process is haemostasis?

A physiological process
- Blood coagulation prevents excessive loss of blood


What type of process if thrombosis?

A pathophysiological process
- Blood coagulates within blood vessel → obstructs blood flow


What is a red thrombus?

Venous thromboses
- High fibrin component


What type os process if atherosclerosis?

A pathophysiological process
- thrombus forms within an atherosclerotic plaque
Plaque rupture → thrombus released into lumen (ischaemia)


What is a white thrombus?

Arterial thromboses
- High platelet components


What is Virchow's traid for thrombus formation?

1. Rate of blood flow
Blood flow is slow/stagnating → no replenishment of anticoagulant factors and balance adjusted in favour of coagulation
2. Consistency of blood
Natural imbalance between procoagulation and anticoagulation factors e.g. Factor V leiden
3. Blood vessel wall integrity
Damaged endothelia → blood exposed to procoagulation factors


What is the cell-based theory of coagulation?

1. Initiation
Small scale production of thrombin
2. Amplification
Large scale thrombin production on the surface of platelets
3. Propagation
Thrombin mediated generation of fibrin strands


What is the process of initiation in coagulation?

Small scale thrombin production
1. Tissue factor (TF)
TF bearing cells activate factors X and V forming → prothrombinase complex
2. Prothrombinase complex
This activates factor II (prothrombin) creating factor IIa (thrombin)
3. Antithrombin (AT-III)
AT-III → initiates fIIa and fXa


How does Dabigatran cause anticoagulation? How is it administered?

Inhibits factor IIa


How does Rivaroxaban cause anticoagulation? How is it administered?

Factor Xa inhibitor


How does Heparin cause anticoagulation? How is it administered?

Activates AT-III (↓fIIa and ↓fXa)
IV or SC


What is Dalteparin? How does it cause anticoagulation?

A low-molecular weight heparin
Activates AT-III (↓fXa)


How does Warfarin cause anticoagulation? How is it administered?

A vitamin K antagonist
Vitamin K is required for the generation of factors II, VII, IX and X


What are the uses of anticoagulant drugs which target initiation?

Venous thrombosis
- Deep vein thrombosis and pulmonary embolism
- Thrombosis surgery
- Atrial fibrillation - prophylaxis of stroke


What drug inhibits factor Xa?



What drug activates AT-III?

(also Dalteparin)


What drug inhibits factor IIa?



What is the process of amplification in coagulation?

Platelet activation and aggregation
1. Thrombin
Factor IIa → activates platelets
2. Activated platelet
- Changes shape
- Becomes 'sticky' and attaches other platelets


What is the process of platelet activation?

- Thrombin binds to protease-activated receptor (PAR) on platelet surface
- PAR activation → rise in intracellular Ca²⁺
- Ca²⁺ rise → exocytosis of adenosine diphosphate (ADP) from dense granules
1. ADP receptors
- ADP activates P2Y₁₂ receptors → platelet activation / aggregation
2. Cyclo-oxygenase (COX)
- PAR activation → liberates arachadonic acid (AA)
- COX generates thromboxane A₂ (TXA₂) from AA
3. Glycoprotein IIb/IIIa receptor (GPIIb/IIIa)
- TXA₂ activation → expression of GPIIb/IIIa integrin receptor on platelet surface
- GPIIb/IIIa - involved in platelet aggregation


How does Clopidogrel prevent platelet activation? How is it administered?

ADP (P2Y₁₂) receptor antagonist


How does Aspirin prevent platelet activation? How is it administered?

Irreversible COX-1 inhibitor- inhibits production of TXA₂


How is Abciximab administered?

IV or SC
Only used by specialists


What are the indications of drugs which target platelet activation?

Arterial thrombosis
- Acute coronary syndromes - myocardial infarction
- Atrial fibrillation - prophylaxis of stroke


What is the process of propagation in coagulation?

Generation of fibrin strands
1. Activated platelets
Large-scale thrombin production
2. Thrombin
Factor IIa → binds to fibrogen and convert to fibrin strands


How do thrombolytics works?

Convert plasminogen → plasmin
Plasmin - protease degrades fibrin


How does Alteplase work as a thrombolytic? How is it administered?

Recombinant tissue type plasminogen activator (rt-PA)


What are the indications of thrombolytics?

Arterial and venous thrombosis
DO NOT remove preformed clots
- Stroke - first-line treatment
- ST- elevated MI


What is deep vein thrombosis? How does it cause pulmonary embolism?

Red thrombus → deep vein of the leg (e.g. popliteal vein)
Caused by:
- ↓ rate of blood flow
- Damage to endothelium
thrombus detachment → pulmonary embolism (PE)


How is DVT or pulmonary embolism managed?

Restore balance between coagulants and anti-coaulants
- ↓ levels of anticoaulant
- Anticoagulants


What is a NSTEMI?

Non-ST elevated myocardial infarction (MI)
- 'White' thrombus → partially occluded coronary artery
Caused by:
- Damage to endothelium
- Atheroma formation
- Platelet aggregation


How is NSTEMI managed?

Reduce lipid accumulation
Reduce platelet aggregation
Prevent further arterial occlusion
- ↓ platelet activation / aggregation
- Anti-platelets


What is a STEMI?

ST-elevated myocardial infarction
- 'White' thrombus → fully occluded coronary artery
Caused by:
- Damage to endothelium
- Atheroma formation
- Platelet aggregation


How is a STEMI managed?

Reduce lipid accumulation
Reduce platelet aggregation
Dissolve thrombus
Prevent death
- ↓ Platelet activation / aggregation
- Dissolve clot
- Anti-platelets and thrombolytics


What is the difference between haemostasis and thrombosis?

Haemostasis is a physiological process preventing blood loss, whereas thrombosis is a pathophysiological process


What is the main risk factor for atherosclerosis?



What is the main difference between LDL and HDL?

Surface apoproteins (these allow the lipoproteins to circulate)
HDL- Apoprotein A-1
LDL- Apoprotein B


What is the exogenous pathway of lipid metabolism?

Intestine- dietary triglycerides and cholesterol

↙︎ ↘︎
FFA Chylomicron remnant
↙︎ ↘︎ ↙︎ ↘︎
Skeletal Adipose Liver Atheroma
muscle tissue


What enzyme turns VLDLs to smaller LDLs?
(Large VLDL → Small VLDL)

Hepatic lipase


What enzyme turns LDLs to larger VLDLs?
(IDL → Small VLDL)

Lipoprotein lipase


Atherosclerosis is an inflammatory process. What cell is involved in this?

They get into the subepithelial space and are converted to foam cells, forming the core of the atheromatous plaque


What is the process of development of an atherosclerotic plaque?

1. LDL moves into the subendothelium
2. LDL is oxidised by macrophages and smooth muscle cells
3. Release of growth factors and cytokines which attract additional macrophages
4. Macrophages become foam cells which accumulate and smooth muscle cell proliferation result in the growth of the plaque


What contributes to endothelial dysfunction in atherosclerosis?

Increased endothelial permeability → Upregulation of endothelial adhesion molecules →Leukocyte adhesion → Migration of leukocytes into the artery wall

Endothelium becomes leaky


What contributes to fatty streak formation in atherosclerosis?

- Adherence and entry of leukocytes
- Migration of smooth muscle cells
- Activation of T cells
- Adherence and aggregation of platelets
- Formation of foam cells


What contributes to the formation of the complicated atherosclerotic plaque?

- Formation of the fibrous cap
- Accumulation of macrophages
- Formation of necrotic core


What are the different types of atherosclerotic lesion?

1. Coronary artery at lesion-prone location
- Adaptive thickening (smooth muscle
2. Type II lesion
- Macrophage foam cells
3. Type III (preatheroma)
- Small pools of extracellular lipid
4. Type 4 (atheroma)
- Core of extracellular lipid
5. Type V (fibroatheroma)
- Fibrous thickening
6. Type VI (complicated lesion)
- Thrombus
- Fissure and haematoma


What inherited condition causes atherosclerosis to occur in teenage years?

Familial hypercholesterolaemia


What type of lipoproteins cause inflammation in atherosclerosis?

Remnant lipoproteins


What is the difference between a vulnerable and stable plaque in atherosclerosis?

In stable plaques the lumen and lipid core is separated by a thick layer of mostly collagen. This is not the case in vulnerable plaques which have a thin layer


A 10% increase in LDL cholesterol results in how much increase in risk of CHD?



What effect does HDL cholesterol have on atherosclerosis?

Has a protective effect for risk of atherosclerosis and CHD
- The lower the HDL cholesterol level the higher the risk for atherosclerosis ad CHD


What causes HDL level to be lower?

- Smoking
- Obesity
- Physical inactivity


How do statins effect the cholesterol synthesis pathway?

- Block HMG-CoA reductase which prevents production of cholesterol from acetyl-CoA
- Increases LDL receptors on hepatocytes, which then internalise LDL and break it down


What is the newest and least potent statin?



How do NSAIDs work>

Inhibit the synthesis of prostanoids
- Lipid mediators derived from arachidonic acid
- Prostaglandins and thromboxanes
- Receptor mediated
NSAIDs inhibit Cyclo-oxygenases (COX-1 and -2)
This inhibits production of PGH₂ which then produces
- Prostacyclin
- PGE₂
- PGD₂
- PGF₂∝
- Thromboxane A₂


What isoform of COX is inhibited by ibuprofen?

Both COX-1 and COX-2


What isoform of COX is inhibited by NSAIDs of the Coxib family? Give an example of these drugs

Inhibits COX-2
e.g. celecoxib


What are the different prostanoid receptors?

- DP1, DP2
- EP1, EP2, EP3, EP4
- FP
- IP1, IP2
- TP


What type of receptor are prostanoid receptors?

G protein-coupled


What receptors are activated by PGE₂?



What are the unwanted actions of PGE₂?

- Increased pain perception*
- Thermoregulation*
- Acute inflammatory response*
- Immune responses
- Tumorigenesis
- Inhibition of apoptosis

* Targeted by NSAIDs


How does PGE₂ increase pain perception?

Stimulation of PG receptors sensitises the nociceptors which cause pain both acutely and chronically


What effect does PGE₂ have on body temperature?

PGE₂ stimulates hypothalamic neurones initiating a rise in body temperature


What is the role of PGE₂ in acute inflammation?

- Irritants stimulate keratinocytes to release PGE₂
- PGE₂ binds to EP3 on mast cells which initiates a cascade resulting in histamine release and release of IL-6


What are the desirable physiological actions of prostanoids?

- Gastroprotection
- Renal salt and water homeostasis
- Bronchodilation
- Vasoregulation (dilation and constriction depending on receptor activated)


How is PGE₂ involved in gastric cytoprotection?

- Downregulates HCl secretion
- Stimulates mucus and bicarbonate secretion


How do NSAIDs contribute to ulceration?

COX-1 mediated
Less mucus production to protect the stomach plus increased HCl secretion


How is PGE₂ involved in salt and water homeostasis?

COX-1 and COX-2 control the glomerulus
COX-2 controls reabsorption in the ascending limb of the loop of Henle
COX-1 controls reabsorption in the collecting duct


How do NSAIDs cause renal toxicity?

- Constriction of afferent renal arteriole
- Reduction in renal artery flow
- Reduced glomerular filtration rate


Why do some asthmatics experience worsening symptoms with NSAIDs?

-COX inhibitor. Blocks production of PGE₂ from arachidonic acid
- PGE₂ is a bronchodilator
- This causes increased production of leukotreines (using lipoxygenase enzyme) which is a bronchoconstrictor
- PGE₂ inhibits lipoxygenase so reduces leukotreines
- LT4 is the most prominent leukotreine in the lungs


What are the unwanted effects of NSAIDs on the CVS?

- Vasoconstriction
- Salt and water retention
- Reduced effect of antihypertensives
Increased risk of:
- Hypertension
- Myocardial infarction
- Stroke


What are the deaths from NSAIDs caused by?

1. CVS
- Stroke
- MI
2. GI bleed


What are the effects of COX-2 on the CVS?

COX-2 inhibitors pose higher risk of CVD than conventional NSAIDs
Mechanism is unclear
- Enhanced probability of coronary atherothrombosis
- Increased risk of heart failure
- Increased long-term CV risk


What strategies other than COX_2 selective NSAIDs limit the GI side effects?

- Topical application
- Minimise NSAID use in patients with history of GI ulceration
- Treat H. pylori if present
- If NSAID is essential, administer with omeprazole or other proton pump inhibitor
- Minimise NSAID use in patients with other risk factors and reduce risk factors where possible (e.g. alcohol consumption, anticoagulant or glucocorticoid steroid use)


What is the mechanism of NSAID Aspirin?

Unique among NSAIDs
- Selective for COX-1
- Binds irreversibly to COX enzymes
- Has anti-inflammatory, analgesic and anti-pyretic actions
- Reduces platelet aggregation


What causes the anti-platelet actions of aspirin?

- Very high degree of COX-1 inhibition which effectively suppresses TXA₂ production by platelets
- Covalent binding which permanently inhibits platelet COX-1
- Relatively low capacity to inhibit COX-2
- Need low dose to allow endothelial resynthesis of COX-2


What are the major side-effects of Aspirin?

- Gastric irritation and ulceration
- Bronchospasm in sensitive asthmatics
- Prolonged bleeding times
- Nephrotoxicity
- Side effects are more likely with aspirin than other NSAIDs because it inhibits COX covalently, rather than its selectivity for COX


What happens if you overdose on paracetamol?

