A comprehensive review introduction


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Overview of mechanisms of action

Psychopharmacology is very complex and extensive division of medicine with roots in the mechanisms of action of psychotropic drugs.

Generally speaking, the mechanism of action of drugs is largely due to pharmacodynamic factors. On the other hand, the onset, duration and magnitude of drug action, are determined by pharmacokinetic factors.

Pharmacokinetic factors: Polarity of psychotropic drugs

Psychotropic drugs are amphiphilic in nature i.e. they possess both hydrophilic and hydrophobic properties. Because of this physical property, psychotropic drugs rapidly reach their sites of action (e.g. cellular membranes, cytoplasm), accounting for the various rapid and short acting anxiolytics and sedatives. Psychotropic drugs either permeate through plasma membrane (hydrophilic) or build up in the hydrophobic interior of lipid bilayer of cell membranes. The movement allows cellular interactions with both the membrane macromolecules and with the cytoplasmic molecules. Essentially, the drug’s polarity is a vital factor that allows it to reach the target site / site of action (25).

The concept of polarity as it refers to the elimination of the drug will be discussed later under the “Elimination” section.

Other examples of psychotropic drugs / psychoactive substances that are amphiphilic in nature are:

  • Fluoxetine (can be used to treat anorexia nervosa at higher does)*

  • Caffeine

  • Imipramine

Absorption and distribution

Absorption refers to the movement of a drug from the site of administration to the blood circulation. In the case of many psychotropic drugs, the site of drug entry is usually the mouth or the veins. In the case of the latter, no absorption takes place since the drug is injected directly into the blood. The different routes of drug administration will be discussed later in detail in the Section IV of this course.

Oral administration of drugs requires disintegration of the formulation, absorption from the small intestines and distribution into the site of action (brain) in order to exert its pharmacological action. The speed at which the stomach empties (gastric emptying rate) its contents into the small intestines is the most important factor that determines the rate of absorption or orally administered drugs. Physical activities, amount of food and the type of food consumed determine the gastric emptying rate. It is this reason that certain drugs are best administered before meals (26).

Another factor that influences drug absorption is its concentration, which is determined by gender, age, body size and comorbidities. Generally, the larger the patient, the greater the dilutions of the drug (due to greater ratio of fat to water) in the fluid volume, which in turn results in lesser amount of drug reaching the target sites. This is why certain individuals require greater dosage than others. Dosages are based on the average individual size: 68 kg between 18-65 years of age.

Gender also plays a role in this absorption factor. Women tend to have smaller fluid volume (where the drug is concentrated) than men, resulting in greater accumulation of the drug at the target site. Finally, the other two factors that influence absorption are solubility and ionization of the drug.

Once absorbed, the drug enters the systemic circulation and distribute into the tissues. Unpredictable differences in protein binding in tissues, regional variations in pH, and differences in the permeability of cellular membranes determine the extent of tissue distribution (27).

Generally, the highest concentrations of drugs are found in the heart, brain, kidneys, and liver. The brain is a lipophilic organ, allowing it to receive about 20% of the blood that leaves the heart. Its lipophilicity enables the rapid distribution of lipid-soluble drugs to brain tissues. However, the blood-brain barrier also restricts the movement of ionized molecules from the blood to the brain.

The blood brain barrier (BBB) plays a vital function in the distribution of psychoactive substances and their subsequent circulation in the brain. For example, alcohol is a lipophilic substance, which readily crosses the blood brain barrier to cause its mind-altering effects.

Protein binding

The binding of drugs with plasma proteins such as albumin and a-glycoproteins (inactive sites) is known as protein binding. It limits the amount of drug that can be distributed to the target site. Because protein-bound drugs do not cause a pharmacological effect, they are kept in reserve. This type of binding is also referred to as depot binding (28).

