Molecular drug targets

• 5 examples of where drugs act:

  -G protein-coupled receptors

  -Ion channels

  -Enzymes e.g., donepezil on acetylcholinesterase

  -Transporters

  -Nuclear receptors
• Autonomic nervous system:


  -Largely outside of voluntary control

  -Consists of Parasympathetic, Sympathetic & Enteric nervous system

  -Mainly regulates heartbeat, smooth muscle contraction and relaxation, exocrine function, some endocrine secretions and regulates some steps in intermediate metabolism.
• Somatic (motor) nervous system

  -Under conscious control

  -Efferent nerves control movement by innervating skeletal muscle.

  -Afferent nerves respond to external stimuli e.g. pain-sensing

  (nociceptive) fibres.
• Parasympathetic nervous system:


  -Part of autonomic nervous system

  -"Rest and digest"

  -Cranial-sacral output

  -Synapse at ganglia close to innervated tissue/organ.

  -Short distance between spinal cord and organ

  -Top and bottom of spinal cord
• Sympathetic nervous system


  -Part of autonomic nervous system

  -"Fight or flight"

  -Thoracic-lumbar output

  -Synapse at ganglia either side of vertebral column (sympathetic chain).

  -Ganglia distal to innervated tissue/organ.

  -Distance between spinal cord and spinal cord
• Cholinergic transmission:


  -All motor nerves release ACh which act on nicotinic acetylcholine receptors

  -Postganglionic parasympathetic nerves release ACh to act on muscarinic acetylcholine receptors

  -ACh release in presynaptic receptors regulated by inhibitory presynaptic M2 muscarinic receptors
• What does the cholinergic system contain?

  -Nicotinic and muscarinic acetylcholine receptors subtypes that can be targeted selectively.
• Breakthrough findings in cholinergic transmission:

  -Muscarine mimics and atropine blocks effects of electrically stimulating the vagal nerve

  -Nicotine could mimic and curare blocks electrical stimulation of NMJ
• Nicotine mechanism of action:

  -Acts on nicotinic AChR
• Clinical relevance of atropine:

  -Smooth muscle relaxant e.g. IBS

  -Cardiovascular e.g. to treat bradycardia after heart attack

  -Anaesthesia: pre-medication and to prevent vagal inhibition of the heart

  -Ophthalmic use to paralyse eye to aid treatment of inflammation
• Atropine mechanism of action:

  -Non selective antagonist on muscarinic AChR
• Why is knowledge of receptor subtypes important?

  -Allows drug discovery to create better drugs

  (more efficacious, safer)
• What are the actions of mAChR agonists?

  -Parasympathetic effects

  -Bradycardia/reduced cardiac output.

  -Vasodilation

  -Increases secretion (salivation, lacrimation, sweating)

  -Bronchoconstriction and bronchial secretion

  -Increased gut motility

  -Reduction of intraocular pressure (due to pupillary constriction)
• What are the actions of atropine?

  -mAChR antagonists

  -Block secretion -salivation, lacrimation, sweating, bronchial secretion

  -Tachycardia (increased heart rate)- modest effect

  -Pupillary dilation (mydriasis) and ciliary muscle paralysis (cycloplegia)

  -Inhibits gut motility

  -Paralysis of bladder

  -Smooth muscle (except gut) relaxation

  -CNS effects: excitatory
• Peripheral nAChRs:


  -Peripheral nAChRs that are present at autonomic ganglia and NMJs are molecularly and pharmacologically distinct.

  -But drugs affecting ANS ganglia do not discriminate between sympathetic and parasympathetic nerves.
• Actions of nAChRs at neuromuscular junction:

  -Competitive antagonists of nAChRs = competitive blockers

  -Agonists which cause a depolarizing block of the muscle fibre endplate = depolarizing blockers
• What are the uses of competitive blockers?

  -Widely used as muscle relaxants as an adjunct to anaesthesia

  -Used in obstetrics as these drugs do not cross placenta.

  -Given IV and vary in duration of action according to surgery

  -Examples: tubocurarine, pancuronium, vecuronium, atracurium
• What are the uses of depolarizing blockers?