Paracetamol forms a toxic metabolite (NAPQI) in overdose which is then converted to an inactive reduced form by Glutathione S-transferase
- If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death
- Will result in irreversible liver failure


What is the antidote for paracetamol poisoning?

- Add compound with -SH groups
- Usually intravenous Acetylcysteine (in cases of attempted suicide)
- Occassionally oral methionine
- If not administered early enough, liver failure may be unpreventable


What are the guidelines on paracetamol sales?

- Pack size restricted to 16 x 500mg tablets
- No more then 2 packs per transaction
- Illegal to sell more than 100 paracetamol in one transaction


Inhibition of which enzyme will reduce platelet aggregation with the fewest side effects?

Thromboxane A₂ synthase
- TXA₂ causes platelet aggregation, but not much else


Assertion: Inhibition of PGI₂ synthesis by low-dose aspirin decreases the risk of stroke
Reason: Decreased PGI₂ reduces platelet aggregation

Assertion: False
Reason: False
Synthesis of PGI₂ (prostacyclin) is inhibited by low-dose aspirin, but it is not this action which decreases the risk of stroke, because PGI₂ actually reduces platelet aggregation. It's te inhibition of thromboxane synthesis


What type of receptor is found on postganglionic receptors?

Nicotinic receptors (receives signals from preganglionic neurons)


Where are muscarinic receptors found? Specifically what types of receptor?

Receives signals from postganglionic
M1→ Brain
M2→ Heart
M3→ Everything else


Why are the effects of ACh transient?

It is broken down by acetylcholinesterase after a few seconds


The action of ACh in the respiratory tract mimics the stimulation of which nerve?

Vagus nerve


What is airway resistance? What factors contribute to airway resistance?

Resistance to the flow of air into the lungs due to surface area
- Bronchoconstriction
- Mucus secretion
- Inflammatory response (histamine and cytokines promote oedema)
- COPD (causes reduction in surface area)
- Intubation
- Parasympathetic nervous system contributes to airway resistance by stimulating bronchoconstriction


How would an antimuscarinic agent help a patient with COPD who smokes?

- Cigarette smoking causes inhalation of irritants into the lungs which stimulates the PNS to induce bronchoconstriction
- PNS stimulates muscarinic receptors to induce bronchoconstriction. An antimuscarinic would prevent this
- If you stop smoking the irritants will clear so the PNS stimulation will stop


What side effects might a patient experience after treatment with an oral muscarinic antagonist?

- Constipation (interferes with gut activity and secretions)
- Tachycardia
- No sweating
- Reduced secretions
- Impaired vision
- Dysregulation of bladder function


Muscarinic antagonists have a range of side effects. How would these be avoided when treating a smoker with COPD?

- Selective for M3 receptor
- Administered by inhalation so low dose can be given straight to target tissue
- Make drug less lipid soluble so it can diffuse across the alveoli


Why does antihistamine not treat asthma?

Because histamine is not the only contributor to asthma symptoms


What endogenous mediators may contribute to the bronchoconstriction observed in patients with asthma?

- Histamine
- Leukotreines
- Antibody mediated (IgE)
- Prostaglandins


What precautions should an asthmatic take if they want to play sports?

- Take β2 agonist (e.g. Salbutamol)
- Warm up (exercise) prior to intense exercise


When comparing a transdermal and oral NSAID in sensitive asthmatics should the different routes of administration influence the severity of bronchoconstriction?

- Depends on the dose
- Transdermal is the best route of administration- it has to be lipid soluble to be administered this way, and will diffuse readily into the blood stream
- Oral administration has more barriers


What is the rational for using a leukotreine antagonist (e.g. montelukast) in an asthmatic to allow them to take NSAIDs?

- Stops bronchoconstriction
- NSAID sensitive asthmatics have upregulated leukotreines so blocking this will prevent bronchoconstriction in the lungs


What is the physiological vomiting pathway?

- A deep breath is taken, the glottis is closed and the larynx is raised to open the upper oesophageal sphincter. Also, the soft palate is elevated to close off the posterior nares.
- The diaphragm is contracted sharply downward to create negative pressure in the thorax, which facilitates opening of the oesophagus and distal oesophageal sphincter
- Simultaneously with downward movement of the diaphragm, the muscles of the abdominal wall are vigorously contracted, squeezing the stomach and thus elevating intragastric pressure. With the pylorus closed and the oesophagus relatively open, the route of exit is clear


What are the consequences of severe vomiting?

- Dehydration
- Loss of gastric H⁺ and Cl⁻ ions may lead to hypochloaemic metabolic alkalosis (↑ blood pH)
- Contributes to a reduction in renal bicarbonate excretion and an increase in bicarbonate reabsorption; accompanied by increased Na⁺ reabsorption in exchange for K⁺, leading to hypokalaemia


What pathways feed into the vomiting centre in the brain?

- Vestibular system
- Chemoreceptor trigger zone (area postrema)
- Vomiting centre (nucleus of tractus solitarius)
- GI tract and heart


What parts of the CNS contribute to vomiting?

- Cortex
- Thalamus
- Hypothalamus
- Meninges


What part of the vestibular system contributes to vomiting?

- H₁ receptor
- M₁ receptor


What part of the chemoreceptor trigger zone contributes to vomiting?

- Chemoreceptors
- D₂ receptors
- NK₁ receptor
- (5-HT₃ receptor)


What part of the vomiting centre contributes to vomiting?

- Chemoreceptors
- D₂ receptors
- NK₁ receptor
- (5-HT₃ receptor)


What part of the GI tract and heart contributes to vomiting?

- Mechanoreceptors
- Chemoreceptors
- 5-HT₃ receptor


What factors affect the vestibular system to induce vomiting?

- Motion
- Labyrinth disorders


What factors affect the chemoreceptor trigger zone to induce vomiting?

- Drugs
- Metabolic products
- Bacterial toxins


What factors affect the peripheral pathways to induce vomiting?

- Mechanical stretch (e.g GI obstruction or stasis)
- GI mucosal injury (e.g. metastases, candida infection, GERD, radiation therapy, chemotherapy)
- Local toxins and drugs


What factors affect the cortex to induce vomiting?

- Sensory input
- Anxiety
- Meningeal irritation
- Increased intracranial pressure


What is the mechanism of action of promethazine?

Mixed receptor antagonists
- Competitive antagonist at histaminergic (type H₁), cholinergic (muscarinic, M) and dopaminergic (type D₂) receptors
- Order of potency of antagonistic activity: H₁>M>D₂ receptors
- Acts centrally (vestibular nucleus, CTZ, vomiting centre) to block activation of vomiting centre


What is the use of promethazine as an anti-emetic?

- Motion sickness - normally used prophylactically, but some benefit may be gained if it is taken after the onset of nausea and vomiting
- Disorders of the labyrinth e.g. Meniere's disease
- Hyperemesis gravidarum
- Pre-and post-operatively (sedative and anti-muscarinic action are also useful)


What are the pharmacokinetics of promethazine?

- Administered orally
- Onset of action 1-2 hours
- Maximum effect circa 4 hours
- Duration of action 24 hours


What are the unwanted effects or promethazine?

- Dizziness
- Tinnitus
- Fatigue
- Sedation
- Excitation in excess
- Antimuscarinic sid-effects


Give examples of dopamine receptor antagonists

- Metoclopramide
- Domperidone


What is the mechanism of action of dopamine (D2) receptor antagonists?

- Acts centrally, especially at chemoreceptor trigger zone (CTZ)
- Prokinetic effects in the GI tract by blocking the inhibitory effect of dopamine on myenteric motor neurons (which suppress intestinal motility)
- Increases smooth muscle motility (from oesophagus to small intestine)
- Accelerated gastric emptying
- Accelerates transit of intestinal contents (from duodenum to ileo-coecal valve)


What are the uses of metoclopramide and domperidone?

To treat nausea and vomiting associated with:
- Uraemia (severe renal failure)
- Radiation sickness
- GI disorders
- Cancer chemotherapy (high doses) e.g. cisplatin (intractable vomiting)
- Parkinson's disease treatments with stimulate dopaminergic transmission in chemoreceptor trigger zone (e.g. L-DOPA, DA agonists)

Not effective against motion sickness


What are the pharmacokinetics of metoclopramide or domperidone?

- May be administered orally; rapidly absorbed; extensive first pass metabolism. May also be given I.V.
- Metoclopramide crosses the BBB
- Crosses the placenta


What is the significance of dopamine receptor antagonists with co-administered drugs?

- Absorption and hence effectiveness of digoxin may be reduced
- Nutrient supply may be compromised; especially important in conditions such as diabetes mellitus


What are the side effects of metoclopramide in the CNS?

No anti-psychotic actions
- Drowsiness
- Dizziness
- Anxiety
- Extrapyramidal reactions: children more susceptible than adults (Parkinsonian-like syndrome: rigidity, tremor, motor restlessness)


What are the side effects of D2 receptor antagonists in the endocrine system?

- Hyperprolactinaemia
- Galactorrhoea
- Disorders of menstruation


What is the mechanism of action of hyoscine?

Acts centrally, especially in the vestibular nuclei and CTZ to block activation of vomiting centre


What is the order of antagonistic potency of metoclopramide?

D₂ >> H₁ >>> Muscarinic receptors


What is the order of antagonistic potency of hyoscine?

Muscarinic >>> D₂ = H₁


What are the uses of hyoscine as an anti-emetic?

- Prevention of motion sickness
- Has little effects once nausea/emesis is established
- In operative pre-medication


What are the pharmacokinetics of hyoscine?

Can be administered orally (peak effect in 1-2 hours), intravenously or transdermally


What are the side effects of hyoscine?

Typical anti-muscarinic side effects:
- Drowsiness
- Dry mouth
- Cycloplegia (paralysis of the ciliary muscle of the eye, loss of accommodation)
- Mydriasis


What is the mechanism of action of ondansetron?

Acts to block transmission in visceral afferents and CTZ


What are the uses of ondansetron as an anti-emetic?

- Main use in preventing anticancer drug-induced vomiting, especially cisplatin
- Radiotherapy-induced sickness
- Post-operative nausea and vomiting


What are the pharmacokinetics of ondansetron?

Administered orally, well absorbed, excreted in urine


What are the side effects of ondansetron?

- Headache
- Sensation of flushing and warmth
- Increased large bowel transit time (constipation)


What is ondansetron used in conjunction with? Why?

Used alone the efficacy may wear off
- 5-HT₃ receptor antagonists may be used for low emetogenic chemotherapy
- Corticosteroids, such as dexamethasone, may be used in combination with 5-HT₃ receptor antagonists for high or moderately high emetogenic chemotherapy
- Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids


How can cannabinoids be used as anti-emetics?

- δ9-tetrahydrocannacinol (THC) isolated from marijuana or the synthetic agent Nabilone
- Effective at treating emesis from anti-cancer drugs which other antiemetic's are not very effective against e.g. Cisplatin
- Act at a number of cited within the CNS via the CB1 receptors which are located pre-synaptically and decrease the release of neurotransmitters associated with triggering the vomiting process
- Also inhibit prostaglandin synthesis which has been implicated in emesis from anti-cancer drugs


What are the risk factors for IBD?

1. Genetic predisposition
- People of white European origin most susceptible
2. Environmental factors which could include:
- Smoking (especially CD)
- Diet / obesity (diseases of affluence)
- Gut microbiome
3. Obesity is a risk factor for CD, but not UC


What is the progression of the defective interaction between mucosal immune system and gut flora in IBD?

Complex interplay between host and microbes

Disrupted innate immunity and impaired clearance

Prof-inflammatory compensatory responses

Granuloma formation and physical damage


What immune cells and cytokines mediate the response in Crohn's disease?

e.g. IFNγ, TNFα, IL-17, IL-23

Florid T cell expansion
Defective T cell apoptosis


What immune cells and cytokines mediate the response in Ulcerative Colitis?

e.g. IL-5, IL-13

Limited clonal expansion
Normal T cell apoptosis


What layers and regions of the gut are affected in IBD?

CD: All layers; any part of the gut (patchy)
UC: Mucosa/submucosa; rectum, spreading proximally (continuous)


What supportive therapies are used for an acutely sick IBD patient?

- Fluid/electrolyte replacement
- Blood transfusion/oral iron
- Nutritional support (malnutrition common)


What is the use of aminosalicylates in IBD?

Ulcerative Colitis
- First line in inducing and maintaining remission
- Good evidence base
Crohn's Disease
- Literature unclear
- Ineffective in inducing remission
- Less clear cut than utility in UC


Give examples of aminosalicylates.

- Mesalazine: 5-aminosalicylic acid (5-ASA)
- Olsalazine (2 linked 5-ASA molecules)
- Anti-inflammatory


What is the mechanism of action of 5-ASA?

- Inhibition of IL-1, TNF-α and platelet activating factor (PAF)
- Decreased antibody secretion
- Non-specific cytokine inhibition
- Reduced cell migration (macrophages)
- Localised inhibition of immune responses


Where is mesalazine and olsalazine absorbed?

- Absorbed in the small bowel and colon
- Metabolised by colonic flora
- Absorbed in the colon


What is the result of research into 5-ASA?

- More effective than a placebo
- Safe drug
- Superior to topical steroids in inducing remission in ulcerative colitis


What is the use of glucocorticoids in IBD?