Protein binding affects the magnitude and duration of drug action. These consequences are listed in the table below:

Protein binding features

Effects on drug action

Rapid binding to inactive sites

Late onset; smaller magnitude

Varying extent of binding

High affinity: less free drug

Low affinity: more free drug

Competitive inhibition or inducement

Drug displacement resulting in toxicity and greater side effects

Unmetabolized bound drug

Prolonged duration


Quick cessation of action

Table 1: The effects of protein binding

Protein binding can cause significant drug-drug interactions. An example is the displacement of phenytoin (Dilantin) from protein binding sites by the NSAID, aspirin and another antiepileptic drug, valproic acid (Depakene). The implication of the interactions between these two drugs with phenytoin is not clinically significant because of the transitory nature of the interactions. The displaced phenytoin (unbound) is rapidly metabolized, maintaining its steady state plasma concentration and preventing untoward side effects. On the other hand, the interaction poses a challenge to clinicians who are monitoring phenytoin levels in certain patient groups.

Other psychotropic medications such as fluoxetine (Prozac) and diazepam (Valium) exhibit an extensive affinity to proteins, thus, making them frequently susceptible to drug interactions.

Another implication of increased protein binding is a slower rate of drug metabolism. A good example is the detection of delta(9)-tetrahydrocannaboid (THC) in the urine even after cessation of cannabis intake several days before a sample is taken for testing. THC is the primary psychoactive component of cannabis, which is lipophilic and stored in fat tissues, making its release and metabolism slow. This concept makes pre-employment and student drug testing possible (205).

Lastly, protein binding is implicated in rapid termination of drug action. A good example is the drug thiopental (Pentothal), a rapid but short-acting, highly lipid soluble barbiturate that is used in the induction of general anesthesia. Its rapid and short duration of action is due to its highly lipophilic nature that allows it to immediately penetrate the blood-brain barrier, distribute into the brain tissues and exit again. The rapid movement is reflected in its blood level that goes up and falls short quickly.


The metabolism of drugs is essential to its final removal from the body. Drug molecules are biochemically changed by enzymatic reactions in the stomach, kidneys, blood, brain, and the liver, where the majority occurs. The process occurs in two stages.

Phase 1 (Stage 1): At this stage, the drug molecules are modified via nonsynthetic chemical reactions that render them water-soluble. The most common reaction that takes place is oxidation followed by reduction, or hydrolysis. Prodrugs rely on oxidation for conversion to an active metabolite. A good example is the anticonvulsant, primidone, which is oxidized to phenobarbital and phenylethylmalonamide (PEMA) by the most important microsomal enzyme - cytochrome P450 family of enzymes.

Phase 2 (Stage 2): The second stage involves the conjugation of the drug molecules with glucuronide (glucuronidation), sulfate and methyl functional groups. Most psychoactive drugs are deactivated by glucuronide conjugation. The resulting metabolic products are almost always biologically inactive and freely water-soluble. However, there are exceptions. Oxazepam, the metabolite of diazepam (prodrug) from glucuronidation, is biologically active and exerts GABA inhibitory effects similar to other benzodiazepines. Oxazepam does not go through hepatic oxidation, which makes it useful in patients with hepatic failure. This is clinically useful in older patients with liver disease because oxazepam is less likely to accumulate and cause adverse reactions.

Other examples of psychoactive prodrugs and their metabolites are shown in the table below:

Stage of metabolism



Stage 1



Stage 1



Stage 1



Stage 1



Stage 1



Stage 2


Propofol‐glucuronide (PG)

Stage 2



Stage 2



Table 2: Psychoactive drugs and their metabolites

There are numerous factors that influence the rate of biotransformation of psychoactive drugs in the liver. These are discussed separately, below:

Enzyme induction

The chronic and heavy use of certain drugs cause a corresponding increased release of cytochrome P450 enzymes in the liver to metabolize them, a phenomenon known as enzyme induction. An example of this is the use of the antiseizure drug, carbamazepine (Tegretol), which induces the family of CYP3A4 enzymes, the same enzyme responsible for the metabolism of estrogen and progesterone hormones. It is for this reason that female patients of reproductive age are not advised to take these two drugs concomitantly since the former decreases the blood levels of the latter and its subsequent contraceptive effects.

