Pharmacology & Therapeutics 2 Flashcards
What second messengers are M1, M3 and M5 receptors coupled to?
G-protein coupled to IP3 and DAG second messengers
What second messengers are M2 and M4 receptors coupled to?
G-protein coupled to cAMP second messengers
What type of ion channel are nicotinic receptors?
Lingand-gated
How many sub units do nicotinic receptors have?
5
α, β, γ, δ, ε
What do the ligand binding properties of a nicotinic receptor depend on?
The subunit combination
What are the muscarinic effect on the eye?
- Contraction of the ciliary muscle: accommodation for near vision
- Contraction of the sphincter pupillae: Constricts pupil (miosis) and improves drainage of intraocular fluid
- Lacrimation (tears)
What leads to glaucoma?
Increased intraocular pressure is produced by a decreased drainage of aqueous humour via the canals of Schlemm, anterior to the iris
How is glaucoma treated?
Stimulating the smooth muscle using a muscarinic agent which causes contraction of the sphincter pupillae which opens the pathway for drainage. This reduced the pressure.
What are the muscaranic effects on the heart?
- Ach effects on M2 acetylcholine receptors in the atria and nodes decrease cAMP. This leads to decreased Ca++ entry and increased K+ reflux.
- Cardiac output and heart rate decrease.
Negative ionotrophic and chronotrophic effect
What are the muscarinic effects on the vasculature?
- Most blood vessels do not have parasympathetic innervation, but instead M3 acetylcholine receptors on vascular endothelial cell
- Acetylcholine acts on vascular endothelial cells to stimulate NO release. This induced smooth muscle relaxation.
- Total peripheral resistance is reduced
- Therefore muscarinic agonists can be used as a possible treatment for hypertension
What are the overall muscarinic effects on the cardiovascular system?
- Decreased heart rate (bradycardia)
- Decreased cardiac output (due to decreased atrial contraction)
- Vasodilation (stimulation of NO production)
- All of these combined can lead to a sharp drop in blood pressure
What are the muscarinic effects on non-vascular smooth muscle?
Smooth muscle that does have parasympathetic innervation tends to respond in the opposite way to vascular muscle- meaning it contracts.
e. g.
- Lung: Bronchoconstriction
- Gut: Increased peristalsis (motility)
- Bladder: Increased bladder emptying
What are the muscarinic effects on the exocrine glands?
- Salivation
- Increased bronchial secretions
- Increased gastro-intestinal secretions (including gastric HCl production)
- Increased sweating (SNS-mediated)
What are the two classes of cholinomimetic drug?
Directly acting
Indirectly acting
Why is acetylcholine of no therapeutic use?
It does not differentiate between nicotinic and muscarinic receptors and it is is rapidly degraded
What type of directly acting cholinomimetic drug is aceytlcholine?
Choline ester
What are the different directly acting cholinomimetic drugs?
1) Acetylcholine
2) Nictone
3) Muscarine
4) Pilocarpine
5) Bethanechol
What type of activity does nicotine stimulate?
Sympathetic and parasympathetic activity.
It stimulates all autonomic ganglia
What type of cholinomimetic drug is pilocarpine?
- Alkaloid
- Non-selective muscarinic agonist with good lipid solubility
What is the half life of pilocarpine?
3-4 hours
What is pilocarpine used as treatment for?
Glaucoma?
What are the side effects of pilocarpine?
- Blurred vision
- Sweating
- Gastro-intestinal disturbance and pain
- Hypotension
- Respiratory distress
What type of cholinomimetic drug is bethanechol?
Choline ester
What makes bethanechol less resistant to degradation that acetylcholine?
Has a similar structure to acetylcholine but has an addition of a methyl group
- Is an M3 acetylcholine receptor agonist
What is the half life of bethanechol?
3-4 hours
What is the use of bethanechol?
- Assist bladder emptying
- Enhance gastric motility
What are the side effects of bethanechol?
- Sweating
- Impaired vision
- Nausea
- Bradycardia
- Hypotension
- Respiratory difficulty
What are the actions of indirectly acting cholinomimetic drugs?
- Increase the effect of normal parasympathetic nerve stimulation by inhibiting the action of acetylcholinesterase therefore preventing the breakdown of acetylcholine.
- Have the potential to increase the cholinergic activity of all cholinergic synapses
- Anticholinesterases
Give examples of reversibly anticholinesterases
- Physostigmine
- Neostigmine
- Donepezil (‘aricept’)
Give examples of irreversible anticholesterases
- Exothiopate
- Dyflos
- Sarin
What does cholinesterase metabolise acetylcholine to?
Choline and acetate
What are the effects of anticholinesterases?
- Enhanced muscarinic activity (at low dose)
- Further enhancement of muscarinic activity with increased transmission at all autonomic ganglia (at moderate dose)
- Can be toxic at a high dose. Showing a depolarising block at all autonomic ganglia.
What are the two types of cholinesterases?
- Acetylcholinesterase (true or specific cholinesterase- highly selective for acetylcholine)
- Butyrylcholinesterase (pseudocholinesterase)
Where are acetylcholinesterases found?
All cholinergic synapses (peripheral and central)
How fast is the action of acetylcholinesterases?
Very rapid
Hydrolysis occurs at over 10,000 reactions per second
Where is butryrylcholinesterase found?
In plasma and most tissues but NOT cholinergic synapses
Describe the specificity of butyrylcholinesterase
Broad substrate specificity
Hydrolysis other esters e.g. suxamethonium
- Shows genetic variation
What is the principle reason for low plasma acetylcholine?
The action of butyrylcholinesterase
How do reversible anticholinesterase drugs work?