Ulcerative Colitis:
- Use of glucocorticoids in decline
- Can be used topically (enema) or I.V. if very severe
- Evidence that aminosalicylates superior
Crohn's Disease
- GCs remain drugs of choice for inducing remission
- Likely to get side effects if used to maintain remission


What are glucocorticoids? Give examples.

Powerful anti-inflammatory and immunosuppressive drugs
Derived from cortisol
Activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors
e.g. Prednisolone, fluticasone, budesonide


How are the unwanted effects of glucocorticoids minimised?

- Administer topically - fluid or foam enemas or suppositories
- Use a low dose in combination with another drug
- Use an oral or topically administered drug with high hepatic first pass metabolsim (e.g. Budesonide) so little escapes into the systemic circulation (used in mild cases as budesonide worse at inducing remission in active CD)


Give examples of immunosuppressive agents and their applications.

Azathioprine and 6-mercaptopurine
- No advantage over placebo in active CD
- Some success in UC
- Efficacy in some IBD patients
- In severe UC only


What are the uses of azathioprine?

- Immunosuppressive
- Mainly used to maintain remission in CD (allows reduction in glucocorticoids)
- Slow onset- 3-4 months treatment for clinical benefit


What are the pharmacodynamics of azathioprine?

It is a prodrug
- Activated by gut flora to 6-mercaptopurine
- Give 6-mercaptopurine directly
- Purine antagonist


What are the effects of azathioprine on immune responses?

It impairs:
- Cell- and antibody-mediated immune responses
- Lymphocyte proliferation
- Mononuclear cell infiltration
- Synthesis of antibodies

It enhances:
- T cell apoptosis


What are the unwanted effects of azathioprine?

- Nearly 10% of patients have to stop treatment because of side effects
- Pancreatitis
- Bone marrow suppression
- Hepatotoxicity
- Increased risk (~4 fold) of lymphoma and skin cancer


What is the significance of azathioprine with gout treatment?

Allopurinol treats gout. It inhibits Xanthine oxidase involved in metabolism of 6-MP (from azathioprine) which diverts metabolism down other pathways, increasing associated side effects


What is the use of methotrexate in Crohn's disease?

- Induces and maintains remission
- Acts as a folate antagonist
- Reduces synthesis of thymidine and other purines
- Not widely used as monotherapy significant unwanted effects


What are the potentially curative therapies for IBD?

1. Manipulation of the microbiome
2. Biologic therapies
- Anti-TNFα (e.g. Infliximab)
- Anti-α-4-integrin (e.g. Natalizumab)


What techniques are used for manipulation of the microbiome?

1. Nutrition-based therapies
- No evidence for probiotics in CD
- Evidence for maintenance of remission in UC
2. Faecal microbiota replacement (FMT) therapies
- Insufficient evidence for FMT
- More studies needed
3. Antibiotic Treatment (Rifaximin)
- Interferes with bacterial transcription by binding to RNA polymerase
- Induces and sustains remission in moderate CD
- May be beneficial in UC
- May be microbiome modulator


What is the use of anti-TNFα in IBD?

- Used successfully in the treatment of CD
- 60% patients respond within 6 weeks
- Potentially curative
- Successful in some patients with refractory disease and fistulae
- Some evidence of effectiveness in UC


What is the mechanism of action of anti-TNFα?

- Reduces activation of TNFα receptors in the gut
- Reduces downstream inflammatory events
- Also binds to membrane associated TNFα
- Induces cytolysis of cell expressing TNFα
- Promotes apoptosis of activated T cells


What are the pharmacokinetics of infliximab?

- Give I.V.
- Very long half-life (9.5 days)
- Benefits can last for 30 weeks after a single infusion
- Most patients relapse after 8-12 weeks
- Therefore repeat infusion every 8 weeks


What are the problems with infliximab?

- Emerging evidence that up to 50% of responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance
- Attempts being made to optimise dosing regimens


What are the adverse effects of infliximab?

- 4x-5x increase in incidence of TB
- Also risk of reactivating dormant TB
- Increased risk of septicaemia
- Worsening of heart failure
- Increased risk of demyelinating disease
- Increased risk of malignancy
- Can be immunogenic- azathioprine reduces risk, but raises TB/malignancy risk


In IBD why does budesonide cause fewer unwanted systemic effects than prednisolone?

It is metabolised and inactivated locally


What drugs can be used to treat gastric and duodenal ulcers?

1. Antibiotics
2. Inhibitors of gastric acid secretion
3. Cytoprotective drugs
4. Antacids
5. Triple therapy


What is peptic ulcer disease?

Area of damage to the inner lining of
- the stomach (gastric ulcer)
- Upper part of the duodenum (duodenal ulcer)


What is the difference between pain from a gastric ulcer and a duodenal ulcer? What is the occurence of both?

Gastric ulcer: Pain at mealtimes when gastric acid is secreted
Duodenal ulcer: Pain relieved by a meal as pyloric sphincter closes; pain 2-3 hours after a meal

Occurrence: duodenal:gastric 4:1


What are the protective factors which ensure integrity of the gastrointestinal mucosa?

Lubricate ingested food and protect the stomach and duodenum from attack by acid and enzymes:
1. Mucous from gastric mucosa creates gastrointestinal mucosal barrier
2. HCO₃⁻ ions trapped in mucous generate a pH or 6-7 at mucosal surface
3. Locally produced prostaglandins stimulate mucous and bicarbonate production (paracrine action) and inhibit gastric acid secretion


What secretions in the stomach have the potential to damage the mucosal barrier?

1. Acid secretion from parietal cells of the oxyntic glands in the gastric mucosa
2. Pepsinogens from chief cells which can erode the mucous layer


What factors may cause damage to the mucosal gastrointestinal barrier?

- Increased acid and/or decreased bicarbonate production
- Decreased thickness of mucosal layer
- Increase in pepsin type I
- Decreased mucosal blood flow
- Infections with Helicobacter pylori may also play a role in pathogenesis of gastric cancer


What are the risk factors of peptic ulcer disease? What is the prevalence?

Risk factors:
- Genetic predisposition
- Stress
- Diet, alcohol, smoking

1:10 of the population in developed countries


How do you test patients for Helicobacter pylori?

Patients swallow urea labelled with an uncommon isotope, either radioactive carbon-14 or non-radioactive carbon-13.
In the subsequent 10-30 minutes the detection of isotope-labelled carbon dioxide in exhaled breath indicates that urea was split; this indicates that urease (which H. pylori uses to metabolise urea) is present in the stomach, so hence there is H. pylori present


What is the rational for antibiotic therapy in patients with a peptic ulcer?

- 50-80% are chronically infected
- 10-20% will go on to develop peptic ulcer disease or neoplasm
- Almost 100% of patients with duodenal ulcer and 80-90% with gastric ulcer are infected
- Current therapy aims for 90% eradication within 7-14 days


What are the methods of transmission of H. pylori?

- Socioeconomic conditions
- Contact with animals and contaminated faeces


What is the best practice in treating peptic ulcer disease?

Triple therapy:
1. Antibiotics (a single antibiotic is not sufficiently effective)
2. Drugs which reduce gastric acid secretion
3. Drugs which promote healing


What are the different types of gastric acid secretion inhibitors?

- Proton pump inhibitors
- Histamine type 2 (H₂) receptors
- Anti-muscarinics


What is the process of gastric acid secretion and it's control?

Parietal cells secrete HCl (pH < 1). The principle stimuli on parietal cells are:
1. Acetylcholine from the vagal nerve of PANS
2. Gastrin, stimulatory hormone produced in the antrum in response to food and vagal PANS, gastrin then releases histamine from the H cells which acts on the parietal cells
3. Prostaglandins E2 and I2 are local hormones that inhibit acid production and promote a good blood supply. Gastrin also indirectly increases pepsinogen secretion, stimulates blood flow and increases gastric motility. Secretin regulates water homeostasis and the pH of the duodenum
Somatostatin inhibits release of gastrin from G cells and histamine from H cells
Inhibitors of gastric acid production:
- Secretin
- GIP (gastric inhibitory peptide)


What are proton pump inhibitors? What is their mechanism of action? Give an example.

e.g. Omeprazole
Inhibits the basal and stimulated gastric acid secretion from the parietal cells by >90%
Mechanism of action:
- Irreversible inhibitors of the H⁺/K⁺ATPase
- Inactive at neutral pH
- As it is a weak base it accumulates in the cannaliculi of parietal cells; this concentrates its action there and prolongs its duration of action (2-3 days) and minimises its effect on ion pumps elsewhere in the body


What are the uses of proton pump inhibitors?

- Peptic ulcers which are resistant to H₂ antagonists
- Component of triple therapy
- Gastroesophageal reflux disease (GERD), oesophagitis
- Prophylaxis of peptic ulcers in the intensive care setting, and among high-risk patients prescribed aspirin, NSAIDs, as antiplatelets and anticoagulants


What are the pharmacokinetics of proton pump inhibitors?

Orally active; administered as an enteric coated slow-release formulation


What are the side effects of proton pump inhibitors?

Rare (short term use)
Long-term and/or high-dose administration associated with several potential side effects e.g. enteric infections (Clostridium difficile), community acquired pneumonia, and hip fracture


What are histamine type 2 (H₂) receptor antagonists? What is the mechanism of action? Give examples

Inhibits gastric acid secretion from the parietal cells by ~60% and are less effective at healing ulcers than PPIs
Mechanism of action:
- Competitive antagonism of H₂ histamine receptors
e.g. Cimetidine, ranitidine


What are the pharmacokinetics of histamine type 2 receptor antagonists

Orally administered, well absorbed

Ranitidine is longer acting than cimetidine


What are the side effects of H₂ receptor antagonists?

Rare (dizziness, headache)
Fewer side effects with Ranitidine (Zantac, available OTC)
Relapses likely after withdrawal of treatment, >90% recurrence within 1 year after initial healing


What is the use of antimuscarinics in peptic ulcer disease?

- Little use as anti-ulcer drugs alone
- More effective combination therapies


What are cyto-protective drugs? Give examples

These drugs enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer

- Sucralfate
- Bismuth chelate
- Misoprostol


What is sucralfate? How does it act?

It is a polymer containing aluminium hydroxide and sucrose octa-sulphate
- Acquires a strong negative charge in an acid environment
- Binds to positively charged groups in large molecules (proteins, glycoproteins) resulting in gel-like complexes, these coat and protect the ulcer, limit H⁺ diffusion and pepsin degradation of mucus
- Increases prostaglandin, mucous and HCO₃⁻ secretion and reduces the number of H. pylori


What are the side effects of Sucralfate?

Most of the orally administered Sucralfate remains in the GIT which may cause constipation or reduced absorption of some other drugs (e.g. antibiotics and digoxin)


What is Bismuth Chelate (Pepto-bismol)? What are its uses?

- Acts like sucralfate
- Used in triple therapy (in cases where resistance to drugs has been shown)
- Anti-inflammatory actions in the stomach
- Weak antibiotic and antacid properties


What is Misoprostol? How does it act?

It is a stable prostaglandin analogue. Orally administered
Mimics the action of locally produced prostaglandin to maintain the gastroduodenal mucosal barrier


What are the uses of Misoprostol?

May be co-prescribed with oral non-steroidal anti-inflammatory drugs (NSAIDs) when used chronically
NSAIDs block the COX enzyme required for prostaglandin synthesis from arachidonic acid
Therefore, there is a reduction in the natural factors that inhibit gastric acid secretion and stimulate mucus and HCO₃⁻ production


What are the unwanted effects of Misoprostol?

- Diarrhoea
- Abdominal cramps
- Uterine contractions (not to be given during pregnancy)


What are antacids? How are they administered?

Mainly salts of Na⁺, Al₃⁺ and Mg₂⁺
- Sodium bicarbonate has rapid effects
- Aluminium hydroxide and magnesium trisilicate have slower actions

Taken orally; primarily used for non-ulcer dyspepsia (OTC)


What is the mechanism of action of antacids?

- Neutralise acid, raises gastric pH, reduces pepsin activity
- May be effective in reducing duodenal ulcer recurrence rates


What are the problems associated with triple therapy?

- Compliance
- Resistance to antibiotics (may be superseeded by vaccination)
- Adverse response to alcohol (metronidazole interferes with alcohol metabolism)


What is gastroesophageal reflux disease?

Stomach and duodenal contents reflux into the oesophagus (oesophagitis)
- occasional and uncomplicated GERD
- heartburn, may treat by self medication with antacids and H₂ antagonists (OTC)
- chronically may progress to pre-malignant mucosal cells and potentially oesophageal adenocarcinoma


How do you treat gastroesophageal reflux disease?

PPIs (drug of choice) or H₂ antagonists (less effective)
Combine with drugs that increase gastric motility and emptying of the stomach e.g. Dopamine D2 receptor antagonist (metoclopramise)


What is the incidence of serious adverse drug reaction?



What percentage of hospital admissions are due to adverse drug reactions?



What percentage of adverse drug reactions are preventable?

30% to 60%


What is the classification of adverse drug reactions?

- Onset
- Severity
- Type


What are the different types of onset of adverse drug reactions?

- Within 1 hour
- 1 to 24 hours
- > 2 days


What are the different severities of adverse drug reactions?

