pharma tutorials

• Volume of distribution


  The volume the drug would occupy if the total amount administered was dissolved in solution at the same concentration as found in the blood plasma
• Reversible competitive antagonist


  Effect on agonist log-concentration response curves
• Pharmacodynamics


  "What the drug does to the body" - the effects on the physiology of an organism as a consequence of its actions at a molecular level
• Reversible competitive antagonists produce a parallel shift to the right of the agonist log-conc. response curve, which is another way of saying that the blocking actions of the antagonist can be overcome by increasing the concentration of the agonist
• Pharmacokinetics


  "What the body does to the drug." How the drug is "handled" by the organism. Important in determining how effective a drug might be as medicines.
• If the volume of distribution is greater than the volume of plasma it means the drug must have left the plasma and distributed to tissues
• If a drug was very lipid soluble and partitioned into body fats, the amount left in plasma would be small, so the plasma concentration would be small and the volume of distribution would be far greater than plasma volume
• Absorption


  Especially important when drugs taken orally as need to be absorbed across the gut wall into the blood. Affected by factors such as molecular size, lipid solubility. Not relevant when drugs are administered intravenously.
• Affinity


  Measure of how strongly the drug binds to the receptor. Both agonists and antagonists have affinity for their receptor.
• Most drugs of any use have Kd values < 10^-9M
• Efficacy


  Measure of the ability of a drug, once bound to a receptor, to initiate a response. Full agonists have high efficacy, partial agonists have low efficacy, competitive antagonists have zero efficacy.
• Potency


  Measure of the concentration range over which a drug is effective. Not a clearly-defined term.
• Half-life


  The time taken for the plasma concentration of a drug to fall by half. For a monoexponential decay the half life can be measured anywhere on the curve.
• The agonist and antagonist molecules are continually going on and off the receptor. While an antagonist molecule is occupying the receptor binding site at any instant of time, an agonist molecule cannot bind. The presence of the antagonist reduces the number of agonist-receptor complexes present at any one instant of time, so the response to the agonist is reduced.
• The number of agonist-receptor complexes can be restored by increasing the agonist concentration further, increasing the probability that an agonist molecule will bind when the receptor becomes free. So the cellular response is restored, but at a higher concentration of the agonist, producing the rightward shift of the curve.
• Noradrenaline increases heart rate by activating "β-adrenergic" receptors in the heart.
• For a patient who was suffering from an inappropriately high heart rate, you might administer a reversible competitive antagonist at β-adrenergic receptors. Such drugs are called β-blockers, examples include propranolol and metoprolol.
• The majority of clinically useful drugs acting at receptors are antagonists rather than agonists.
• Effects of the SNS

  • Salivary glands: Production of a thick, viscous saliva
  • Eyes: Dilation of the pupil
  • Airways: Bronchodilation
  • Gastrointestinal (GI) tract: Decrease in GI motility; Constriction of sphincter muscles
  • Heart: Increases heart rate Increased force of contraction
  • Blood vessels: Mostly vasoconstriction; Dilation of blood vessels supplying skeletal muscle
  • Sweat glands: Sweat production
  • Bladder: Relaxation; Sphincter contraction
• Effects of the PNS

  • Salivary glands: Production of thin, enzyme-rich saliva
  • Eyes: Constriction of the pupil; Contraction of the ciliary muscle focussing the eye for near vision (accommodation)
  • Airways: Bronchoconstriction
  • Gastrointestinal (GI) tract: Increase in GI motility; Dilation of sphincter muscles; Secretion of gastric acid and digestive enzymes
  • Heart: Decrease in heart rate
  • Blood vessels: No direct effect
  • Sweat glands: No effect
  • Bladder: Contraction; Sphincter relaxation
• Effects of the SNS

  • Salivary glands: Production of a thick, viscous saliva
  • Eyes: Dilation of the pupil
  • Airways: Bronchodilation
  • Gastrointestinal (GI) tract: Decrease in GI motility; Constriction of sphincter muscles
  • Heart: Increases heart rate; Increased force of contraction
  • Blood vessels: Mostly vasoconstriction; Dilation of blood vessels supplying skeletal muscle
  • Sweat glands: Sweat production
  • Bladder: Relaxation; Sphincter contraction
• Effects of the PNS

  • Salivary glands: Production of thin, enzyme-rich saliva
  • Eyes: Constriction of the pupil; Contraction of the ciliary muscle focussing the eye for near vision (accommodation)
  • Airways: Bronchoconstriction
  • Gastrointestinal (GI) tract: Increase in GI motility; Dilation of sphincter muscles; Secretion of gastric acid and digestive enzymes
  • Heart: Decrease in heart rate
  • Blood vessels: No direct effect
  • Sweat glands: No effect
  • Bladder: Contraction; Sphincter relaxation
• The enzyme monoamine oxidase (MAO) is found in sympathetic nerve terminals where it breaks down noradrenaline. It is also found in the cells lining the gut where it breaks down dietary monoamines, notably tyramine.
• Tyramine


  An indirectly acting sympathomimetic amine drug
• Suxamethonium


  • Acts as an agonist at NAChR (it is two molecules of ACh joined together)
  • It is not however broken down by acetylcholinesterase at the neuromuscular junction (NMJ)
  • Consequently, it acts for much longer than ACh in the NMJ, leading to "depolarising block"
• How suxamethonium causes muscle relaxation

  1. Continual activation of the nicotinic receptors leads to a prolonged depolarisation of the muscle membrane at the neuromuscular junction (the so-called muscle end plate)

  2. This leads to inactivation of the the voltage-dependent Na+ channels responsible for the muscle action potential

  3. This means that action potentials cannot be initiated and this in turn means no muscle contraction
• Suxamethonium


  • Used as a short-term (5-10 minute) muscle relaxant during endotracheal intubation or ECT
  • It is short-acting because it is broken down by plasma cholinesterase (sometimes called pseudocholinesterase or butyryl cholinesterase)
• Inhibitors of acetylcholinesterase are used to overcome the blockade produced by non-depolarising muscle relaxants.
• Non depolarising muscle relaxants

  • Reversible competitive antagonists at nicotinic ACh receptors
  • Their blocking action can be overcome by increasing the concentration of agonist (ACh) by preventing its breakdown by acetylcholinesterase
• Muscarinic agonists cannot be used to dilate the pupil of the eye.
• Muscarinic agonist


  Will constrict the pupil, e.g. role of ACh released by the PSNS in the light reflex
• Muscarinic antagonists


  Can be used to dilate the pupil in ophthalmic examinations
• Anticholinesterase drugs


  Have a parasympathomimetic action
• ACh is the key neurotransmitter in the PSNS, acting in both the ganglia and at the neuroeffector junction.
• Noradrenaline synthesis


  Can be reduced by inhibition of the enzyme tyrosine hydroxylase
• Tyrosine hydroxylase is the first enzyme in the synthetic pathway for noradrenaline, converting tyrosine to DOPA. It is the "rate limiting step" i.e. the slowest stope, in the synthetic pathway.
• Noradrenaline activates only G-protein coupled receptors (GPCRS).
• The receptors at the skeletal neuromuscular junction are nicotinic
• Botulinum toxin inhibits the release of the neurotransmitter by exocytosis
• Bethanechol used occasionally to stimulate GI motility