- Compete with acetylcholine for active site on the cholinesterase enzyme
- Donates a carbamyl group to the enzyme which blocks the active site. This prevents acetylcholine from binding
- The carbamyl group is removed by slow hydrolysis (mins)
- This increases the the duration of type that acetylcholine acts in the synapse
Where does physostigmine primarily act?
Postganglionic parasympathetic synapse
What is the half life of physostigmine?
30 mins
What is physostigmine used for?
- Treatment of glaucoma aiding intraocular fluid drainage
- Treats atropine poisoning, particularly in children
How do irreversible anticholinesterase drugs work?
- Rapidly react with the enzyme active site, leaving a large blocking group
- This is stable and resistant to hydrolysis, recovery may require the production of new enzymes (days/weeks)
Which irreversible anticholinesterase drug is in clinical use?
Ecothiopate
- others commonly used as insecticides and nerve gas
What does ecothiopate inhibit?
Potent inhibitor of acetylcholinesterase
What is ecothiopate used in the treatment of?
Glaucoma
- Acts to increase intraocular fluid drainage with a prolonged duration of action
What are the systemic side effects of ecothipate?
- Sweating
- Blurred vision
- GI pain
- Bradycardia
- Hypotension
- Respiratory difficulty
What type of anticholinesterases can cross the blood brain barrier?
Non-polar
What are the outcomes if anticholinesterases cross the blood-brain barrier?
Low doses: Excitation with the possibility of convulsions
High doses: Unconsciousness, respiratory depression, death
What anticholinesterase drugs are used as a treatment for Alzheimer’s?
Donepezil
Tacrine
- Potentiation of central cholinergic transmission relieves the symptoms but does not affect degeneration
- Ach is important in leaning and memory
What can accidental exposure to organophosphates used in insecticides result in?
Severe toxicity
- Increased muscarinic activity, CNS excitation and a depolarising neuromuscular block
What is used to treat organophosphate poisoning?
- IV atropine
- Artificial respiration
- IV Pralidoxime
- The phosphorylated enzymes age within a few hours
What are the differences between agonists and antagonists with regards to affinity and efficacy?
Agonists show affinity and efficacy (binding & response)
Antagonists show affinity (binding & no response)
What are the two groups of cholinoreceptors?
Nicotinic
Muscarinic
Why can a drug interfering with nicotinic cholinoreceptors have the ability to intefere with the whole of the autonomic nervous system?
Nicotinic receptors are present at all autonomic ganglia
Give examples of nicotinic receptor antagonists
Hexamethhonium: 1st antihypertensive
Trimetaphan: hypotension during surgery (short acting)
What are clinically useful nicotinic receptor antagonists called?
Ganglion blocking drugs
- They block the ion channel which preents ions from moving through the channel pore
- These drugs interfere with both parasympathetic and sympathetic action with widespread effects
What does the term ‘use-dependent block’ refer to?
The fact that nicotinic receptor antagonists work most effectively when the ion channels are open. The more agonist that is present at the receptor, the more opportunity there is for the antagonist to block the channel. Therefore, the more useful and effective these drugs can be
What is the effect when a nicotinic cholinoreceptor is administered to sympathetically dominated tissues?
Sympathetic effects are lost.
- Shows hypotensive effects.
- Blood pressure falls because sympathetically driven responses to reduce blood pressure are lost
- Examples of sympathetically dominated tissues include the kidneys and blood vessels
What effect does the muscarinic receptor antagonist atropine have on the CNS
Normal dose: little effect
Toxic dose: mild restlessness -> agitation (less M1 selective)
What effect does the muscarinic recepotr antagonist hyoscine have on the CNS?
Normal dose: Sedation, amnesia
Toxic dose: CNS depression or paradoxical CNS excitation (associated with pain)
How is the muscarinic receptor antagonist tropicamide use clinically?
- Acts on receptors within the iris of the eye to cause pupil dilation
- Used in eye exams to examine the retina
Why are muscarinic receptor antagonists good for anaesthetic premedication?
- They cause the airways to dilate (useful when administering a gas mask)
- Dry the throat a bit, reducing the risk of aspiration.
- Reduce secretions in the lungs and mouth (inhaling secretions -> pneumonia)
- Removes parasympathetic effects of slowing heart rate and reducing contractility. Anaesthetic already reduced rate and contractility.
What are the clinical uses of the muscarinic receptor antagonist Hyoscine?
- Hyoscine patch for motion sickness
- Muscarinic receptors important in relaying information from inner ear to vomiting centres
- Muscarinic receptor antagonist reduce flow of information, reducing nausea
- Controls eye movements to maintain vision whilst in motion
How are muscarinic receptor antagonists used in treating Parkinson’s disease?
- Not first line treatment
- Nigrostial dopamine neurons in the brain are lost in Parkinson’s disease. They are important for fine control and movement.
- Muscarinic receptors have a negative effect on dopamine signalling from these neurons
- Antagonists take out the M4 receptors, losing the inhibitory effect. The last few dopamine neurons can fire at a maximum rate.
Which muscarinic receptor antagonist is used in treating asthma and COPD
Ipratropium Bromide
- Removes the effect of bronchoconstriction
How can muscarinic receptor antagonist be used in irritable bowel syndrome?
- Removing parasympathetic effects within the gut reduced smooth muscle contraction, gut motility and gut secretion.
- This relieves some of the symptoms of irritable bowel syndrome.
What are the unwanted side effects of muscarinic receptor antagonists/
- Hot as hell (decreased sweating interferes with thermoregulation)
- Dry as a bone (reduced secretions everywhere )
- Blind as a bat (due to effects on accomodation ability of ciliary muscle- cyclopegia)
- Mad as a hatter (high doe effect CNS agitation, restlessness, confusion, etc)
How is poisoining from muscarinic receptor antagonists treated?
- With anti-cholinesterase such as Physostigmine
- Massive amount of atropine overloads the system and the Ach receptors become blocked.
