A historical appreciation of drugs helps contextualise the long standing use of drugs in altering consciousness, extending thousands of years stemming back to the use of mushrooms in tribal rituals, for example. In a clinical context, drugs first came to be used in the mid twentieth century to treat psychiatric disorders such as depression and psychosis.
Pharmacokinetics refers to the movement and time course through the body. It is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as the ADME scheme:
• Absorption - the process of a substance entering the blood circulation.
• Distribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.
• Metabolism (or Biotransformation) - the irreversible transformation of parent compounds into daughter metabolites.
• Excretion (or Elimination) - the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.
Absorption can be done oral, rectal, transdermal, subcutaneuos, sublingual, lingual and intramuscular. The specifics of this are decided based on feasibility, absorption rate, tolerability, safety and invasiveness.
The 'blood-brain' barrier is there to protect us as a huge amount of blood needs to service the brain and a flood of something psychoactive or neurotoxic could be devastating without filter protection. Drugs therefore need to transpose the 'blood-brain barrier' and either need to be compatible with the transport system, lipid soluble, or they have to be small so that the drugs can pass successfully through it. Heroine and morphine provide a synonymous example once within the brain, but the way they are absorbed is very different, thus giving them different potencies.
Half life can be used in various domains. It usually refers to the ‘elimination’ half life. This means the half life for half of the drug to be completely metabolized. Half life is important to achieve steady state concentration. This allows for us to get to efficacious doses without reaching toxic levels or overdose.
The psychopharmacological industry have developed several mathmatical models to help determine doses and pharmacokinetic profiles of drugs. Dose-response relationships will differ across individuals, due to individual differences. Drugs will have a number of effects, each with their own dose-response relationship. Similar drugs, even with similar mechanism of action will differ. Drugs will have a phlethora of effects: Wanted effects and side effects. Sometimes the metabolites will have the effect you are interested in and it is this that dose-relationship needs to focus on.
Figure 1. Dose-Response Relationship
Two abbreviated terms are important in pharmacokinetics. ED50 refers to concept that 50 percent of the population experience efficacious doses at this level. LD50 refers to the concept that 50% of the population die at this dose (lethal). The larger the window between the two figures, the safer the drug. LD50 divided by ED50 gives therapeutic index- the ratio of safety in other words. Indexes of around 100 are considered safe.
Pharmacodynamics refers to the process by which drugs work and take effect, there mechanism of action. There are 7 main drug actions:
• stimulating action through direct receptor agonism and downstream effects
• depressing action through direct receptor agonism and downstream effects (ex.: inverse agonist)
• blocking/antagonizing action (as with silent antagonists), the drug binds the receptor but does not activate it
• stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows to stabilize general receptor activation, like buprenorphine in opioid dependent individuals or aripiprazole in schizophrenia, all depending on the dose and the recipient)
• exchanging/replacing substances or accumulating them to form a reserve (ex.: glycogen storage)
• direct beneficial chemical reaction as in free radical scavenging
• direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage (cytotoxicity or irritation)
The clinical trials process is a thorough process, that is often completed over a number of years across multiple sites. They are often very specific, typically beginning with animal testing, and ending with human testing. In the human testing phase, there is often a group of subjects, one group is given a placebo, and the other is administered a carefully measured therapeutic dose of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority and is either commercially introduced to the public via prescription, or deemed safe enough for over the counter sale. Specifically, phases consist of:
Phase 1- small (20-80) test of experimental drug to determine safety, dosing and identify side effects.
Phase 2- larger (100-300) safety and efficacy
Phase 3- large scale (500+) efficacy within target population, monitor side effects and compare standard treatments.
Phase 4- Licence studies to provide further information and detail on risk and efficacy.
Figure 2. Drug Development Process
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