- requires no change in therapy
- requires change in therapy, additional treatment, hospitalisation
- disabling or life-threatening


What is a severe adverse drug reactions?

- Results in death
- Life-threatening
- Requires or prolongs hospitilisation
- Causes disability
- Causes congenital anomalies
- Requires intervention to prevent permanent injury


What is a type A adverse drug reactions? Give examples of drugs which cause type A reactions

- Extension of pharmacological effect
- Usually predictable and dose dependent
- Responsible for at least two-thirds of ADRs
- e.g. atenolol and heart block, anticholinergics and dry mouth, NSAIDs and peptic ulcer; paracetamol; digoxin


What is a type B adverse drug reactions? Give examples of drugs which cause type B reactions

- Idiosyncratic or immunologic reactions
- Includes allergy and "pseudoallergy"
- Rare (even very rare) and unpredictable
- 1/10,000 people: irreversible and mostly fatal
- e.g. chloramphenicol and aplastic anaemia, ACE inhibitors and angiodema


What is a type C adverse drug reactions? Give examples of drugs which cause type C reactions

- Associated with long-term use
- Involves dose accumulation
- e.g. methotrexate and liver fibrosis, antimalarials and ocular toxicity


What is a type D adverse drug reactions? Give examples of drugs which cause type D reactions

- Delayed effects (sometimes dose independent)
- Carcinogenicity (e.g. immunosuppressants)
- Teratogenicity (e.g. thalidomide)


What are the different types of type E adverse drug reactions? Give examples of causes of each type of reaction

Withdrawal reactions
- Opitates, bencodiazepines, corticosteroids

Rebound reactions
- Clonidine, β-blockers, corticosteroids

"Adaptive" reactions
- Neuroleptics (major tranquillisers)


What is clonidine? What happened during withdrawal?

A potent antihypertensive. Makes you drowsy and tired
Missed doses will cause the blood pressure to suddenly increase causing strokes or death in some cases
Usually given in long acting preparations to prevent this from happening


What is the ABCDE classification of adverse drug reactions?

A Augmented pharmacological effect
B Bizarre
C Chronic
D Delayed
E End-of-treatment


What are the different types of allergic reactions? Give examples of the causes of each

Type I - immediate, anaphylactic (IgE)
- e.g. anaphylaxis with penicillins
Type II - cytotoxic antibody (IgG, IgM)
- e.g. methyldopa and haemolytic anaemia
Type III - serum sickness (IgG, IgM)
- antigen-antibody complex
- e.g. procainamide-induced lupus
Type IV - delayed hypersensitivity (T cell)
- e.g. contact dermatitis


Give examples of pseudoallergies. What are the mechanisms behind each?

Aspirin/NSAIDs - bronchospasm
- bronchospasm affects mainly asthmatics
- blocking cyclooxygenase pathways which usually makes prostaglandins- AA is converted to leukotreines

ACE inhibitors - cough/angioedema
- ACE inhibitors stop the breakdown of inflammatory proteins (bradykinin) which irritate sensory nerves in the lungs and cause a cough


What are the common causes of adverse drug reactions?

- Antibiotics
- Antineoplastics*
- Anticoagulants
- Cardiovascular drugs*
- Hypoglycemics
- Antihypertensives
- NSAID/Analgesics*
- CNS drugs*

*account for ⅔ of fatal ADRs


What is the relationship between adverse drug reactions frequency and drug use?

Polypharmacy increases adverse drug reactions

The higher the number of drugs the higher the frequency of adverse drug reaction


What are the different methods of reporting adverse drug reactions?

Subjective report
- patient complaint
Objective report
- direct observation of event
- abnormal findings
• physical examination
• laboratory test
• diagnostic procedure


What is the yellow card scheme?

- Introduced in 1964 after thalidomide
- Run by the Committee on Safety of Medicines (part of the Medicines Control Agency)
- Entirely voluntary
- Can be used by doctors, dentists, nurses, coroners and pharmacists
- Includes blood products, vaccines, contrast media
- For established drugs only report SERIOUS adverse reactions (fatal, life-threatening, needing hospital admission, disabling)
- For "black triangle" drugs ∇ (newly licensed, usually <2 years) report any suspected adverse reaction


What are pharmaceutical interactions?

Drugs interacting outside the body (mostly IV infusions)


What are pharmacodynamic drug interactions?

Additive, synergistic or antagonistic effects from co-adminitration of two or more drugs
- Synergistic actions of antibiotics
- Overlapping toxicities - ethanol and benzodiazepines
- Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)


What are the effects of pharmacokinetic drug interactions?

- Alteration in absorption
- Proteins binding effects
- Changes in drug metabolism
- Alteration in elimination


How do pharmacokinetic drug interactions alter absorption of a drug?

- Irreversible binding of drugs in the GI tract (stops absorption of the drug and prevents entry into the circulation)
- Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe²⁺), antacids (Al³⁺, Ca²⁺, Mg²⁺), dairy products (Ca²⁺)


How do pharmacokinetic drug interactions affect protein binding interactions of a drug?

Competition between drugs for protein or tissue binding sites
- Increase in free (unbound) concentration may lead to enhanced pharmacological effect
Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions
PB interactions are not usually clinically significant but a few are (mostly with warfarin)


What are the different types of drug metabolism and elimination?

1. Drug excreted unchanged by the kidney
2. Phase 1 - original drug altered but then cleared by the liver or kidney
3. Drug altered once then altered again before being excreted by the kidney

(Drug converted from lipid to water soluble so it is easier to excrete in the kidney)


What is phase I metabolism?

- Oxidation
- Reduction
- Hydrolysis


What is phase II metabolism?

- Glucuronidation
- Sulphation
- Acetylation


What happens to drug metabolism with coadministration of other drugs?

Drug metabolism is inhibited or enhanced by coadministration of other drugs
- CYP 450 system has been most extensively studied
Phase 2 metabolic interactions (glucoronidation, etc) occur, research in this area is increasing


What is the metabolism of CYP 450 substrates?

Metabolism by a single isozyme (predominantly)
- few examples of clinically used drugs
- examples of drugs used primarliy in research on drug interactions
Metabolism by multiple isozymes
- Most drugs metabolised by more than one isozyme
• Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
- If co-administered with CYP450 inhibitor, some isozymes may "pick up slack" for inhibited isozyme


What CYP450 isozyme metabolises the largest proportion of drugs?



What drugs inhibit CYP 450?

- Cimetidine
- Erythromycin and related antibiotics
- Ketoconazole etc
- Ciprofloxacin and related antibiotics

- Ritonavir and other HIV drugs
- Fluoxetine ad other SSRIs
- Grapefruit juice

(Many HIV drugs are potent inhibitors of CYP 450)


What drugs are CYP 450 inducers?

- Rifampicin
- Carbamazepine
- (Phenobarbitone)
- (Phenytoin)
- St John's wort (hypericin)


Give examples of drug elimination interactions? Where do they occur?

Almost always in renal tubule
- Probenecid + penicillin (Good- induces elimination of penacillin)
- Lithium + thiazides (Bad- Causes toxic accumulation in the blood as thiazides reduce clearance of the drug. Toxic and potentially lethal)


Give examples of deliberate coadministered drug interactions. How do they work?

Levodopa + carbidopa
- Allows lower doses to be used because not broken down in the periphery
ACE inhibitors + thiazides
- Enhance each other's antihypertensive effects
Penicillins + gentamycin
- Due to severe staphylococcal infections
Salbutamol + ipratropium
- Treatment of asthma and COPD


What are the important functional groups in morphine?

- Tertiary nitrogen: Important to anchor the drug to the receptor; also determines if the drug is an agonist or an antagonist
- Two hydroxyl groups which prevent the drug from easily passing through lipid membranes


What is the difference between the structure of heroin and morphine? What difference does this make to the drug?

The two hydroxyl side chains in morphine have been acetylated in heroin. This makes the drug pass through lipid membranes easily


What is the structural difference between morphine and codeine? What effect does this have on the drug?

The 3 position hydroxyl group in morphine is converted to CH₃OH in codeine. It is effectively methyl codeine
Decreases the potency of the drug, as it changes the metabolism


What is the difference between morphine and methadone?

In methadone there is only a tertiary nitrogen but the phenyl group and quaternary carbon remain


What is the difference between morphine and fentanyl?

Very powerful but it only has a tertiary carbon


What are the pharmacokinetics of opioid administration? How is it administered?

Given orally; it is ionised in the stomach (pKa>8); relatively well absorbed in the small intestine.
Heavily metabolised in the liver- extensive first pass metabolism. Only ~20% opioids get into the blood.
The solution if to inject the drug- But still enters the brain relatively slowly


What are the pharmacokinetics of methadone or fentanyl?

They are far more lipid soluble than morphine
Fentanyl cay be given as a patch- will cross the skin
It is very addictive; can be administered sub-lingually


Why is methadone used to ween people off heroin over fentanyl?

Methadone and fentanyl are more lipid soluble than heroin and therefore more potent.
Fentanyl has fast metabolism and so would wear off quickly whereas methadone has slow metabolism so is long lasting.


What is codeine a prodrug of?



What are the different endogenous opioid peptides?(What opiate receptors do they bind to?)

- Endorphins (μ or δ)
- Enkephalins (δ)
- Dynorphins/neoendorphins (κ)


Where are the μ opiate receptors located? What do they influence?

- Thalamus
- Amygdala
- Nucleus accumbens



Where are the δ opiate receptors located? What do they influence?

- Nucleus accumbens
- Cerebral cortex
- Amygdala



Where are the κ opiate receptors located? What do they influence?

- Hypothalamus



What is the cellular mechanism of opiate receptors?

They depress the CNS. Three basic mechanisms
1. Hyperpolarisation (increase K efflux)
2. Decrease Ca inward current
3. Decrease adenylate cyclase activity (causing a general decrease in cellular activity)


What are the effects of opioids?

- Analgesia*
- Euphoria*
- Depression of cough centre (anti-tussive)*
- Depression of respiration (medulla)
- Stimulation of chemoreceptor trigger zone (nausea/vomiting)
- Pupillary constriction
- G.I. effects


What analgesic effect do opioids have?

- Decrease pain perception
- Increase pain tolerance


What is the process of modulation of pain transmission?

- Pain sensed in the periphery
- Relayed to dorsal horn
- Spinothalamic tracts relay to thalamus
- Sent to cortex to add emotional input (exaccerbate pain
Depress (pain tolerence pathway)
- PAG (peri aquaductal grey region): integrating centre for pain tolerance (signals from thalamus and cortex)
- NRM (nucleus raffae magnus): initiating point of effecting arm (signal from PAG)
- NRM depresses pain from dorsal horn
- LC (locus correliois): sympathetic nervous system reduces pain signalling (acts on dorsal horn)

- NRPG (nucleus reticularis paragigantocellularis): INDEPENDENT. Automatically regulates pain tolerence before rest of brain (reflex) by activating NRM


What role does the hypothalamus play in modulation of pain transmission?

Regulates PAG response based on health


How does NRM depress pain from the dorsal horn?

1. Automatically depresses signal from the dorsal horn (not processed)
2. Activates the substantia gelatinosa (mini brain of spinal cord) for further processing of signals- which then acts on dorsal horn


Where do opioids act in the pain pathway?

- Periphery
- Dorsal horn


How do opioids cause euphoria?

- Opiates act on μ receptor
- This reduces GABA firing
(GABA inhibits VTA (ventral tegmental area)
- Reduced firing stops inhibition which causes release of dopamine


What is the cough pathway?

1. Stimulation of mechanoreceptors or chemoreceptors (throat, respiratory pathway or stretch receptors in lungs)
2. Afferent impulses to cough centre (medulla)
3. Efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung
4. Increased contraction of diaphragmatic, abdominal and intercostal muscles = cough


How do opioids have an anti-tussive effect?

1. Prevent relay of sensory via Ach/NK C-fibres info to vagus
2. Act directly on cough centre
3. Inhibit 5HT¹ᴬ receptors


How do opioids cause respiratory depression?

They interfere with central chemoreceptors so control centre can't respond to change in blood CO2
Act on respiratory centre which generates breathing rhythm


How do opioids induce nausea/vomiting?

Act on chemoreceptor trigger zone which induces nausea (probably interference with GABA)


How do opioids cause miosis? What is the clinical relevance of this?

μ receptor on Edinger-Westphal nucleus in the preganglionic parasympathetic neurones to the eye. This is stimulates by opioids

Essential to diagnose heroin overdose if the patient is unconscious with pin-point pupils


How do opioids cause GI disturbances?

μ and κ receptors are everywhere in the enteric nervous system and opioids activate them


What is urticaria? What is the significance of this in association with opioids?

Looks like an allergic reaction to opioids. Not fully understood. Opioids induce histamine release (in some patients)- not receptor mediated
Influences pKA
6 position hydroxyl group has to be present to induce this response- SOLUTION switch the drug


How does tolerence occur with opioid use?

Not pharmacokinetic
Chronic opioid use upregulates arrestin which causes over-intenalisation of opioid receptors which increases tolerence of opioids


How does dependence occur with opioid use?

All recreational drugs have psycological dependence but only a few have physical dependence
- Cells upregulate adenylate cyclase to compensate for drug action
- When you withdraw this disrupts cell metabolism (for 1-2 weeks)


What is the treatment for opioid overdose?

Same structure as morphine but with long side chain on tertiary nitrogen group preventing it from activating the receptor (antagonist effect)


What can cause a difference in response to dose administration?