- Anti-cholinesterase prevents ACh breakdown in the synapse, so AcH levels out-compete Atropine, slowly clearing Atropine from the body
What is the mechanism of Botulinum Toxin?
- It interferes with exocytosis (ACh release from nerve terminals)
- Binds to SNARE complex, which would usually allow vesicles to fuse with the membrane and release ACh
- Botulinum toxin prevents this so the vesicles remain in the nerve.
What is the clinical use of Botulinum Toxin?
Botox
What types of adrenoreceptors does adrenaline show more selectivity for?
b1 = b2 > a1 = a2
What types of adrenoreceptors does noradrenaline show more selectivity for?
a1 = a2 > b1 = b2
Give examples of directly acting SNS agonists
- Adrenaline (non-selective)
- Phenylephrine (a1)
- Clonidine (a2)
- Dobutamine (b1)
- Salbutamol (b2)
What are the uses of adrenaline?
1) Allergic reaction and anaphylactic shock (IV) Reverses potentially life-threatening hypotension and bronchoconstriction
2) COPD. Relieves breathing difficulties.
3) Acute management of heart block
4) In spinal anaesthesia (IV)
5) To prolong duration of local anaesthetics (local administration)
6) To treat glaucoma (eye drops)
What are the unwanted actions of adrenaline?
1) Secretions- reduced and thickened mucous
2) CNS- minimal
3) CVS
- tachycardia, palpitations, arrhythmias
- cold extremities, hypertension
- overdose- cerebral haemorrhage, pulmonary oedema
4) GIT- minimal
5) Skeletal muscle- tremor
Which adrenoreceptors is phenylephrine more selective for?
Selective for a1 receptors
a1»a2»>b1/b2
What is phenylephrine resistant to?
Resistant to COMT but not MAO
What is phenylephrine chemically related to?
Adrenaline
What are the clinical uses of phenylephrine?
- Vasoconstriction
- Mydriatic
- Nasal decongestant
Where does phenylephrine have unwanted actions?
Cardiovascular system
Which adrenoreceptors is clonidine selective for?
a2 receptors
a2»a1»>b1/2
What are the clinical uses of clonidine?
1) Treatment of hypertension and migraine
2) Reduces sympathetic tone
- a2 adrenoreceptor mediated presynaptic inhibition of NA release
- Central action in brainstem within baroreceptor pathway to reduce sympathetic outflow
What adrenoreceptors is isoprenaline selective for?
B1 and B2 receptors
ß1=ß2»»α1/2
Isoprenaline is chemically similar to adrenaline. How does it differ?
Isoprenaline is less susceptibile to uptake 1 and MAO breakdown
What is the plasma half life of isoprenaline?
2 hours
What are the clinical uses of isoprenaline?
- Cardiogenic shock
- Acute heart failure
- Myocardial infarction
Why must isoprenaline be used with caution?
B2-stimulation in vascular smooth muscle in skeletal muscle results in a fall in venous blood pressure. This triggers a reflex tachycardia via the stimulation of baroreceptors
What adrenoreceptors are Dobutamine selective for?
Beta-1 receptors
β1»β2»>α1/2
What are the clinical uses of dobutamine?
- Cardiogenic shock
- Lacks isoprenaline’s reflex tachycardia
- Administered by IV infusion
What is the plasma half life of dobutamine?
2 minutes
It is rapidly metabolised by COMT
What adrenoreceptor is salbutomol selective for?
Beta-2 receptors
b2»b1»>a1/2
What is salbutamol (ventolin)?
A synthetic catecholamine derivative with relative resistance to MAO and COMT
What are the clinical uses of salbutamol?
1) Treatment of asthma
- Beta-2 relaxation of bronchial smooth muscle
- Inhibition of release of bronchoconstrictor substances from mast cells
2) Treatment of threatened premature labour
- Beta 2- relaxation of uterine smooth muscle
What are the side effects of salbutamol?
Reflex tachycardia
Tremor
Blood sugar dysregulation
Give examples of indirectly acting SNS agonists
- Cocaine (uptake 1 inhibitor)
- Tyramine
What are the actions of cocaine on the CNS?
Low doses:
- Euphoria, excitement, increased motor activity
High doses:
- Activation of chemoreceptor trigger zone, CNS depression, respiratory failure, convulsions and death
What are the actions of cocaine on the CVS?
Low doses:
- Tachycardia, vasoconstriction, raised blood pressure
High doses:
- Ventricular fibrillation and cardiac arrest
What is the clinical use of cocaine?
- Local anaesthetic in ophthalmology (rare); do not co-administer with adrenaline
- Well absorbed from all sites; readily crosses blood-brain barrier- unlike adrenaline or noradrenaline
- Degraded by plasma esterases and hepatic enzymes; plasma half life approximately 30 minutes excreted in urine
What is tyramine?
A dietary amino acid
(cheese, red, wine and soy sauce)
- Acts as a ‘false’ transmitter
- It is not a problem when normal mechanisms for degradation of monoamines are in operation
How does tyramine operate?
1) Has soem weak agnostic activity in its own right at post synaptic adrenoreceptors
2) Competes with catecholamines for uptake 1- it is taken up into adrenergic nerve terminals
3) Displaces no-adrenaline from intracellular storage vesicles into cytosol
4) Nor-adrenaline and tyramine compete for sites on MAO
5) Cytoplasmic nor-adrenaline leaks through the neuronal membrane to act at postsynaptic adrenorececptors
- Not usually a problem due to first pass metabolism and short half life so does not enter the CNS
Why does tyramine cause problems when MOAs are inhibited?