  -Continuous stimulation of the NMJ by agonists causes muscle paralysis

  -Muscle contracts due to maintained depolarization, but cannot repolarize (relax) causing loss of excitability (sodium channels cannot inactivate)

  -Example: suxamethonium (succinylcholine)

  -Used to cause paralysis during anaesthesia:

  -Suxamethonium is short-acting ~ 10 mins (compared to competitive, non-depolarizing blockers) because it is rapidly hydrolysed by cholinesterases.
• Clinical relevance of Donepezil:

  -Used for treatment of mild to moderate Alzheimers

  -Acteylcholinesterase enzyme inhibitor (anticholinesterase)
• Botulinum toxin type A clinical relevance:

  -Blocks vesicle docking/release

  -Botulism caused by food poisoning

  -Causes dry mouth/blurred vision, but leads easily to respiratory paralysis (LD50 = 10 ng/kg)
• Therapeutic indications for botulinum toxin:

  -Treatment for muscle spasm(s) which can result from stroke, brain or spinal cord injury, cerebral palsy

  -Migraine as facial muscle contraction stimulates headache

  -Excessive secretion (drooling or sweating) that is not managed by topical agents. Treatments effective for 6-10 months
• Name 2 other anticholinesterases:

  -Rivastigmine -Galantamine
• What is adrenergic transmission?

  -The vast majority of postganglionic sympathetic fibres release noradrenaline to act either on a or b-adrenoceptors

  
  

  (Important exception is sympathetic innervation of sweat glands where ACh acts on mAChRs)

  
  

  -Presynaptic receptors: NA release is regulated by inhibitory presynaptic a2-adrenoceptors
• Where is noradrenaline released ?

  -Released by post-ganglionic sympathetic nerves

  -Transmitter
• Where is adrenaline secreted?

  -Hormone secreted by adrenal gland
• What is dopamine?


  -CNS transmitter and precursor of noradrenaline and adrenaline
• What is isoproterenol?


  -synthetic catecholamine
• What are the effects of a-selective NA?

  -Causes vasoconstriction (a1),

  -Causes reflex bradycardia (baroreceptor response) due to ACh action at vagal nerve.

  -Overall increase in BP
• What are the effects of b-selective ISO?

  -Predominantly causes vasodilation (b2); tachycardia (b1).

  -Overall decrease in BP
• What are the effects of ADR?

  -intermediate action, low concentration ~ ISO

  -Higher conc. ~ NA.

  -Overall increase in BP
• Adrenergic transmission:


  -Noradrenergic neurone has thousands of varicosities

  -Tyrosine hydroxylase only found in noradrenergic neurones
• Name 3 receptors agonists of adrenergic transmission:

  -a1 noradrenaline

  -b2 salbutamol

  -a2 clonidine
• Name 1 receptors antagonist of adrenergic transmission:

  -b1 atenolol
• Clinical relevance of salbutamol:

  -Used for asthma treatment

  -Selective b2-adrenoceptor agonist causes bronchodilation
• Atenolol clinical relevance:


  -Cardio-selective b1-adrenoceptor antagonist (b-blocker)

  -Caused to treat hypertension
• Pseudoephedrine clinical relevance:


  -Used to treat nasal decongestion

  -Substrate for biogenic amine uptake system = sympathomimetic
• What is an example of uptake 1 indirect sympathomimetics?

  -Systemic pseudoephedrine (Sudafed®) used as nasal decongestants

  -Pseudoephedrinesubstrates for uptake system leading to NA release and thus vasoconstriction of the mucosal blood vessels, which in turn reduces oedema of the nasal mucosa.
• What are blockers of uptake 1?

  -Psychoactive agents

  -Cocaine

  -Tricyclic antidepressants (imipramine) used to treat depression (potentiates biogenic amines including NA and serotonin
• Uses of tyramine, amphetamine & other derivatives?

  -Substrates of uptake 1

  -Used therapeutically in narcolepsy, appetite suppression and ADHD (due to enhanced attention and concentration)
• Types of adrenoreceptor:


  -a1 and a2 adrenoceptors

  -b1 and b2-adrenoceptor agonists and antagonists modulate physiological effects.

  -Selective agents