1. Error in prescription or dispensing
2. Patient non compliance
3. Drug formulation


What factors cause relative overdose or underdose?

1. Environmental exposure to chemical, inducing other drugs
- Enzyme induction
- Enzyme inhibition
2. Food intake
- Drugs may interact chemically with components of food; this may alter their absorption
- Foods delay gastric emptying and alter gastric pH
3. Fluid intake
- Most drugs are better absorbed if taken with water (e.g. may dissolve better)
- Fluids may stimulate gastric emptying
4. Age
5. Disease


How does age affect the response to a drug?

Newborn infants have:
- more body water than adults
- poorer renal function, with immature tubular secretion
- an immature BBB
- lower capacity for drug metabolism
They elderly have an overall deterioration in many physiological functions that may affect:
1. Drug absorption: decreased absorptive surface of small intestine
- Altered gastric and gut motility
- Increased rate of gastric emptying
2. Drug distribution: reduced lean body mass and body water, relative increase in fat
- Lipid soluble drugs have increased Vd and decreased blood levels
- Water soluble drugs have decreased Vd and increased blood levels
- Reduced plasma albumin, so fewer plasma protein binding sites
3. Drug metabolism
- Splanchnic and hepatic blood flow decrease by 0.3-1.5%/year
- Liver size and hepatocyte number decrease
- Hepatic enzyme activity and induction capacity decrease
4. Drug excretion: changes in renal function are probably the most important factors affecting drug handling in the elderly. With age there is a steady decline in the following factors:
- Reduced renal mass
- Reduced renal perfusion
- Reduced glomerular filtration rate
- Reduced tubular excretion
These changes are normal, may be compounded if the patient has renal disease
5. Organ sensitivity: the elderly tend to be more sensitive to CNS active drugs


How does disease affect the response to a drug?

1. General nutritional status
- Unbalanced diets may lead to deficiency states and enzyme abnormalities
- Starvation: decreased plasma protein binding and metabolism
- Obesity: increased lipid fraction
2. GI disorders e.g. achlorhydria, coeliac disease, Crohn's disease
- Altered drug metabolism
3. Congestive heart failure (especially in the elderly) may lead to:
- Reduced splanchnic blood flow
- Intestinal mucosal oedema
- Reduced hepatic clearance
4. Kidney failure (especially in the elderly) may lead to:
- Decreased drug excretion leading to toxicity
- Water overload leading to changes in drug concentration in different body fluid compartments
5. Liver failure may lead to:
- Reduced metabolism
- Reduced first pass metabolism (hence increased bioavailability)
- Decreased biliary secretion and hence decreased removal
- Decreased albumin synthesis and hence reduced plasma protein binding
6. Other acute or chronic disease states


What effect does Clarithromycin have on Warfarin? What other drugs have this effect?

Warfarin and clarithromycin are metabolised by the same liver enzymes, so co-administration causes them to compete and means there is more active drug in the system for longer
Other drugs: PPIs (e.g. omeprazole)


What effect does St. Johns wort have on Warfarin? What other drugs have this effect?

St Johns wort increases induction of liver enzymes and therefore increases metabolism of warfarin, reducing the amount of active drug in the system
St John's wort is an antidepressant
Other drugs: barbiturates


What must be checked before a dose of digoxin is increased? How would you ensure the dose of digoxin is correct?

Digoxin acts on the K⁺ binding site of the Na⁺K⁺ATPase to decrease heart rate so the blood K⁺ level must be monitored
To ensure the correct dose of digoxin you can measure the level of digoxin in the blood


What would cause the difference in response to Temazepam in a young adult and an elderly patient?

Temazepam is relatively water soluble. The percentage of body fat is higher in the elderly therefore water soluble drugs will be more effective


Why would weight loss change the effect of Warfarin?

- Warfarin is >90% plasma protein bound so weight loss (muscle/protein loss) will decrease the plasma proteins and therefore increase the amount of active Warfarin in the system
- Liver enzymes are also very dependent on nutritional status, so poor nutrition means there is decreased metabolism, so more drug remains in the blood and has greater effects.


What transport occurs across cells in the proximal convoluted tubule of the kidney?

H₂O and Na⁺ move down the concentration gradient (into the interstitium). Na⁺K⁺ATPase on basal membrane to actively pump Na⁺ out of cell to maintain the concentration gradient
Carbonic anhydrase converts HCO₃⁻+H⁺→CO₂+H₂O to be moved into the cell, then converted back to HCO₃⁻+H⁺ and is them pumped out of cell into the interstitium with Na⁺ cotransporter; H⁺/Na⁺ exchanger (into tubule lumen from cell) is coupled to Glucose/AA transport


What ion transport occurs in the loop of Henle? Where does it occur?

Occurs in the ascending limb of the loop of Henle
On apical membrane Na⁺2Cl⁻K⁺ co transporter moves ions into the cell and Na⁺K⁺ exchanger and K⁺Cl⁻ cotransporter move ions into the interstitium


What ions are transported in the distal tubule?

Na⁺Cl⁻ cotransporter from tubule into cell
Na⁺K⁺ exchanger and Cl⁻K⁺ cotransporter into interstitium


What ions are transported in the collecting duct?

Aldosterone in the cell drives Na⁺ reuptake ( delivered in the blood and diffuses into the cell)
Binds to mineralocorticoid receptor (to nucleus) increases production of Na⁺ channels and Na⁺K⁺ATPase
Vasopressin induces AQP2 to increase water resorption


What are the different classes of diuretics?

1. Osmotic diuretics
2. Carbonic anhydrase inhibitors
3. Loop diuretics
4. Thiazides
5. Potassium sparing diuretics


How do osmotic diuretics work? Give an example

They are pharmacologically inert. Injected into the blood stream, they are filtered by the glomerulus but NOT reabsorbed
No effect on Na⁺ reabsorption
Increase the osmolarity of tubular fluid
Decrease H₂O reabsorption where the nephron is permeable to water (i.e. proximal tubule, descending loop of Henle, collecting duct) e.g. Mannitol


How do carbonic anhydrase inhibitor diuretics work? Give an example

Act in the proximal convoluted tubule. Block carbonic anhydrase in the cell and on the apical membrane.
Inhibit Na⁺ and HCO₃⁻ reabsorption in proximal tubule (increased retention in the urine).
↑ tubular fluid osmolarity/↓ osmolarity of medullary interstitium = ↓ H₂O reabsorption in the collecting duct
Other effects: ↑ delivery of HCO₃⁻ to distal tubule, ↑ K⁺ loss
e.g. acetazolamide


How do loop diuretics work? Give an example

Act on the Na⁺2CL⁻K⁺ cotransporter to effect the countercurrent mechanism
↑ tubular fuid osmolarity/↓osmolarity of meduallary interstitium = H₂O reabsorption in the collecting duct
↑ delivery of Na⁺ to distal tubule ↑ K⁺ loss (↑ Na+/K⁺exchange
Lose Na⁺, Ca²⁺ and Mg²⁺ because there is a small leak of pottassium by blocking the cotransporter you are adjusting the membrane potential which means less reabsorption of Ca²⁺ and Mg²⁺

Causes up to 30% fluid loss
e.g. furosemide


What is the mechanism of thiazide diuretics?

Acts in the distal convoluted tubule to block to the Na⁺Cl⁻ cotransporter which prevents NaCl reuptake which also reduces water reabsorption by increasing tubular fluid osmolarity
Also ↑ delivery of Na⁺ to distal tubule and ↑ K⁺ loss (↑Na⁺K⁺ exchange)
↑ Mg²⁺ loss and ↑ Ca²⁺ reabsorption
e.g. bendroflumethiazide


What diuretic would have the most powerful effect on renin secretion?

Chronic diuretic use (especially loop diuretics and thiazides) will result in resistance
- Blood Na⁺ level will fall
- Renin will be released in response to low Na⁺ entering the macula densa cell which will counter the effects of the diuretics


What are the different classes of K⁺ sparing diuretics? Give examples

- Aldosterone receptor antagonists (e.g. spironolactone)
- Inhibitors of aldosterone-sensitive Na⁺ channels (e.g. amiloride)


What is the mechanism of potassium sparing diuretics?

- Aldosterone receptor antagonists block the action of aldosterone on the mineralocorticoid receptor which reduces Na⁺ channels and Na⁺K⁺ATPase
- Na⁺ channel inhibitors block the Na⁺ channels which prevents Na⁺ entry into the cell
Increase tubular fluid osmolarity
↑ H⁺ retention
Only 5% decrease in fluid output


What are the common side effects of diuretics? Which diuretics cause them and what is the mechanism?

Loop diuretics and Thiazides:
- Hypovolaemia: ↑ NaCl in the tubule = ↑ water in the tubule (30% LD; 10% T)
- Hyponatremia: ↑Na⁺ excretion (30% LD; 10% T)
- Metabolic alkalosis: due to Cl⁻ excretion
- Hypokalemia: Na⁺K⁺ exchange- Na⁺ passed to later parts of the nephron and then exchanged with K⁺ so large volumes are lost.
- Hyperuricemia: drugs acting on different parts of the kidney are excreted across the cell to be excreted in the urine (different mechanisms across the kidney; usually by different transporters) e.g. Organic anion transporter clears uric acid in the blood, diuretics are also transported using this, so they compete.
Carbonic anhydrase inhibitors
- Metabolic acidosis: due to HCO₃⁻ loss
Potassium sparing diuretics
- Hyperkalaemia: Less Na⁺K⁺ exchange


What diuretics are used to treat hypertension? Why use this type?

1st line treatment in most countries
Particularly useful for salt sensitive hypertension
- Initial response (4-6 weeks) due to ↓ plasma volume
- After 4-6 weeks plasma volume restored
- Chronic thiazides: ↓TPR - Activation of eNOS (endothelium), Ca²⁺ channel antagonism, opening of K(Ca) channel (smooth muscle


What conditions are treated with diuretics?

- Hypertension
- Heart failure


How do diuretics treat hypertension?

- Heart failure = ↓ CO
- Body responds to ↓ CO by activating sympathetic nervous system and RAAS - which worsens the heart failure (by ↑ water retention + vasoconstriction)
- Loop diuretics - 30% Na⁺ load- acute reduction in congestion
- Chronic use associated with resistance as eventually RAAS will activate in response
- Now add potassium sparing diuretics which tries to block rebound RAAS activation


What is the function of the presynaptics GABA receptors?

Negative feedback in response to high GABA concentrations


What is the process of GABA metabolism? Where are the enzymes located?

↓ GABA T (GABA Transaminase)
Succinic Semialdehyde (SSA)
↓ SSDH (Succinic semialdehyde dehydrogenase)
Succinic Acid

Mitochondrial enzymes


What drugs inhibit GABA metabolism in the brain? What is the overall effect of these drugs?

1. Sodium valproate (Epilim)
2. Vigabatrin (Sabril)
Both anticonvulsant drugs used to treat epilepsy
Cause a large ↑ in brain GABA


What is the mechanism of action of the GABAᴬ receptor complex?

Made up of 4 proteins
1. GABA receptor protein (GABA-R)
2. Benzodiazepine receptor protein (BDZ-R)
3. Barbiturates receptor protein (BARB-R)
4. GABA modulin
GABA binds to the GABA-R and opens the Cl⁻ channel.
GABA-R is linked to BDZ-R; binding BZD facilitates GABA action and enhances affinity of GABA-R for GABA. This is a reciprocated relationship
Barbiturates bind to BARB-R and increase GABA action and binding but this relationship is not reciprocated


What is Bicuculline and Flumazenil?

Bicuculline: Competitive GABA antagonist
Flumazenil: Competitive benzodiazepine antagonist


What affect do benzodiazepines and barbiturates have on the GABA receptor?

Allosteric action (need GABA to act on receptor)
Benzodiazepines increase the frequency of Cl⁻ channel opening
Barbiturates increase the duration of Cl⁻ channel opening
Barbiturates are less selective than benzodiazepines (↓ excitatory transmission)


What are the clinical uses of benzodiazepines and barbiturates? Give examples

- Anaesthetics (barbiturates only: Thiopentone)
- Anticonvulsants (Diazepam; Clonazepam; Phenobarbital)
- Anti-spastics (Diazepam)
- Anxiolytics
- Sedatives / Hypnotics


What is an anxiolytic?

Removes anxiety without impairing mental or physical activity ("Minor tranquillisers)


What is a sedative?

Reduces mental and physical activity without producing loss of consciousness


What is a hypnotic?

Induces sleep


What is the clinical use of barbiturates? Give examples. What are the side effects?

- Amobarbital for severe intractable insomnia (t½ 20-25h)
Unwanted effects (not drugs of 1st choice)
- Low safety margins (depress respiration, overdosing lethal)
- Alter natural sleep (↓REM) = hangovers/irritability
- Enzyme inducers
- Potentiate effect of other CNS depressants (e.g. alcohol)
- Causes tolerance
- Dependence: withdrawal symdrome (insomnia, anxiety, tremor, convulsions, death)


What are the pharmacokinetics of benzodiazepines? Give examples

- Well absorbed (orally)
- Peak [plasma] ≈ 1h
- IV vs status epilepticus (IV administration used to treat prolonged seizures)
- Bind plasma proteins strongly
- Highly lipid soluble (wide distribution)
- Usually extensive (liver)
- Urine; glucuronide conjugates
Duration of action (varies greatly)
- Short
- Long acting slow metabolism and/or active metabolites

e.g. Diazepam (t½ 32h)
Oxazepam (t½ 8h)
Temazepam (t½ 8 hours)


Give examples of anxiolytics.

