Pharmacology And Therapeutics Flashcards
What two nervous systems make up the autonomic nervous system?
Sympathetic
Parasympathetic
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?
Acetylcholine
Cholinergic
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?
Acetylcholine
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?
Acetylcholine
What neurotransmitter stimulates muscarinic receptors?
Acetylcholine
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?
Acetylcholinesterase
What two components are used to produce acetylcholine?
Acetyl CoA + Choline
What is converted to DOPA to produce dopamine?
Tyrosine
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?
Atropine
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
Amphetamine
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?
Administration Absorption Distribution Metabolism Excretion
What are the different methods of administration of a drug? (4)
Local
Systemic
Enteral
Parenteral
What is the most rapid and effective way to administer a drug?
Intravenously
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?
Non-polar
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)
Oxidation
Reduction
Hydrolysis
What are the phase II metabolic changes that are made to a drug? (6)
Glucuronidation Acetylation Amino acid conjugation Sulphation Methylation 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?
Hydroxylation
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?
NADH⁺ and NADPH⁺
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?
Salivation
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?
Liquids Syrups Tinctures Powders Soluble (effervescent) tablets Capsules 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
Trimetaphan
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)
Atropine
Hyoscine
Tropicamide
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?
Hyoscine
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?
Botox
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 Minimal 3) CVS effects - tachycardia, palpitations, arrhythmias - cold extremities, hypertension - overdose - cerebral haemorrhage, pulmonary oedema 4) GIT Minimal 5) Skeletal muscle Tremor
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
Tremor
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?
Hypertension
Cardiac arrhythmias
Angina
Glaucoma
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?
Bronchoconstriction Cardiac failure Hypoglycaemia Fatigue 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
Sedation
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
BOTH CAUSE CONSTRICTION OF THE SPHINCTER PUPILAE
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?
Spasmolytics
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?
Tubocurarine
Suxamethonium
What drugs target the propagation of an action potential along the muscle fibre and muscle contraction?
Spasmolytics
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.
Tubocurarine
Atracurium
Give an example of a depolarising neuromuscular blocking drug.
Suxmethonium
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?
Atracurium
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
1) HYPOTENSION
- 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)
3) BRONCHOSPASM
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.
Pindolol
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.
Barbiturates
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?
Verapamil
- 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?
Uses:
- 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?
Contraction
↓ radius
↑ resistance
↓ flow
Relaxation
↑ 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
OR
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.
Uses:
- 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?
Amlodipine
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?
Inhalation
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’)
Miscellaneous
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?
- Presynaptic inhibition of GABA (by cannabis binding to CB₁) increases MCH (melanin concentrating hormone) neuronal activity
- 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
