Drug mechanisms around the body

Question 1

Methods and mechanisms of drug absorption

Answer 1

• Bioavailability: fraction of unchanged drug that reaches the system circulation, is decreased by poor absorptions and first pass metabolism (IV drug delivery have 100% bioavailability)
• Absorption depends on route of administration and chemical nature of compound: lipophilicity, charge, size, and formulation
• Routes of administration include: intramuscular/subcutaneous, sublingual, orally/rectally, and transcutaneous
• Liquids absorb faster than capsules/tables due to greater surface area:
• Formulation drugs:
  1. Gelatine-coating tablets (aspirin) slows absorption and decreases local peak concentrations
  2. Capsules containing granules with different soluble coating allow for controlled release
  3. Intramuscular injection of oil depot (decanoate) of lipophilic drugs allows very slow release
• lipophilic molecules cross membranes and pinocytosis occurs for some particulate material
• Distribution (how drugs equilibrate after entering systemic circulation) has different outcomes:
  1. No distribution – large drugs or those binding to plasma protein (e.g heparin)
  2. Distribute through extracellular space (modified by natural barriers e.g blood brain barrier/placenta)
  3. Distribute throughout total body water
  4. Accumulate in cells (e.g specific transporters like bretylium)
  5. Distribute to fat (for lipophilic drugs or inhaled anaesthetics)
• Volume of distribution: volume of fluid required to contain total amount of drug in body at same concentration as that present in the plasma
  * Vd= D/Cp (D = amount of drug, Cp = concentration of drug in the plasma)
• Vd can calculate dose required to hit target concentration
• Many drugs bind to circulating proteins, particularly albumin
• Free concentration of drug determines its action, so binding decreases initial free concentration, slows distribution, slows clearance, and prolongs duration of action
• When there is more than one drug bound by albumin present, there can be competition for binding, increasing free drug concentration
• Distribution and elimination are usually the sum of two exponential processes

Question 2

How are drugs metabolised?

Answer 2

• Metabolism is carried out by enzymes, takes place anywhere in the body, but majority of small molecules occurs in the liver
• 2 phase process:
  1. Phase 1 (modification) = involves cytochrome P-450 dependent mixed function oxidase (oxidation/reduction/hydrolysis) creates highly reactive compounds
• problem with phase 1 metabolites: highly reactive compounds can react with other molecules, include compounds in liver
  2. Phase 2 (conjugation) = joins phase 1 metabolites to other molecules making it charged (glutathione/sulfate/glycine/glucuronic acid)
• Effect of dosing may continue in the absence of drug due to active metabolites
• Problem with drug molecules: in active form, they would not be absorbed, would not cross membrane
• Pharmacogenetics: study of how genetic difference in metabolic pathways can affect individual response to drugs
• Pharmacometabolomic: study of how drugs are metabolised with a view to allow personalised medicine, involves study of metabolite concentrations to determine how a person responds to similar types of drugs (focus on phenotype rather than genotype)

Question 3

How are drugs excreted from the body?

Answer 3

• Routes for drugs and their metabolites are either renal (major), hepatic/ biliary (faecal or enterohepatic), or other (sweat, milk, or breath)
• Kidney filters plasma and then reabsorbs substances the body needs but allows everything else, including many drug metabolites, to travel into the urine
• Liver itself has its own method of secretion and so during development, the liver performs as a ‘pocket’ of the gut and so remains connected to it via the bile duct and so there a drainage from the liver into the gastrointestinal system which means some metabolites can be directly excreted into the bile, which then travels down from the liver and then into the second part of the duodenum
• Sometimes substances can recycle back into the body through the distal of the small bowel (intrahepatic circulation) in which metabolites produced in the liver can pass into the bowel, into the duodenum and then within the duodenum they can be chemically modified again in substances that can be reabsorbed in the terminal ileum

Question 4

Presynaptic modulation at cholinergic synapse

Answer 4

• Ach is neurotransmitter at NMJ, lots of Ach release ensures the synapse does not fail
• Synthesis of Ach by choline acetyltransferase is then loaded into vesicles by Ach carrier, presence of Ach esterase breaks down Ach into choline and acetate (only choline is take back into presynaptic membrane)
• Presynaptic nAchR works in a positive feedback mechanism on release
• No drugs interfere with CAT process, however, carrier transports Ach into vesicles is blocked by Vesamicol, choline transporter is blocked by hemicholinium, and exocytosis is blocked by toxins
• Botulinum toxin: has 2 subunits where one binds selectively to the presynaptic membrane and the other cleaves proteins involved in exocytosis (prevent Ach release leading to muscle paralysis)
• Treatment for botulinum poisoning involves:
  1. Pharmacological = 4-aminopyridine used to block voltage gated K+ channels and increase action potential (presynaptic mechanism) increase in Ach release, decreases K+ efflux during repolarisation (prolonged depolarisation = ↑ Ca2+ influx)
  2. Immunological = uses antitoxin (antibody of toxin) where binding prevents entry into nerve terminal (more effective treatment)

Question 5

Post synaptic neuromuscular blockers

Answer 5

• Adjunct to general anaesthetics, act at nAchR, and include non-depolarising (antagonist) and depolarising (agonist) blockers
• Non-depolarising: use pancuronium/vecuronium, have competitive action at nAchR to cause decrease in endplate potential, used to adjunct general anaesthesia causing muscle relaxation through IV administration (allows for lower dose of general anaesthetic)
• Depolarising: use suxamethonium, has agonist action at nAchR, has 2 phases of block
  1. Phase 1: causes endplate depolarisation, action potential, and uncoordinated fine contractions
• not broken down by AchE in synaptic cleft so prolonged depolarisation can lead to paralysis
  2. Phase 2: due to inactivation of nAchRs, suxamethonium is broken down by plasma cholinesterase (rapid recovery)
• Has unwanted effects including: bradycardia, K+ release via nAchR , increase in intraocular pressure, and prolonged paralysis

Question 6

Post synaptic modulators

Answer 6

• Cholinesterase inhibitors interact with Ach + plasma cholinesterase and work to prevent breakdown of Ach in order to enhance synaptic function
• Drugs differ in terms of their type of chemical interaction with an enzyme
• Reverse effects of non-depolarising NMJ blockers cause end of operation in which Ach levels increase, compete with antagonist → increase end point potential
• Depolarising blocker has worse effect, Ach acquire suxamethonium-like action
• Myasthenia gravis: autoimmune disease caused by cholinesterase inhibitors, where antibody works against nAchR causing muscle weakness
• AchE can be used to treat myasthenia gravis by increasing Ach levels to overcome decrease in nAchR