Ingestion of foods may cause a hypertensive crisis
‘cheese reaction’
What are the types of adrenoreceptors?
a1- Vasoconstriction, relaxation of GIT
a2- Inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions
B1- Increased cardiac rate and force, relaxation of GIT, renin release from kidney
B2- Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
B3- Lipolysis
What are the different types of adrenoreceptor antagonists?
- Non- selective: (a1+ b1) Labetalol
- a1 + a2: Phentolamine
- a1: Prazosin
B1 + B2: Propanolol
B1: Atenolol
What are the clinical uses of SNS antagonists and false transmitters?
- Hypertension
- Cardiac arrhythmias
- Angina
- Glaucoma
What is hypertension defined as?
Sustained diastolic arterial pressure greater than 90 mmH
What are the main elements that contribute to hypertension?
- Blood volume
- Cardiac output
- Peripheral vascular tone
What are the tissue targets for antihypertensives?
- Sympathetic nerves that release the vasoconstrictor noradrenaline
- The kidney: blood volume/vasoconstriction
- The heart
- Arterioles: determine peripheral resistance
- CNS: determined blood pressure set point and regulates some systems that are involved in blood pressure control and ANS
How can B-blockers be classified?
Whether they are non-selective (propranolol), cardioselective (atenolol) or whether they have some additional a1 atagonist activity
How do B-adrenoceptor antagonists work?
Competitive antagonism of b1 adrenoreceptors
What is the mode of action of b-adrenoceptor antagonists?
- Reduced sympathetic tone in the CNS
- Acts on the heart (B1) to reduce heart rate and cardiac output. This effect disappears in chronic treatment
- Acts on the kidney (B1) to reduce renin production. A common long term feature in their anti-hypertensive action is a reduction in peripheral resistance.
What are the pre-synaptic effects of B-adrenoceptor antagonists?
Presynaptic beta receptors have a positive effect on the synthesis and release of noradrenaline.
B1 antagonists cause a blockade on this presynaptic facilitation.
This may contribute to the antihypertensive effect.
What are the unwanted effects of B-adrenoceptor antagonists?
- Bronchoconstriction: Has little importance in the absence of airway disease. In asthmatic patients, this can be dramatic and life-threatening. Has clinical important in patients with obstructive lung disease e.g. bronchitis
- Cardiac failure: patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output. Removal of this by blocking B receptors will produce a degree of cardiac failure.
- Hypoglycaemia (sweating, palpitations, tremor)
- Fatigue: Due to reduced cardiac output and reduced muscle perfusion
- Cold extremities: Loss of B-receptor mediated vasodilation in cutaneous vessels
- Bad dreams
Why are the unwanted effects of hypoglycaemia more dangerous with the use of non-selective B-antagonists?
- The use of B antagonists mask the symptoms of hypoglycaemia
- Use of non-selective B antagonists are more dangerous in such patients since they will also block the B2 receptors driven breakdown of glycogen.
- B1-selective agents may have advantages since glucose release from the liver is controlled by B2-receptors.
What type of Beta-blocker in propranolol?
B1+B2- non-selective
What are the effects of of propranolol in a subject at rest?
- Causes very little change in heart rate, cardiac output or arterial pressure. However, it reduces the effect of exercise or stress on these variables
Why does propranolol produce all the typical adverse effects?
It is non-selective
How is the selectivity of atenolol described?
It is a B1 selective drug
Cardioselective
What are the effects of atenolol?
- As it is B1 selective, it mainly antagonises the effects of noradrenaline on the heart but will affect any tissue with B1 receptors such as the kidney
- Has less effect on airways than non-selective drugs but is still not safe with asthmatic patients
What type of adrenoceptor antagonist is labetalol?
Dual acting B1 and A1 antagonist.
Has a ratio of B1 to A1 of 4:1
What are the effects of labetalol?
- The drug lowers blood pressure via a reduction in peripheral resistance
- Like B-blockers, labetolol induces a change in heart rate or cardiac output. This effect wanes with chronic use
Why do non-selective alpha-adrenoceceptor antagonists cause a rapid fall in arterial pressure?
- Cause a rapid fall in arterial pressure as alpha receptors are the main mediators of peripheral resistance
- Due to subcutaneous vasodilation which causes increased blood flow through cutaneous and splanchnic vascular beds. Has only slight effects on vascular smooth muscle
What are the side effects of non-selective alpha-adrenoceptor antagonists?
Postural hypotension induced reflex tachycardia.
B-receptors show a reflex response due to the fall in arterial pressure
What type of antagonist is phentolamine?
Non-selective alpha-antagonist
What are the effects of phentolamine?
- Causes vasodilation and a fill in blood pressure due to blockade of alpa-1 receptors
- However, concomitant blockade of alpha-1 receptors tends to increased noradrenaline release. This enhances the reflex tachycardia that occurs with any blood pressure lowering agent.
- Increased GIT motility, diarrhoea is a common problem
- It is no longer clinically used
What type of antagonist is prazosin?
Alpha -1 antagonist
What are the effects of prazosin?
- Vasodilation and a fall in arterial pressure
- Less tachycardia than non-selective antagonists since they do not increase noradrenaline release form nerve terminals (no alpha-2 actions)
- Cardiac output decreases, due to fall in venous pressure as a result of dilation of capacitance vessels
- Dramatic hypotensive effect
- Does not affect cardiac function appreciably, although postural hypotension is troublesome
- Differs from other anti-hypertensives as alpha-1 antagonists cause a modest decrease in LDL and an increase in HDL cholesterol
What is methyldopa and what is it used for?
Is a false transmitter
Used as an antihypertensive agent
How does methyldopa work?
- Taken up by noradrenergic neurons
- Decarboxylated and hydroxylated to form the false transmitter, alpha-methyl noradrenaline
Why does methyldopa accumulate in larger quantities than noradrenaline?