- Diazepam (Valium)
- Chlordiazepoxide (Librium)
- Nitrazepam

Oxazepam is considered long-acting in cases of hepatic impairment as it is metabolised slowly


Give examples of sedative/hypnotics.

- Temazepam
- Oxazepam

Nitrazepam will aid sleep at night and have an anxyolytic effect during the day; or used to treat people who sleep at night but wake up very early in the morning


What are the advantages of using benzodiazepines?

Wide margin of safety:
- Overdose→prolonged sleep (rousable)
- Give flumazenil (shorter half life so need 2 doses)
- Does not induce liver enzymes


What are the unwanted effects of benzodiazepines?

- Sedation, confusion, amnesia, ataxia (impaired manual skills)
- Potentiate other CNS depressants (alcohol, barbs)
- Tolerance (less that barbs; 'tissue' only)
- withdrawal syndrome similar to barbs (less intense
- Withdrawal slowly
- Free [plasma] ↑ by coadministration e.g. aspirin, heparin


What is zopiclone?

- A short acting sedative/hyponotic (t½ ≈5g)
-Acts at BZD receptors (cyclopyrrolong)
Similar efficacy to BZ
- Minimal hangover effects BUT dependency still a problem


Give examples of some anxiolytic drugs.

Some antidepressant drugs:
- Effective/delayed response/popular

Some antiepileptic drugs
- e.g. Valproate, Tiagabine

Some antipsychotic drugs
- e.g. olanzapine, quetiapine
- Marked side effects

- Improves physical symptoms (tachycardia: β₁; tremor: β₂)

- 5HT₁ᴬ agonist
- Fewer side-effects (


Benzodiazepines are used to treat "panic attacks" and other anxiety states. By what mechanism do they produce their anti-anxiety effects?

Enhancement of the action of GABA at GABA-A receptors


Which of the following drugs is commonly used in the treatment of insomnia?
1. Thiopental
2. Phenytoin
3. Baclofen
4. Sodium valproate
5. Temazepam

5. Temazepam


What is the difference between Parkinson's and Schizophrenia?

Parkinson's is not enough dopamine
Schizophrenia is too much dopamine


What is the nigrostriatal system? What disease affects this system?

Control of movement
Cell bodies originate in the substantia nigra zona compacta and project to the striatum
Affected in Parkinson's


What is the mesolimbic system? What disease affects this system?

Involved in emotion
Cell bodies originate in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule
Affected in Schizophrenia


What is the tuberoinfundibular system?

Regulates hormone secretion
Short neurones running from the arcuate nucleus of the hypothalamus to the medial eminance and pituitary gland


What dopamine receptors make up the D1 and D2 family?

D1: D1 and D5
D2: D2, D3 and D4


What is dopamine produced from?

Tyrosine in the diet


How common is Parkinson's disease?

1/1000 - general population
1/100 - > 60 years
Mean age of onset is 65
Male:Female 4:1
~8% of cases are familial Parkinson's disease
92% are Idiopathic Parkinson's disease:
- environmental
- oxidative stress
- altered protein metabolism
- risk gene


What are the cardinal signs of Parkinson's disease?

- Resting tremor
- Rigidity (stiffness, limbs feel heavy/weak)
- Bradykinesia (slow movement)
- Postural abnormality
- Unilateral onset
- Spreads to bot sides of the body


What are the presenting symptoms of Parkinson's disease?

- Pill-rolling rest tremor
- Difficulty with fine movements - micrographia
- Poverty of blinking
- Impassive face
- Monotomy of speech and loss of volume of voice (lack of diaphragm control and loss of tone around vocal cords)
- Disorders of posture - flexion of the neck and trunk
- Lack of arm swing
- Loss of balance - lack of righting reflex, retropulsion
- Short steps, shuffling gait
- Unilateral onset (does spread to both sides and worsen)


What are the non-motor symptoms of Parkinson's disease?

- Depression
- Sleep disturbance
- Pain
- Taste and smell disturbances
- Cognitive decline/Dementia

Autonomic dysfunction
- Constipation
- Postural hypotension
- Urinary frequency/urgency
- Impotence
- Increased sweating


What is the neuropathology of Parkinson's disease?

- Principally affected area- Substantia nigra (cell loss)
- Putamen-projecting pathways degenerate significantly
- Lewy bodies are present (defensive mechanism to protect against toxic altered proteins; eventually they spill out and cause toxicity)
- Cell loss in locus coruleus
- Other affected areas: dorsal vagus nucleus, nucleus basalis of mynert


When do symptoms appear in Parkinson's? Why is this?

Lose 80-85% of dopaminergic neurons and deplete 70% of the striatal dopamine bfore symptoms appear
Compensatory mechanisms (e.g. neuron overactivity and upregulation of DA receptors) prevent appearance of symptoms


What system us used to stage Parkinson's disease?

Stages describe the affected areas
Stage 1-2
- Dorsal motor nucleus of vagus
- Raphe nucleus
- Locus coerulus
Stage 3:
- Substantia nigra pars compacta
Stage 4
- Amydala
- Nucleus of Meynert
- Hippocampus
Stage 5-6
- Cingulate cortex
- Temporal cortex
- Frontal cortex
- Parietal cortex
- Occipital cortex


What is the rational for dopamine replacement therapy? What drug is used?

- DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme DOPA decarboxylase (DD)
- DD is also present in peripheral tissues and 95% would be converted in the periphery causing nausea and vomiting
- Inhibitors cannot cross the BBB so DOPA can be converted to dopamine in the brain
Drug: Peripheral DOPA decarboxylase inhibitor + L-DOPA


What is the use of L-DOPA?

Treats hypokinesia, rigidity and tremor
(effectiveness declines with time)


What are the side effects of L-DOPA?

- Nausea (prevented by Doperidone: peripheral acting antagonist)
- Hypotension
- Psychological effects - confusion, disorientation and nightmares
- Dyskinesias: (abnormal limb and face movements) can occur within 2 years of treatment.
- "On-Off" effects: rapid fluctuation in clinical state. Off periods last from minutes to hours


What receptors do Parkinson's treatments target?

Can only synthesise drugs which act on D2 receptors.
Drugs targeting D1 do not enter the brain


What are the actions of dopamine agonists? Give examples

- Act on D2 receptors
- Bromocriptine, Pergolide, Ropinerol
- Longer duration of action than L-DOPA
- Smoother and more sustained response
- Actions independent of dopaminergic neurones
- Incidence of dyskinesia is less
- Can be used in conjunction with L-DOPA


What are the adverse effects of dopamine agonists?

Common: confusion, dizziness, nausea/vomiting, hallucinations
Rare: constipation, headache, kyskinesia
Ergot structure (within chemical structure): causes a problem with heart valves
Non-ergot structure: causes addictive behaviours (OCD, gambling etc)


What is Deprenyl (selegiline)?

MAO inhibitor
- Selective for MAO-B, predominates in dopaminergic areas of CNS. Actions are without peripheral side effects of none-selective MAO-I's
- Can be given alone in the early stages of disease
- Or in combination with L-DOPA, reduce the dose of L-DOPA by 30-50%
- Side effects are rare: hypotension, nausea/vomiting. confusion and agitation


What is Resagiline?

MAO inhibitor
Shown to have neuroprotective properties by inhibiting apoptosis - promotes anti-apoptosis genes. Early clinical trials suggest that this drug may slow the disease down but subsequent studies not so positive


What is the action of COMT?

Catechol-O-methyl transferase
CNS- Breaks down catecholamines (e.g. dopamine) in the brain
Periphery- Converts L-DOPA to 3-OMD which compete for the same transport system across the BBB


What is the action of COMT inhibitors? Give examples. What are the side effects?

CNS- Prevents the breakdown of dopamine in the brain
Peripheral- Stop 3-OMD formation and thus increasing the penetration of L-DOPA across the BBB thus increasing brain concentrations, where it is converted to dopamine. Allows L-DOPA dose reduction
Side effects: cardiovascular complications (can cause heart attack)


What are the clinical features of schizophrenia?

Positive symptoms:
- Hallucinations
- Delusions
- Disorganised thoughts
Negative symptoms:
- Reduced speech
- Lack of emotion and facial expression
- Diminished ability to begin and sustain activities
- Diminished ability to find pleasure
- Social withdrawal
Cognitive deficits:
- Memory
- Attention
- Planning
- Decision making


What is the role of genetics in Schizophrenia?

Strong genetic tendency
1st degree relatives: 50%
2nd degree relatives: 25%
3rd degree relatives: 12.5%


What are the different outcomes that occur following a Schizophrenia diagnosis?

1. Resolves completely, with/without treatment and never returns: 10-20%
2. Recurs repeatedly; full recovery after each episode: 30-35%
3. Recurs repeatedly; incomplete recovery; persistent defective state develops becoming more pronounced each time: 30-35%
4. Persues a downhill course: 10-20%


What is the neurochemical involvement in Schizophrenia?

Excessive dopamine transmission in the mesolimbic system and striatal region leading to positive symptoms - mediated through D2 receptors
Whilst dopamine deficit in pre-frontal region, mediated by D1 receptors leads to negative symptoms


What is the glutamate theory for Schizophrenia?

- NMDA receptor antagonists produce psychotic symptoms
- Glutamate and dopamine exert excitatory and inhibitory effects respectively on GABA-ergic striatal neurons, which project to the thalamus and constitute a 'sensory gate'. Too little glutamate or too much dopamine disables the gate, allowing uninhibited sensory input to reach the cortex (causes patient to overanalyse normal situations)


What is the aetiology and pathogenesis of Schizophrenia?

- Gene for neuregulin-1-synaptic development and plasticity effects NMDA receptor expression causeing schizophrenia phenotype


What is the mechanism of action of anti-psychotics?

- All neuroleptic drugs are antagonistic at dopamine "D2 like" receptors
- Most neuroleptics block other receptors (e.g. 5-HT) thus accounting for some of their effects
- Drugs treat positive symptoms but not the negative ones
- Takes weeks to work, initially neuroleptics induce an increase in DA synthesis and neuronal activity (declines with time)


What are the side-effects of neuroleptics?

- Anti-emetic effect
- Blocking dopamine receptors in the chemoreceptor trigger zone. Neuroleptic Phenothiazine, effective at controlling vomiting and nausea induced by drugs (e.g. chemotherapy), renal failure
- Many neuroleptics also have blocking action at histamine receptors. Effective at controlling motion sickness


What are the side effects of antipsychotics?

Extrapyramidal side effects - blockade of dopamine receptors in the nigrostriatal system can induce "Parkinson" like side effects
- Acute dystonia: involuntary movements - muscle spasm, protuding tongue, fixed upward gaze, neck spasms etc often accompanied by Parkinson's features. Occur in the first few weeks, often declining with ongoing therapy. Reversible on drug withdrawal or anti-cholinergic
Tardive dyskinesias: Involuntary movements, often involving the face and tongue, but also limb and trunk (20% of patients after several months or years). More associated with typical antipsychotics. Made worse by drug withdrawal or anticholinergics. May be related to proliferation in pre-synaptic DA D2 receptors or glutamate excitotoxic striatal neurodegeneration
- Endocrine effects: dopamine is involved in the tuberoinfundibular system and acts to inhibit prolactin secretion via the D2 receptors. Antipsychotics increase serum prolactin concentrations which can lead to breast swelling (men and women) and sometimes lactation in women
- Blocking α-adrenoceptors: causes orthostatic hypotension
- Blocking 5-HT receptors: weight gain
- Blockade of cholinergic muscarinic receptors: typical peripheral anti-muscarinic side effect (e.g. blurring of vision, increased intraocular pressure, dry mouth, constipation, urinary retention)


What are the clinically desirable effects of general anaesthetic?

- Loss of consciousness (at low concentration)
- Suppression of reflex responses (at high concentration)
- Relief of pain (analgesia)
- Muscle relaxation
- Amnesia


What are the different types of general anaesthetics?

- Nitrous oxide
- Diethyl ether
- Halothane
- Enflurane

- Propofol
- Etomidate


What effect does lipid solubility have on the effect of a general anaesthetic?

Anaesthetic potency increases in direct proportion with oil/water partition coefficient
(The more lipid soluble it is the better the anaesthetic)


What is the mechanism of action of intravenous general anaesthetics?

Alter synaptic function
Enhance GABA (inhibitory)
β₃ - suppression of reflex responses
α₅ - amnesia


What is the mechanism of action of inhalational general anaesthetics?

Alter synaptic function
Enhance GABA / compete with glycine, so prevents receptor activation
α₁ - suppression of reflex responses
Nitrous oxide - blocks NMDA-type glutamate receptors

Not as powerful as IV


What effect do inhalational agents have on nicotinic ACh receptors?

Increase in administration of inhalational anaesthetic causes a decrease in firing of nACh receptors


How do inhalational agents reduce neuronal excitability?

Enhancement of TREK (background leak) K⁺channels
- increases duration of hyperpolarisation so they are more difficult to excite


What types of general anaesthetic are more specific?

Intravenous agents are more specific and inhalational agents are active at more sites


How do general anaesthetics cause loss of consciousness?