Enzyme inhibition

Much like induction, the activity of enzymes can also be prevented. The phenomenon of metabolic enzyme inhibition is the primary mechanism of action of the drug, disulfiram (Antabuse). Disulfiram is an enzyme inhibitor of aldehyde oxidase. Alcoholics to discourage their own alcohol intake use this drug.

Alcohol is oxidized to its intermediate metabolite, acetaldehyde in the liver, which is in turn further oxidized to the final metabolite, acetic acid, by aldehyde oxidase enzyme. This action is demonstrated through the equation (below):

Alcohol dehydrogenase Aldehyde oxidase

alcohol ---------------------------> acetaldehyde --------------------> acetic acid

Disulfiram prevents the oxidation of acetaldehyde by blocking aldehyde oxidase. The metabolic inhibition causes the toxic accumulation of acetaldehyde, which is manifested in the form of severe hangover symptoms. These symptoms are often more severe than a “regular” hangover.

Genetic polymorphism

The genetic make up of individuals (e.g. existence or absence of mutations) influence the metabolism of drugs and substances in the body. For example, Asian men are more susceptible to hangovers than their Caucasian counterpart. The presence of the genetic mutation, ALDH2*2 alleles in Asian genes resulted in their reduced capacity to metabolize the intermediate metabolite of alcohol, acetaldehyde, the substance primarily responsible for the symptoms of hangover (29).


The principal role of metabolism is to prepare drugs for elimination via the liver and kidneys. Other routes of elimination include the breast milk, sweat, hair, feces and breath. The water-soluble metabolites are trapped by the kidney tubules and subsequently filtered out in the form of urine.

Pharmacodynamic interactions

Pharmacodynamic interactions refer to the physiological and biochemical activities of the drug with the body tissues. There are four chief proteins which can bind any drug:

  1. Enzymes

  2. Membrane carriers

  3. Ion channels – pore-forming membrane proteins that act as gate-keepers to the flow of ions across the cell membrane

  4. Receptors – surface proteins to which specific signaling molecules may bind

The role of drug-receptor interactions has been discussed briefly in the preceding pages and will be discussed in detail in the succeeding pages of this section.

Psychotropic drugs exert their pharmacologic action primarily by agonism or antagonism of neurotransmitter receptors, inhibition of regulatory enzymes or blockade of stimulators of neurotransmitter membrane transporters (see table below).

General mechanism of actions of psychotropic drugs


Synthesis and storage of neurotransmitters


Release of neurotransmitters from presynapse

Zolpidem, benzodiazepine

Blockade of receptors

Tricyclic antidepressants

Breakdown of neurotransmitters

MAO inhibitors, amphetamines

Reuptake of neurotransmitters


Transduction of G-proteins

Phenothiazines, butyrophenones

Effector system


Table 3: General mechanisms of action of psychoactive drugs

Drug receptors are large protein molecules in the cell's plasma membrane, cytoplasm and nucleus that bind with ligands (e.g. drugs, xenobiotics, hormones, neurotransmitters) at the receptor binding (active) sites. The binding of a drug with a receptor results in the formation of drug-receptor complex. A good example of a drug-receptor complex is the binding of GABA receptors with gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. GABA receptors are of two types:

  1. GABAA / ionotropic receptors which form ion-channel pores that allow ions such as Na+, K+, Ca2+, or Cl- to pass when GABA binds with its active site. Benzodiazepines primarily act on GABAA receptors.

  2. GABAB / metabotropic receptors are connected with potassium ion channels via G-proteins (transducers). The binding of GABA with these receptors triggers a series of intracellular events that result in the opening of ion channels and activation of secondary messengers.