It is not deaminated within the neuron by Mono Amine Oxidase (MAO) and therefore tends to accumulate in larger quantities than noradrenaline, and displaces noradrenaline from synaptic vesicles
What is the mechanism of action of methyldopa?
- The false transmitter is release in the same way as noradrenaline
- Differs in two important respects in its action on adrenoceptors
1) Less active than noradrenaline on a1- receptors, less effective in causing vasoconstriction
2) More active on presynaptic (a2) receptors, auto-inhibitory feedback mechanism operates more strongly, reduces transmitter release below normal levels - Also some CNS effects, stimulates vasopressor centre in the brainstem to inhibit sympathetic outflow
What are the benefits of methyldopa?
- Renal and CNS blood flow is well maintained, widely used in hypertensive patients with renal insufficiency or cerebrovascular disease
- Recommended in hypertensive pregnant women, has no adverse effects on the foetus despite crossing the blood-placenta barrier
What are the adverse effects of methyldopa?
- Dry mouth
- Sedation
- Orthostatic hypotension
- Male sexual dysfunction
What is the main cause of arrhythmias?
Myocardial ischaemia
- There is an increase in sympathetic tone after myocardial infarction.
- An increase in sympathetic drive to the heart via B1 can precipitate or aggravate arrhythmias
- AV conductance depends critically on sympathetic activity, and the refractory period of the AV node is increased by B-adrenoceptor antagonists, intefering with AV conduction in atrial tachycardias and to slow ventricular rate
Which B-antagonist acts as a antiarrhythmics?
Propanolol- a non selective B-antagonist. Also classed as a class II antiarrhythmic- mainly due to beta-1 antagonism
- Reduces the mortality of patients with myocardial infarction
- Particularly successful in arrhythmias that occur during exercise or mental stress
What is angina?
Pain that occurs when the oxygen supply to the myocardium is insufficient for its needs
It is brought on by exertion or excitement
Where is pain distributed in angina?
Chest, arm, neck
What is stable angina?
Pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels. E.g. atheroma
What is unstable angina?
Pain with less and less exertion, culminating with pain at rest.
Platelet-fibrin thrombus associated with a ruptures atheromatous plaque, but without complete occlusion of the vessel.
There is a risk of infarction
What is variable angina?
Occurs at rest, caused by coronary artery spasm.
It is associated with atheromatous disease.
What is used to treat angina?
B-adrenoceptor antagonists in order to reduce myocardial oxygen
How do B-adrenoceptor antagonists treat angina?
- Reduce myocardial oxygen on demand
- Decrease heart rte
- Decrease systolic blood pressure
- Decrease cardiac contractile activity
- At low doses, B1-selective agents, metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle
- Reduce the oxygen demand whilst maintaining the same degree of effort
What are the adverse effects of B-adrenoceptor antagonists being used to treat angina?
- ## Fatigue, dizziness, sexual dysfunction, bronchospasm, bradycardia, heart block, hypotension, decreased myocardial contractility.
In which cases should B-adrenoceptor antagonists not be used to treat angina?
In patients with bradycardia, bronchospasm, hypotension, AV block or sever congestive heart failure
Where is aqueous humour produced and what course does it take to drain into the canal of Schlemm?
- Produced by blood vessels in ciliary body via the actions of carbonic anhydrase
- Flows into posterior chamber, through the pupil anterior chamber
- Drains into trabecular network and into veins and canal of Schlemm
What is the production of aqueous humour indirectly related to?
Blood pressure and blood flow in the ciliary body
What non selective beta-antagonists are used to treat glaucoma?
- Carteolol hydrochloride, levobunolol hydrochloride, timolol maleate
- Reduce the rate of aqueous humor formation by blocking the receptors on the the ciliary body
What selective beta antagonists are used to treat glaucoma?
B1 antagonist betaxolol hydrochloride
What are some other uses of Beta-antagonists?
- Anxiety states: to control somatic symtpoms associated with sympathetic over reactivity, such as palpitations and tremor
- Migraine prophylaxis
- Benign essential tremor
What is a neuromuscular junction?
The synapse of the axon terminal of a motor neuron with a motor end plate, the highly excitable region of muscle fibre plasma membrane which is responsible for the initiation of action potentials across the muscles surface which causes the muscle to contract
Which neurotransmitter is involved in neurotransmission at the neuromuscular junction?
Acetylcholine
What is the nicotinic acetyl-choline receptor made up of?
- 5 sub units
- All arranged symmetrically around a central pore
- Each subunit comprises 4 transmembrane domains with both the N and C terminus located extracellularly
What drugs affect CNS processes of the musculoskeletal system?
Spasmolytics
eg. Diazepam and Baclofen
What drugs affect the conduction of nerve action potential in the motor neurone?
Local anaestetics
What drugs affects acetylcholine release?
Ca++ entry blockers
What drug affects choline reuptake?
Hemicholinium
What drugs affect propagation of action potentials along muscle fibres?
Spasmolytics
eg. Dantrolene
What are neuromuscular blocking drugs?
Act at the final site at which drugs can act- the neuromuscular junction.
They prevent depolarisation of the motor-end plate and post-synaptic action potential initiation
They act post-synaptically
What are the types of neuromuscular blocking drugs?
1) Non-depolarising- competitive antagonists eg. Tubocarine and atracurium
2) Depolarising- agonists eg. suxamethonium (succinylcholine)
What are the affects of neuromuscular blocking drugs?
- Do NOT affect consciousness or pain sensation
- DO affect respiratory muscles therefore respiration must always be assisted until the drug is inactive or antagonised
What is the mode of action of Tubocarine?
- Non-depolarising neuromuscular blocking drug
- Competitive nicotinic Ach receptor antagonist
- A 70-80% block is necessary to achieve the desired effects
- Produces a graded block, in which there are different proportions of fibres blocked
What are the pharmacokinetics of tubocarine?