Depress excitability of thalamocortical neurones
Influences reticular activating neurones (major consciousness centre in the brain)
RAN: sensory signals sent here increases consciousness
GABA and background leak K⁺ channels decrease the link between the cortex and the RAN
nAChR agents decrease the link between the thalamus and the RAN


How do general anaesthetics induce suppression of reflex responses?

Cause depression of reflex pathways in the spinal cord


How do general anaesthetics cause amnesia?

Cause decreased synaptic transmission in the hippocampus/amygdala
- There are a larger number of GABA with α₅ subunits in the hippocampus
Means you lose the ability to form memories


How do IV general anaesthetics get into the brain? How are they metabolised?

IV into the blood, they then have free access to the brain
The liver metabolises the agent to return consciousness


If an inhalational general anaesthetic has a low blood:gas partition coefficient what effect does this have on it's effect?

Won't dissolve in the blood very well therefore it will be more available to the brain


If an inhalational general anaesthetic has a high blood:gas partition coefficient what effect does this have on it's effect?

Less lipid soluble so dissolves in the blood and therefore has slow transfer to the brain


How is the administration of inhalational general anaesthetics controlled?

The process is very controllable
Process reverses very quickly if you stop administering the agent


What are the main differences between inhalation and intravenous anaesthetics?

- Rapidly eliminated
- Rapid control of the depth of anaesthesia
- Fast induction
- Less coughing / excitatory phenomena


In a clinical setting what general anaesthetics would be used for loss of consciousness and suppression of reflex responses? What would be used for relief of pain, muscle relaxation and amnesia?

Induction: Propofol (IV)
Maintenance: Enflurane (inhalation)
Relief of pain: Opioid
Muscle relaxation: Neuromuscular blocking drugs
Amnesia: Benzodiazepines


What is the process of generation of an action potential?

Resting membrane potential -70mV
1. Resting Na⁺ channels open; Na⁺ enters cells
2. Na⁺ channels close (inactivation); K⁺ channels open, K⁺ leaves the cell
3. Na⁺ channels restored to resting state but K⁺ channels still open therefore cell refractory
4. Hyperpolarisation
5. Na⁺ and K⁺ channels restored to resting state therefore cell will respond normally to further depolarising stimulus


What is the structure of local anaesthetics?

Aromatic region: important for action and metabolism
Basic amine side chain: (tertiary amine) hydrophilic
Ester or amide bond: bridges between other two groups

Exception- Benzocaine: has alcarve chain not an amino (weak LA)


What bridging group does cocaine and lidocaine have?

Cocaine- ester
Lidocaine- amide


What is the hydrophilic pathway for the interaction of local anaesthetics with sodium channels?

- LA will be in ionised form
- Non-ionised form passes through neurone sheath and into an axon where it is then converted back into ionised (cationic) form
- It is the cationic form which acts as a LA
- Binds to the inside of voltage-sensitive Na⁺ channels and blocks the channels
- This reduces the propagation of an action potential


What is use-dependency in the hydrophilic pathway for action of local anaesthetics?

As the nerve is stimulated the channels open, the faster the channels open the more LA can get into the channel to block the firing


What is the hydrophobic pathway for local anaesthetic action in an axon?

Non-ionised drug passes into the membrane, and can move into the Na⁺ channel whilst in the membrane


What are the effect of local anaesthetics?

1. Prevent generation and conduction of action potentials
2. Do NOT influence resting membrane potential
3. May also influence
- Channel gating
- Surface tension
4. Selectively block
- Small diameter fibres
- Non-myelinated fibres

LAs are weak bases (pKa 8-9)


What are the effects of administering LA into effected tissue?

In infected tissue more of the LA is ionized so it is less effective


What are the different routes of administration of local anaesthetics? Describe each.

1. Surface anaesthesia
- Mucosal surface (mouth, bronchial tree)
- Spray (or powder)
- High concentrations → systemic toxicity
2. Infiltration anaesthesia
- Directly into tissues → sensory nerve terminals
- Minor surgery
- Adrenaline co-injection (NOT extremities)
3. Intravenous regional anaesthesia
- IV distal to pressure cuff
- Limb surgery
- Systemic toxicity of premature cuff release
4. Nerve block anaesthesia
- Close to nerve trunks e.g. dental nerves
- Widely used - low doses - slow onset
- Vasoconstrictor co-injection (adrenaline and phalopressin)
5. Spinal anaesthesia (into CSF- intrathecal)
- Sub-arachnoid space - spinal roots
- Abdominal, pelvic, lower limb surgery
- ↓BP; prolonged headache
- Glucose (↑ specific gravity)
6. Epidural anaesthesia (outside of dural membrane)
- Fatty tissue of epidural space - spinal roots
- Uses as for 5 and painless childbirth
- Slower onset - higher doses
- More restricted action - less effect on BP


What are the pharmacokinetic properties of lidocaine (amide)?

Absorption (mucous membranes): Good
Plasma protein binding: 70%
Metabolism: Hepatic N-dealkylation
Plasma half-life: 2 hours


What are the pharmacokinetic properties of cocaine (ester)?

Absorption (mucous membranes): Good
Plasma protein binding: 90%
Metabolism: Liver and plasma, non-specific esterases
Plasma half-life: 1 hour


What are the unwanted effects of lidocaine?

CNS (paradoxical)
- stimulation
- restlessness, confusion
- tremor
CVS (Na⁺ channel blockade)
- myocardial depression
- vasodilation
- ↓ BP


What are the unwanted effects of cocaine?

- euphoria, excitation
- ↑CO
- vasoconstriction
- ↑BP
(all sympathetic actions)


What are the symptoms of depression?

Emotional (psychological)
- Misery, apathy, pessimism
- Low self-esteem
- Loss of motivation
- Anhedonia
Biological (Somatic)
- Slowing of thought and action
- Loss of libido
- Loss of appetite, sleep disturbance


What is unipolar depression/depressive disorder?

- Mood swings in same direction
- Relatively late onset
Reactive depression
- stressful life events
- non-familial
Endogenous depression
- unrelated to external stressors
- familial pattern
- Drug treatment


What is bipolar depression? (manic depression)

- Oscillating depression/mania
- Less common : early adult onset
- Strong hereditary tendency
- Drug treatment (Lithium carbonate)


What is the monoamine theory of depression?

Depression = functional deficit of central MA transmission : mania = functional excess
Monoamines = NA and 5-HT (serotonin)
- Delayed onset of clinical effect of drugs
- Down regulation: α2, β, 5-HT receptors
- HPA axis (↑CRH level)
- Hippocampal neurodegeneration


What is the mechanism of action of Tricyclic Antidepressants (TCAs)?

- Neuronal monoamine re-uptake inhibitors
NA = 5-HT >> DA
Other receptor actions
- α₂
- mAChRs
- Histamine
- 5-HT
Delayed down-regulation of β-adrenoceptors and 5-HT₂ receptors


What are the pharmacokinetics of TCAs?

- Rapid oral absorption
- Highly PPB (90-95%)
- Hepatic metabolism - active metabolites - renal excretion (glucuronide conjugates)
- Plasma half-life: 10-20 hours


What are the unwanted effects of TCAs?

At therapeutic dosage:
- Atropine-like effects (amitriptyline)
- Postural hypotension (vasomotor centre)
- Sedation (H1 antagonism)
Acute toxicity (overdose)
- CNS: excitement, delirium, seizures → coma, respiratory depression
- CVS: cardiac dysrhythmias → ventricular fibrillation/sudden death
- Care- attempted suicide


What are the effects of drug interactions on TCAs?

- Plasma protein binding: ↑ TCA effects (aspirin phenytoin)
- Hepatic microsomal enzymes: ↑ TCA effects as they compete with TCAs (neuroleptics : oral contraceptives)
- Potentiation of CNS depressants (alcohol)
- Antihypertensive drugs (monitor closely): can sometimes increase and sometimes decrease


What is the mechanism of action of monoamine oxidase inhibitors?

MAO-A : NA and 5-HT
- Most are non-selective MAOIs
- Irreversible inhibition → long duration of action
- Rapid effects : ↑ cytoplasmic NA and 5-HT
- Delayed effects: clinical response
- down-regulation of β-adrenoceptors and 5-HT*2 receptors
- Inhibition of other enzymes


What are the pharmacokinetics of MAOIs?

- Rapid oral absorption
- Short plasma half-life (few hours) but longer duration of action
- Metabolised in the liver: excreted in urine


What are the unwanted effects of MAOIs?

- Atropine-like effects (


What drug interactions occur with the use of MAOIs? Which type of MAOI has decreased drug interactions?

Serious problem
- 'Cheese reaction' : Tyramine-containing foods + MAOI → hypertensive crisis (throbbing headache, ↑BP, intracranial haemorrhage)
- MAOIs + TCAs → hypertensive episodes (avoid)
- MAOIs + pethidine → hyperpyrexia, restlessness, come and hypotension

Moclobemide: reversible MAO-A inhibitor (RIMA), ↓ drug interactions, ↓ duration of action


What is the mechanism of action of selective serotonin reuptake inhibitors?

- Selective 5-HT re-uptake inhibition
- Less troublesome side-effects: safer in overdose
- But less effective in severe depression


What are the pharmacokinetics of SSRIs?

- Oral administration
- Half life: 18-24 hours
- Delayed onset of action (2-4 weeks)
- Fluoxetine competes with TCAs for hepatic enzymes (avoid coadministration)


What are the unwanted effects of SSRIs?

- Nausea, diarrhoea, insomnia and loss of libido
- Interact with MAOIs (avoid coadministration)
- ↑ suicidality (<18 years old)
- Fewer than TCA/MAOIs


What is Venlafaxine?

Dose-dependent reuptake inhibitor
5-HT > NA > DA
2nd line treatment for severe depression


What is Mertazapine?

α2 receptor antagonist
↑ NA and 5-HT release
Other receptor interactions (sedative)
Useful in SSRI-intolerant patients


Why does Parkinson's disease occur in younger people? What is Parkinson's?

Early onset = <55 years old
- Genetically linked
- Less that 10% of people with Parkinson's disease are <55 years
- Loss of dopaminergic neurons which originate in the substantial nigra and project to the striatum (caudate putamen) causing loss of fine motor skills
- D2 receptors are found in the brain
- Must lose 80% of neutrons before you see effects


What are the symptoms of Parkinson's disease?

- Postural abnormalities
- Tremor
- Bradykinesia
- Rigidity, muscle stiffness


How is dopamine produced in the brian?

- Tyrosine from the diet enters the brain through amino acid transporters
- Tyrosine is converted to L-DOPA (Tyrosine hydroxylase)
- DOPA is converted to dopamine (DOPA decarboxylase)


Why is L-DOPA used to treat Parkinson's rather than dopamine or tyrosi

Dopamine is hydrophilic so it can't cross the the BBB, also there are very low levels of dopamine transporter in BBB so it cannot penetrate the brain
L-DOPA uses the same transporter as tyrosine so it can get into the brain
Tyrosine hydroxylase is the rate limiting step so it is better to use L-DOPA instead of tyrosine


What is Carbidopa?

A DOPA decarboxylase inhibitor
- It cannot cross the BBB
- It prevents the conversion of L-DOPA to dopamine peripherally so when used with L-DOPA more is converted in the brain and it also prevents the nausea and vomiting associated with dopamine stimulating the chemotactic trigger zone where there are fewer tight junctions than in the brain


What are on-off fluctuations in Parkinson's disease? How is it treated?

They occur as Parkinson's progresses when pulses of dopamine are released and so the stores are depleted.
This can be prevented by splitting the dose across more administration or increasing the initial dose.
MAO and COMT break down dopamine so if you inhibit these then the life of dopamine in the synapse can be prolonged. The most commonly used is a COMT inhibitor (Entacapone)


What is Pergolide? What are the side effects and how can they be treated?

A dopamine receptor agonist
It causes nausea by binding to dopamine receptors in the chemoreceptor trigger zone
Treated using domperidone (peripherally acting D2 receptor antagonist)


What side effect is caused by high levels of L-DOPA? How can this be avoided?

Dyskinesia. D2 agonists don't cause dyskinesia to the same extent


What drugs that act on the brain can precipitate Parkinson like symptoms?

D2 antagonist (anti-psychotics/neuroleptics


Anti-psychotics can induce strange movements in the arms and face (sticking out the tongue etc). What is this? What other side effects do these drugs induce?

Tardive dyskinesias (brain over-sensitised to dopamine)
The brain is trying to compensate by upregulating dopamine receptors in that part of the brain (it is reversible)
Other uses:
- Anti-emetics
- Increases prolactin secretion = galactorrhoea, lactation, inhibits fertility, amenorrhoea


What is the main risk factor for Alzheimer's disease?

Mostly sporadic (92%) remaining is genetic


What are the symptoms of Alzheimer's disease?

1. Memory loss- especially recently acquired information
2. Disorientation/confusion- forgetting where they are
3. Language problems- stopping in the middle of a conversation
4. Personality changes- becoming confused, fearful, anxious
5. Poor judgement- such as when dealing with money


What is the Amyloid hypothesis for physiological and pathophysiological process of Alzheimer's disease?