Common characteristics of drug-receptor complexes that induce physiological and pharmacological effects, include:

    • Specificity: Affinity for a receptor is specific, i.e. the structure of the ligand must conform to the 3D structure of the receptor. High affinity results in high efficacy. Drugs with high affinity and exert pharmacological effects are called agonists. A good example of an agonist is morphine, which mimics endogenous endorphins at opioid receptor binding sites.

    • Receptor occupation: Drugs that compete with agonists for the same receptor binding sites but have no efficacy are called competitive antagonists. A good example of a drug that exhibits its pharmacological action through competitive antagonism is memantine. It is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist that is used in Alzheimer’s disease. It blocks the excitatory effects of the neurotransmitter, glutamate, in the brain by displacing it from the binding site, essentially preventing neuronal excitotoxicity (a hypothetical pathologic cause of Alzheimer’s disease). Another type of antagonism via receptor interaction is the binding of a drug with a different receptor that results in the inhibition of drug effect. In this case, the antagonist did not compete for the same receptor hence, the name, non-competitive antagonist. A good example of this antagonistic interaction is the binding of ketamine, another NMDA receptor antagonist with the NMDA receptor channel pore while the endogenous agonist, glutamate, binds to the extracellular surface of the receptor. Activation of two different binding sites results in non-competitive inhibition.

    • Longevity of complexes: The binding of ligands with receptors is either temporary (reversible) or permanent (irreversible). The drug-receptor complex remains as long as there’s no competition for its binding site. With irreversible antagonists, the drug-receptor complex bond cannot be broken nor overcome simply by increasing the dose of the agonist. On the other hand, some agonists can be displaced from the receptor-binding site by increasing the dose of the antagonist and vice versa.

    • Receptor structural change: The binding of drugs with receptors alters the 3D protein structure of the receptor to cause pharmacological effects.

    • Receptor population: The number of receptors available to bind with drugs influences drug response. The up-regulation and down-regulation of receptors is responsible for drug desensitization (tolerance) and tachyphylaxis.

Partial agonists are those drugs that have the affinity for the receptor-binding site but do not exert full efficacy. An example is the anxiolytic, buspirone, which is a partial serotonin 5-HT1A receptor agonist.

Psychoactive drugs are almost always used over a long period of time since they are used to control symptoms rather than treat the root cause one time, unlike antibiotics which kill/inactivate offending microorganisms. The chronic use results in changes in the degree of receptor activation and enzyme population. These changes are responsible for some of their most well-known adverse effects.

Up-regulation: An increase in the number of receptors as a compensatory response after continual absence of agonists.

Down-regulation: A decrease in the number of receptors as a compensatory response after chronic presence of agonists.

Withdrawal syndrome: Withdrawal syndrome is a group of symptoms that results from the abrupt discontinuation of receptor activation, following chronic administration of an agonist.

Rebound effect: The return of symptoms that were previously under control when an agonist is abruptly withdrawn is known as the rebound effect. Examples are rebound depression and insomnia, which happen when benzodiazepines are suddenly discontinued. Because of this, benzodiazepines should be discontinued slowly, with doses tapered off gradually over a period of weeks.

Tolerance (receptor desensitization): The scale of drug response (e.g. tolerance) is influenced by the concentration of the agonist at the receptor-binding site. Also, the sensitivity of the receptor to the agonist plays a role. Tolerance is basically the body’s adaptation to the constant presence of an agonist. Once the body develops a tolerance for a drug, its sensitivity for it is reduced, thus, requiring a higher dose to produce the original effect.

Tachyphylaxis: It is a form of drug tolerance that is sudden in onset following successive doses of agonists in short intervals. Heroin causes tachyphylaxis and so do psilocybin and LSD, all well-known illicit drugs.

Psychotropic drugs are most often classified according to their effects on the central nervous system functions (see table below).




Drug examples

Vigilance / Alertness






Barbiturates, benzodiazepines






Dysphoric drugs


Psychic mechanism


Atypical antipsychotics




PCP, marijuana






Amnestic drugs


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