- Administered intravenously (highly charged)
- Duration of action = Between 40 and 60 minutes
- Not metabolised
- Excreted 70% in urine and 30% in bile. Therefore, care must be taken if the patient has their renal or hepatic function impaired.
What are the effects of tubocarine?
- Flaccid paralysis
- First the extrinsic eye muscles are affected. The patients will experience double vision
- Second, the small muscles of the face, limbs and pharynx are affected
- Lastly, the respiratory muscles are effected
- Recovery occurs in the reverse order
What are the clinical uses of tubocarine?
- Relaxation of skeletal muscles during surgical operations so that less anaesthetic is required
- Permits artificial ventilation
How can the actions of tubocarine be reversed?
Anticholinesterases such as Neostigmine, co-administered with Atropine
What are the unwanted effects of tubocarine?
- Ganglion block & histamine release from mast cells
- Ganglion block > decreased peripheral resistance > hypotension and reflex tachycardia
- Histamine release > bronchospasm, excessive bronchial salivary secretions
- Apnoea also caused by histamine release
What is Atracarium?
Antagonist of Ach at the post-synaptic site at the neuromuscular junction.
Non-depolarising blocker like Tubocarine but the effects have a shorter duration
What is suxamethonium (succinulcholine)?
- Depolarising neuromsucular blcoker
- Structure is related to acetylcholine and is a post synaptic nAChR agonist
- Causes excitation for a long period of time, action potentials can no longer be produced as the cell cannot repolarise.
- Degraded by Butyrylcholinesterase
What are the main effects of the sympathetic nervous system on the heart?
- Increased force of contraction (positive ionotropic effect)
- Increased heart rate (positive chronotropic effect)
- Increased automaticity
- Reploarisation and restoration of function following generalised cardiac depolarisation
- Reduced cardiac efficiency (i.e. cardiac oxygen consumption is increased more than cardiac work)
What are the effects of the sympathetic nervous system on the heart mainly due to?
- The activation of Beta-1 adrenoceptors
- Activation stimulates adenyl cyclase resulting in production of cyclic AMP from ATP. This acts as an intracellular messenger which increases intracellular Ca++ and stimulates Na-K ATPase in cardiac myocytes
What are the effects of activation of the parasympathetic system on the heart?
- Cardiac slowing
- Reduced automaticity
- Inhibition of AV conduction
What do the drugs used to treat the symptoms of angina aim to improve?
The balance between supply and demand for oxygen
Give an example of an organic nitrate
Glyceryl trinitrate
How do organic nitrates act?
- Act mainly as venodilators, reducing venous return and cardiac work via the Frank Starling relationship
- They release nitric oxide
- Nitrates ay also have weak anti-platelet actions and cause coronary arterial vasodilation.
Which potassium channel opener is used in angina?
Nicorandil
How do potassium channel openers work in anginda?
- Open KATP channels and also act as nitric oxide donors.
- These agents cause venodilation and arterial dilation.
What are the adverse effects of nitrates?
Hypotension
Headache
What are the two classes of calcium antagonists?
1) Rate slowing (cardiac and smooth muscle actions)
- Phenylalkylamines (eg. Verapamil)
- Benzothirazepine (e.g. Diltizaem)
2) Non-rate slowing (smooth muscle actions-more potent)
- Dihyropyridines (e.g. amlodipine)
- No effect on the heart. Profound vasodilation can lead to reflex tachycardia
How do calcium antagonists act to reduce cardiac workload?
They bind to and inhibit the opening of L-type calcium channels
They cause arterial vasodilation.
Why does verapamil have negative chronotropic and ionotropic actions?
Reduce Ca++ entry into cardiac myocytes
What are the side effects of verapamil?
Heart block
Heart failure
Constipation
What are the side effects of calcium antagonists?
Flushing
Headaches
Hypotension
Ankle swelling
What are the limitations of the Vaughan Williams classification?
It is widely cites but not helpful in predicting the effects of a particular anti-dysrhythmic agent and a number of useful agents cannot be classified by this system
What are the determinants of myocardial oxygen supply?
Coronary blood flow
Arterial 02 content
What are the determinants of myocardial oxygen demand?
Heart rate
Preload
Afterload
Contractility
What decreases with vasodilation?
Afterload
What decreases with venodilation?
Preload
What is the Vaughan-Williams classification of arrhythmic drugs?
I- Sodium channel blockade
II- Beta adrenergic blockade
III- Prolongation of repolarisation
IV- Calcium channel blockade
Give examples of antidysrhythmic agents
Adenosine
Verapamil
Amiodarone
Digoxin and cardiac glycosides
What is adenosine?
- Endogenous mediator
- Produced by metabolism of ATP
- Acts on A1 receptors to hyperpolarise cardiac tissue and slow conduction through the AV node
- Used intravenously to terminate superventricular tachyarrhythmias (SVT)
Why is adenosine safer than verapamil?
Its actions are short lived- 20 to 30 seconds
What are the uses of verapamil?
- Reduction of ventricular responsiveness to atrial arrhythmias
- Prevents recurrence of paroxysmal SVT
- Reduced ventricular rate in patients with atrial fibrillation provided they do not have Wolff-Parkinson-White or similar abnormal conduction pathwyas
What is the mechanism of action for verapamil?
Depresses automaticity of SA node and subsequent AV node conduction
What are the uses of amiodarone?
- Superventricular and ventricular tachyarrhythmias- often due to reentry
What is the mechanism of action for amiodarone?
- Complex action probably involving multiple ion channel block
What are the adverse effects of amiodarone?
- Accumulates in the body (half life= 10-100 days)
- Has a number of effects which include:
- Photosensitive skin rashes
- Hypo/hyper -thyroidism
- Pulmonary fibrosis
How do digoxin and cardiac glycosides work?