In a healthy individual γ-secretase, α-secretase and amyloid precursor protein (APP) are present in the membrane of neuronal cells.
APP is cleaved by α-secretase and then cleaved by γ-secretase
1. APP is cleaved by α-secretase
2. sAPPα is released - C83 fragment remains
3. C83 → digested by γ-secretase
4. Products removed
Pathological process
APP is instead cleaved by β-secretase and then by γ-secretase
1. APP cleaved by β-secretase
2. sAPPβ released - C99 fragment remains
3. C99 → digested by γ-secretase releasing β-amyloid (Aβ) protein
These β-amyloid (Aβ) proteins activate together and forms plaques which are deposited on the surface of neuronal cells


What is the Tau hypothesis for physiological and pathophysiological process of Alzheimer's disease?

- Soluble protein present in axons
- Important for assembly and stability of microtubule
In Alzheimer's disease hyperphosphorylated tau is insoluble → self-aggregates to form neurofibrillary tangles
Tau are neurotoxin This also results in microtuule instability


What is the inflammation hypothesis for physiological and pathophysiological process of Alzheimer's disease?

Microglia are specialised CNS immune cells - similar to macrophages
- ↑ release of inflammatory mediators and cytotoxic proteins
- ↑ phagocytosis
- ↓ levels of neuroprotective proteins


What anticholinesterases are used in the treatment of Alzheimers disease?

All drugs treat the symptoms. None treat the underlying pathology. Only last for 2-3 years and then the drugs are not that effective. Only prescribed for mild to moderate Alzheimer's disease
1. Donepezil
2. Rivastigmine
3. Galantamine


What is the mechanism of action of Donepezil?

Gold-standard. First line treatment
- Reversible cholinesterase inhibitor
- Long plasma half life (can be given once a day)


What is the mechanism of action of Rivastigmine?

- Pseudo-reversible AChE and BChE (buteryl cholinesterase enzyme) inhibitor
- 8 hour half-life
- Reformulated as a transdermal patch
- Causes liver problems as it inhibits BChE


What is the mechanism of action of Galantamine?

- Reversible cholinesterase inhibitor
- 7-8 hour half-life
- α7 nAChR agonist


Other than anticholinesterases what other drugs are prescribed for Alzheimer's disease? What is it's mechanism of action?

NMDA receptor blocker. Only licensed for moderate to severe Alzheimer's
- Use-dependent non-competitive NMDA receptor blocker with low channel affinity
- Long plasma half-life (administered once a day)


Give an example of a mycolic bacteria. What does this mean?

M. tuberculosis
The call wall of the bacteria has a layer of peptidoglycan surrounded by mycolic acid


What is the different between Gram +ve and Gram -ve bacteria?

Gram +ve have a prominent, thick peptidoglycan cell wall
Gram -ve have a thin pedptidoglycan layer surrounded by an outer membrane with lipopolysaccharides making up the cell wall


What is the process of prokaryotic protein synthesis?

1. Nucleic acid synthesis
- Dihydropterate (DHOp) is produced from paraaminobenzoate (PABA) and then converted into dihydrofolate (DHF).
- DHF is converted to tetrahydrofolate (THF) by DHF reductase. THF is important in DNA synthesis
2. DNA replication
DNA gyrase (topoisomerase) releases tension in the DNA strand
3. RNA synthesis
RNA polymerase produces RNA from DNA template
4. Protein synthesis
Ribosomes (30s and 60s) produce protein from RNA templates


What antibiotic target nucleic acid synthesis?

Inhibit dihydropterate synthase

Inhibits dihydrofolate reductase


What antibiotic targets bacterial DNA replication?

Fluroquinolones (e.g. Ciprofloxacin)
Inhibits DNA gyrase and topoisomerase IV


What antibiotic targets bacterial RNA synthesis?

Rifamycons (e.g. Rifampicin)
Inhibits bacterial RNA polymerase


What antibiotics target bacterial protein synthesis?

Inhibits ribosomes:
- Aminoglycosides (e.g. Gentamycin)
- Chloramphenicol
- Macrolides (e.g. Erythromycin)
- Tetracyclines


What is the process of bacterial wall synthesis?

1. Peptidoglycan (PtG) synthesis
- A pentapeptide is created on N-acetyl muramic acid (NAM).
- N-acetyl glucosamine (NAG) associates with NAM forming PtG
2. PtG transportation
PtG is transported across the membrane by bactoprenol
3. PtG incorporation
PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides


What antibiotic targets peptidoglycan synthesis? How?

Glycopeptides (e.g. Vancomycin)
Binds to the pentapeptide preventing PtG synthesis


What antibiotic targets peptidoglycan transportation? How?

Inhibits bactoprenol regeneration preventing PtG transportation


What antibiotic targets peptidoglycan incorporation? How?

Bind covalently to transpeptidase inhibiting PtG incorporation into cell wall
- Carbapenems
- Cephalosporins
- Penicillins


What antibiotic targets cell wall stability? How?

Lipopeptide (e.g. Daptomycin)
Disrups Gram +ve cell walls

Binds to LPS and disrupts Gram -ve cell membranes


What are the causes of antibiotic resistance?

- Unnecessary prescription
- Livestock farming
- Lack of regulation
- Lack of development


What are the different mechanisms of antibiotic resistance?

1. Additional target production
Bacteria produce another target that is unaffected by the drug
(e.g. E. coli produce another DHF reductase enzyme making them resistant to trimethoprim)
2. Hyperproduction of enzyme
Bacteria significantly increase levels of DHF reductase
(e.g. E.coli produce additional DHF reductase enzymes making trimethoprim less effective)
3. Alterations in target enzymes
Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective
(e.g. S. aureus mutation in the ParC region of topoisomerase IV confers resistance to quinolones)
4. Alterations in drug permeation
Reductions in aquaporins and increased efflux systems
(e.g. Primarily of importance in Gram -ve bacteria)
5. Production of destruction enzymes
β-lactamases hydrolyse C-N bond of the β-lactam ring
(e.g. Flucloxacillin is β-lactamase resistant; Amoxicillin is broad spectrum)


What are the different classification of fungal infection?

1. Superficial - Outermost layers of skin
2. Dermatophyte - skin, hair or nails
3. Subcutaneous - innermost skin layers
4. Systemic - primarily respiratory tract


What are the two most common categories of anti-fungal drug?

1. Azoles: Fluconazole
2. Polyenes: Amphotericin


What is the mechanism of azoles in anti-fungal treatment? Give an example and it's uses.

- Inhibits cytochrome P450-dependent enzymes involved in membrane sterol synthesis
- Fluconazole (oral) used for candidiasis and systemic infections


What is the mechanism of polyenes in anti-fungal treatment? Give an example and it's uses.

- Interact with cell membrane sterols forming membrane channels
- Amphotericin (IV) for systemic infections


What types of hepatitis require treatment?

Hepatitis B and C


What drug is used to treat hepatitis B? What is the mechanism of this drug?

Nucleotide analogue, givent sometimes with Peginterferon α


What drug is used to treat hepatitis C? What is the mechanism of this drug?

Ribavirin and Peginterferon α
Ribavirin: nucleoside analogue prevents viral RNA synthesis
Boceprevir: protease inhibitor most effective against Hep C genotype 1


What is the life cycle of HIV?

1. Attachment and entry
- HIV GP120 attaches to CD$ receptor
- GP120 also binds to either CCr5 or CXCR4
- GP41 penetrates host cell membrane and viral capsid is endocytosed
2. Replication and integration
- Within cytoplasm - reverse transcriptase enzyme converts viral RNA → DNA
- DNA transported into nucleus and integrated into host DNA
3. Assembly and release
- Host cell's 'machinery' utilised to produce viral RNA and essential proteins
- - Gag precursor encodes all viral structural proteins
- HIV protease cleaves Gag precursor protein
- Virus is assembles within cells → mature virion is released


What do the specific drugs used to treat Hepatitis C and the duration of treatment depend on?

- HCV genotype
- Viral load
- Past treatment experience
- Degree of liver damage
- Ability to tolerate the prescribed treatment
- Need for liver transplant


What drugs target the attachment and entry of HIV? How?

- Binds to HIV GP41 transmembrane glycoprotein

- Block CCR5 chemokine receptor


What are the different drugs that inhibit HIV replication? Give examples

1. Nucleoside reverse transcriptase inhibitors
- Activated by 3-step phosphorylation process
e.g. Zidovudine
2. Nucleotide reverse transcriptase inhibitors
- Fewer phosphorylation steps required
e.g. Tenofovir
3. Non-nucleoside reverse transcriptase inhibitors
- No phosphorylation required
- Not incorporated into viral DNA
e.g. Efavirenz


What drug inhibits HIV integrase?



What drug inhibits HIV protease? What is this typically co-administered with? Why?

Saquinavir (1st generation PI)
Co-administered with Ritonavir which reduced PI metabolism (by inhibiting cytochrome P450) - co-administered to boost Squinavir concentrations in the body


What is hepres simplex virus? How is it treated?

Double stranded DNA virus, surrounded by tegument and enclosed in a lipid bilayer
Treatment: Acyclovir (nucleoside analogue)


What is influenza virus? How is it treated?

Multipartite single stranded RNA virus. Envelope protein neuraminidase → release
Tropism: nose, throat, bronchi
Treatment: Oseltamivir (Tamiflu) a neuraminidase inhibitor


What are the different types of general seizures?

Begins simultaneously in both hemispheres of the brain
- Tonic-clonic seizures
- Absence seizures
- Myoclonic seizures


What are the different types of partial/focal seizures?

Begins within a particular area of the brain and may spread out (may be the result of injury of insult to the brain)
- Simple/complex partial
- Temporal lobe epilepsy


What techniques can be used to measure brain activity?

- Electroencephalography
- Magnetoencephalography (MEG)
- Functional magnetic resonance imaging (fMRI)


What are the different waves of brain activity? How does this differ to brain activity during a seizure?

Regular activity: Distinctive firing patterns associated with certain activities (high to low Hz)
- Gamma: awareness - hyperactive
- Beta: awareness - thinking
- Alpha: awareness - relaxed
- Theta: drowsiness, meditation
- Delta: deep sleep
During a seizure there is irregular/asynchronous firing patterns due to neuronal over-activity


What receptors are activated at a glutaminergic synpase?

Excitatory post-synaptic receptors:
- Kainate


What is Carbamazepine used for? How does it work?

Voltage-gated Na channel blocker
- Drug of choice for partial seizures and tonic-clonic seizures
- Stabilises inactive state of channel

- Induces expression of hepatic enzymes
- 16-30 hour half-life
- Dangerous in individuals with HLA-B*1502 allele


What is Phenytoin used for? How does it work?

Voltage-gated Na channel blocker
- Indicated for most forms of epilepsy (not absence)
- Class 1b channel blocker

- Fast onset (10 mins) and long half-life (10-20 hours)


What is Retigabine used for? How does it work?

Voltage-gated K channel enhancer
- Potassium channel opener specific for Kᵥ7 α-subunit
- Only licensed for adjunctive treatment
- Fast onset (30mins); ∼10 hour half-life


What is Ethosuximide used for? How does it work?

Voltage-gated calcium channel blocker
- T-type Ca²⁺ channel antagonist
- Mainly used for absence seizures
- Long half-life (50 hours)


What is Gabapentin used for? How does it work?

Voltage-gated calcium channel blocker
- Thought to inhibit α2δ subunit
- Indicated for partial seizures


What is Levetiracetam used for? How does it work?

- Binds to synaptic vesicle associated protein (SV2A) preventing glutamte release
- Monotherapy for focal seizures
- Fast onset (1 hour); half-life (10 hours)


What is Topiramate used for? How does it work?

- Inhibits GluK5 subunit of kainate receptor
- Also affects VGSCs and GABA receptors
- Indicated for most types of epilepsy
- Fast onset (1 hour); long half-life (20 hours)


What is Perampanel used for? How does it work?

- Selective inhibitor of AMPA receptor
- Only licensed in 2013 as an adjunct for partial seizures
- Fast onset (1 hour); long half-life (24 hours)


What is the process of neurotransmission at a GABAergic synapse?

1. GABA can be released tonically and also following neuronal stimulation
2. GABA activates inhibitory post-synaptic GABAᴬ receptors
3. GABAᴬ receptors are chloride (Cl⁻) channels → membrane hyperpolarisation
4. GABA is taken up by GAT
5. GABA is metabolised by GABA transaminate (GABA-T)


What is Clonazepam used for? How does it work?

- Benzodiazepine (BZD) indicated for all forms of epilepsy
- Fast onset (2 hours); long half-life (30 hours)


What is Phenoparbital used for? How does it work?

- Indicated for most forms of epilepsy except absence seizures
- Acts as a sedative in adults and may cause behavioural disturbances in children
- Interacts with numerous drugs
- Very fast-onset (20 mins); long half-life (60 hours)


What is Tiagabine used for? How does it work?

- Selective inhibitor of GAT-1 (GABA transporter)
- Adjunctive treatment for partial seizures
- Fast onset (45 mins); short half-life (6 hours)


What is Sodium Valproate used for? How does it work?

- Indicated for all forms of epilepsy
- Inhibits GABA transaminase
- Fast onset (1 hour); half-life (12 hours)


What is Vigabatrin used for? How does it work?

- Irreversible inhibits GABA transaminase enzyme
- Monotherapy for infantile spasms or as an adjunct for partial seizures


What drug would be used for a tonic-clonic seizure?



What drugs would be used for an absence seizure?



What drug would be used for a myoclonic seizure?



What drug would be used for a partial/focal seizure?