Act as inhibitors of the Na-K ATPase (Na/K) pump
What are the cardiac effects of digoxin?
- Cardiac slowing and reduced rate of conduction through the AV node (largely as a result of central vagal stimulation)
- Increased force of contraction
- Disturbances of rhythm especially:
- Block of AV conduction
- Increased ectopic pacemaker activity
What are the uses of digoxin and cardiac glycosides?
- Atrial fibrillation and flutter lead to a rapid ventricular 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 node. Fewer impulses reach the ventricles and the ventricular rate will fall.
What are the adverse effects of digoxin and cardiac glycosides?
- Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
- Hypokalaemia lowers the threshold for digoxin toxicity
What are cardiac ionotropes?
Agents that increase the force of cardiac contraction and are used to treat heart failure in some situations (eg. after cardiac surgery or in cardiogenic or septic shock)
What is Dobutamine?
Beta1 Adrenoceptor agonist that stimulates cardiac contraction without a major effect on heart rate
How do inhibitors of phosphodiesterase have ionotropic effects?
Inhibit the breakdown of cyclic AMP in cardiac myocytes
Give an example of an inhibitor of phosphodiesterase
Milrinone
What are the uses of ACE inhibitors?
- Hypertension
- Heart failure
- Post-myocardial infarction
- Diabetic nephropathy
- Progressive renal insufficiency
- Patients at high risk of cardiovascular disease
What are the adverse affects of ACE inhibitors and angiotensin receptor blockers
- Cough (ACEI)
- Hypotension (both)
- Urticaria/ Angioedema (ACEI- rare)
- Hyperkalaemia
- Fetal injury (both)
- Renal failure in patients with renal artery stenosis (both)
What mediates most of the affects of angiotensin II?
AT1 receptor
What is spironolactone an antagonist of?
The mineralcorticoid- aldosterone
It inhibits the sodium retaining effects of aldosterone
What is spironolactone useful for?
Heart failure
Resistant cases of hypertension
What are the unwanted effects of spironolactone?
- Can cause hyperkalaemia due to its aldosterone antagonism
- Steroid like effects such as gynaecomastia, menstrual disorders and testicular atrophy
Give an example of an ACE inhibitor
Enalapril
What are the types of calcium channel blockers?
Dihydropyridines:
- More selective for blood vessels
- Nicardipine- does not cause any negative ionotropy
- Also licensed for prophylaxis of angina
Non-DHPs (rate limiting):
- Verapamil- large negative ionotropic effect
What are the uses of beta-adrenoreceptor blockers?
Angina Post myocardial infarction Cardiac dysrhythmias Chronic heart failure Hypertension Thyrotoxicosis Glaucoma Anxiety states Migraine prophylaxis Benign essential tremor
Why might beta blockers be an effective treatment for hypertension
- Causes a decrease in heart rate and force of contraction. Therefore there is a decrease in cardiac output
- The heart does not have to work as hard so there is a reduction in blood pressure
- Renin and Angiotensin II release decreases
Why does Carvedilol have additional vasodilator properties to Atenolol?
Atenolol is B1- selective.
Carvedilol is a mixed B-alpha blocker.
The Alpha-1 gives additional vasodilator properties
What is hydralazine?
A direct vasodilator that acts mainly on arteries and arterioles
Under what circumstances would hydralazine cause a reflex tachycardia?
In the absence of a beta-blockade due to the drugs vasodilator effects
How does doxazosin act as an arterial vasodilator?
It is an alpha blocker (competitive antagonist of a1-adrenoceptors). Acts as an arterial vasodilator by inhibiting the vasoconstrictor effects of the sympathetic nervous system acting via a1-adrenoceptors on vascular smooth muscle
When is phenoxybenzamine used?
- It is an irreversible non-selective alpha antagonist
- Provides a long-lasting alpha-blockade in pheochromocytoma (combined with a beta blocker)
Give examples of centrally acting antihypertensive agents
Clonidine
-methyldopa (a2-adrenoceptor agonists)
Moxonidine (imidazole agonist)
Reserpine (depletes neuronal noradrenaline)
- These agents act by reducing sympathetic activity
What is guanethidine?
Adrenergic neuron blocker
What is trimethaphan?
Short acting ganglion blocker
- Is occasionally used in anaesthesia to lower blood pressure
What is sumitriptan and what does it do?
Agonist at 5HT1D receptors.
Causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission
What is sumitriptan used for?
Treats migraine attacks, contraindicated in patients with coronary disease
What are the side effects of sumitriptan?
Dizziness
Drowsiness
Asthenia
Fatigue
When can adrenaline be used?
Cardiac arrest
Anaphylactic shock
How is blood pressure calculated?
cardiac output x total peripheral resistance
How is hypertension defined?
Being consistently above 140/90 mmHg
What is hypertension a major risk factor if?
Stroke
Myocardial infarction
Chronic kidney disease
What is chronic heart failure?
Impaired cardiac function due to ischaemic heart disease, hypertension or cardiomyopathy that results in fluid retention, oedema and fatigue
What do patients with chronic heart failure typically receive?
- Diuretic
- ACE Inhibitor (ARB)
- Beta blocker
- +/- spironolactone
- +/- digoxin
What is a narcotic?
A drug that produces morphine like effects
What causes the euphoric feeling obtained from drugs?
- The mesolimbic system and pathways go up into the nucleus accumbens go up into the nucleus accumbens to release dopamine
- The release dopamine into the nucleus accumbens causes the euphoric feeling- this is also the natural reward pathway?
Where do the mesolimbic system and pathways originate?
Ventral tegmental area
What are the different routes of administration for drugs of abuse?
1) Snorting (intra-nasal)- drug crosses the mucous membranes of nasal sinus, into the blood then systemic circulation back to the heart then up to the brain (slow absorption)
2) Eating (oral)- drug absorbed in GI tract, passes through liver then goes back into circulation (very slow absorption)
3) Smoking (inhalation)- drug transfers across small airways and into blood (rapid absorption and distribution)
4) Injection (intra-venous)- rapid absorption
How are drugs of abuse classified?
Nacrotics/painkillers- opiate like drugs e.g. heroin
Depressants- ‘downers’ e.g. alcohol, benzodiazepines (valium), bariturates
Stimulants- ‘uppers’ e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’)
Miscellaneous- e.g. Cannabis, ecstacy (MDMA)
How many compound does herbal cannabis contain?
Over 400 compounds including over 60 cannabinoids
What is the most potent psychoactive agent in cannabis?
9-tetrahydrocannabinol
What are cannabinoids present in?
- Marijiuana/CAnnabis: leaves and flowering tops of cannabis sativa plants
- Hashish- resinous material of cannabis plant, leaves, flowers and seeds of the plants, and also in the resin secretion by the female plant
Hash oil- plant extract (with organic solvents
How does oral ingestion of cannabinoids differ from it being smoked?
Blood concentration are 25-30% of those obtained by smoking the same dose- due to first pass metabolism.
Onset of action is delayed (0.5-2h) but duration is prolonged to slow absorption from the gut
What is a major metabolite of cannabinoids?
11-hydroxy-THC
- is a postent cannabinoid itself
Where are cannabinoids metabolised?
Liver
Where are cannabinoids excreted?
Urine (25%)
Gut (65%)
They are reabsorbed from the gut which further prolongs their actions
What are the neuronal cannabinoid receptors?
CB1
Present in hippocampus/cerebellum/cerebral cortex/basal ganglia
What are the cannabinoid receptors in immune cells?
CB2
What is the endogenous agonist of cannabinoids?
Anandamide- an arachidonic acid derivative
What are the psychological effects of cannabinoids?
- Effects on perception: colours seem brighter, music is more vivid, emotions more poignant
- Perceived time goes faster than clock time
How do cannabinoids affect cognition and psychomotor performance?
Slow reaction times, motor incoordination, defects in short term memory
What are the CVS effects of cannabinoids?
- Tachycardia up to 160 beats/minute
- Widespread vasodilation
- Reddening of the conjunctivae- a characteristic sign of cannabis use
- Postural hypotension and fainting may occur
- Risk factor for severe mental illness
What is the purpose of the anterior cingulate cortex?
Involved with performance monitoring with behavioural adjustment in order to avoid losses
How does cannabis affect the anterior cingulate cortex?
Leads to hypo-activity
- This is associated with poor control
How does cannabis affect food intake?
- Positive effect on orexigenic neurones in lateral hypothalamus
1) Presynaptic inhibition of GABA increases MCH neuronal activity
2) Increased orexin production
What are the peripheral effects of cannabis?
- Immunosuppressant
- Tachycardia/vasodilation
What is Dronabinol used for?
Treats nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type of nausea and vomiting without good results
- Also treats loss of appetite and weight loss in people who have AIDS
Which drugs target the cannabinoid system?
- Dronabinol and Nabilone
- Savitex
- Rimonabant
What examples of disease show how the up-regulation of CB receptors can mitigate a disease?
- In multiple sclerosis and schizophrenia, activating CB1 and CB2 receptors, has a beneficial effect as it stops the toxic necrosis of the neurons in the brain.
What are the different forms cocaine is available in?
IV, ORAL, INTRANASAL:
1) Paste- 80% cocaine (organic solvent)
2) Cocaine HCl- dissolve in acidic solution
INHALATION:
3) Crack- precipitate with alkaline solution e.g. baking soda
4) Freebase- dissolve in non-polar solvent (e.g. ammonia and ether)
Why is there slower absorption when cocaine is snorted as opposed to smoked?
It is absorbed through the mucous membranes that line the sinuses.
100-500ng/mL
What are the routes of administration of cocaine that have rapid absorption?
- Smoking
- Cocaine HCl being injected IV
How is cocaine metabolised?
Cocaine metabolises primarily into ecgonine methyl ester and benzolyecgonine on first passage through the liver which are renally excreted.
These metabolites account for 75-90% of cocaine metabolism
What is the half life of cocaine?
90 minutes
What effects does cocaine have on the reward pathway?
Inhibit the reuptake of dopamine in the Nacc
How does cocaine have a local anaestetic effect?
Cocaine blocks sodium channels to prevent nerve conduction. (major therapeutic use of cocaine)
- Cocaine also binds to and inhibits monoamine transporter proteins. Influences the transport of neurotransmitters. Cocaine blocks the transporters e.g. for serotonin, dopamine and noradrenaline
How does cocaine induce euphoria?
- Cocaine directly affects the mesolimbic neurons
- Binds to dopamine transporter present on the terminals of dopaminergic neurons and prevents the re-uptake on dopamine.
- If dopamine is prevented from being removed from the synapse in the nucleus accumbens, the effect is prolonged and this is how the euphoria is caused
How does cocaine affect the CNS?
- Cocaine is a stimulant and enhances CNS effects
- An overdose can induce severe effects like irritability, hostility, anxiety and insomnia
What are the cardiovascular effects of cocaine?
- Cocaine increases the production of endothelin-1 (powerful vasoconstrictor)
- Decreases NO production (vasodilator
- Increases platelet activation and sympathetic stimulation and an overall increase in heart rate.
- This explains the link between cocaine use and sudden death
What is nicotine?
Plant derived alkaloid that is contained within tar droplets, which are very lipid soluble and pass down into the lungs and onto the bloodstream