Fundamentals of pharmacology

The action of a drug depends on multiple factors. Pharmacokinetics concerns what the body does to the drug. Pharmacodynamics, on the other hand, concerns what the drug does to the body. Furthermore, when a drug is administered in combination with other drugs, a variety of drug interactions may take place that synergistically or antagonistically modify the effect of the given drug (e.g., the activation or inhibition of cytochrome p450 enzymes by certain medications). The knowledge of drug interactions and the pharmacokinetic properties of a drug help to determine the ideal route of administration (topical, oral, IV). Drugs that are eliminated by the liver may attain high serum concentrations when hepatic function is impaired, which increases the risk of drug toxicity. The same principle applies to drugs that are eliminated via the kidneys.

• Pharmacokinetics (what the body does to the drug)
  • LADME is an acronym for the important phases of pharmacokinetics:
    • Liberation
    • Absorption
    • Distribution
    • Metabolism
    • Excretion
• Pharmacodynamics (what the drug does to the body)
  • Receptor types and their interaction with the drug
  • Dose-response relationship
• Pharmacogenetics: deals with the effect of genetic variations on drug metabolism and drug action.
• Clinical trials: : phases of drug development, testing, and regulatory approval (occur after preclinical studies )

Clinical trial phase	Purpose	Study population
Phase 0 trial	Evaluate pharmacodynamic and pharmacokinetic properties of the drug	Small number of healthy individuals (∼ 10–15)
Phase I trial	Evaluate safety	Small number of healthy individuals (∼ 15–30)
Phase II trial	Evaluate efficacy against placebo or the gold standard	Small number of patients with a specific disease (∼ 10–100)
Phase III trial	Final confirmation of efficacy and safety	Randomized control trial with a large number of patients with a specific disease (∼ 100–1000)
Phase IV trial	Safety studies following approval	Large number of patients with a specific disease after drug approval
Phase V trial	Post-marketing surveillance: compares the real-life effectiveness to the efficacy found in research studies

Before clinical trials begin, drugs are first tested in preclinical studies. Preclinical studies do not include human subjects!

References:^[1]

Pharmacokinetics is concerned with the drug absorption, distribution, metabolism, and excretion!

Liberation

• The process by which the drug is released from its pharmaceutical form (e.g., capsule, tablet, suppository, etc.)
• The most common routes of drug administration are:
  • Injection; (the drug is introduced directly into the bloodstream or into tissue)
  • Inhalation
  • Peroral administration
  • Dermal administration
  • Rectal administration
  • Less common routes: buccal, sublingual, and intra-articular administration

Absorption

The process by which the drug reaches the bloodstream. The following factors affect drug absorption:

• Bioavailability describes the rate and concentration at which the drug appears in circulation. It is expressed as a percentage of the dose that was initially administered.
  • Bioavailability is affected by two mechanisms:
    • First pass effect: Orally administered drugs are absorbed from the GI tract and reach the liver via the portal circulation.; In the liver they undergo first pass metabolism before they enter systemic circulation, which decreases the bioavailability of the drug.
    • Ability to pass through lipid membranes: dependent on the nature of the substance (see the table below)
• Bioequivalence: Two proprietary preparations of a drug are said to be bioequivalent if they exhibit the same bioavailability when administered in equal doses.

	Chemical nature	Clinical significance	Example
Lipophilic	Predominantly nonpolar compounds	The drugs can easily diffuse across the lipid bilayer of the cell membrane. These drugs can be administered topically. CNS penetration: free diffusion across the blood-brain barrier These drugs are biotransformed in the liver and then excreted through the bile duct.	Scopolamine (hyoscine) Tertiary amine Used to treat motion sickness
Hydrophilic	Predominantly polar compounds	These drugs can cross the lipid bilayer only via facilitated transport Smaller hydrophilic molecules can diffuse along a concentration gradient through pores in the membrane. The drugs are eliminated by the kidneys.	Butylscopolamine (hyoscine butylbromide) Quarternary amine Used as an antispasmodic to treat GI colic
Amphiphilic	Both lipophilic and hydrophilic		Local anesthetics, e.g., lidocaine

Distribution (pharmacology)

After the drug reaches the bloodstream, it is initially distributed in the most vascularized organs!

• Distribution coefficient: measure of hydrophobicity/hydrophilicity of a drug
  • C (drug concentration in the organic solvent)/ C (drug concentration in water)
• Volume of distribution: V_D (usually expressed in liters/kg body weight) = M (amount of drug administered)/C (plasma concentration of the drug)
  • This value measures the tendency of the drug to be distributed in plasma rather than body tissues.
  • Lipophilic substances tend to have a large volume of distribution
• Binding to plasma proteins: Different drugs have different affinities to bind to plasma proteins (e.g., albumin).
  • Only the unbound fraction of the drug has a pharmacological effect.
  • Different drugs may compete to bind to plasma proteins
• Redistribution: transfer of a drug between the different compartments within the human body
  • Lipophilic substances (e.g., inhalation anesthetics) are redistributed from plasma into fat tissue → initially decreased action of the applied drug
  • Drug is stored but over time is released again from fat tissue into plasma → delayed elimination and prolonged action of the specific drug ).

Metabolism (biotransformation)

Biotransformation is the chemical alteration of substances (e.g., drugs) within the body by the action of enzymes and mainly takes place in the liver. Biotransformation detoxifies drugs and facilitates their elimination.

• Types of drug kinetics
  • Zero order kinetics: : The rate of metabolism and/or elimination remains constant and is independent of the concentration of a drug (e.g., metabolism of alcohol)
  • First order kinetics: : The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (applies to most drugs)
• Phases of biotransformation
  • Phase I reaction: The drug is transformed into a polar metabolite (mostly through oxidation by the cytochrome P450 system) → allows phase II reactions to take place
  • Phase II reactions (conjugation reaction): involves coupling the metabolite with glucuronic acid (most common coupling reaction), acetyl groups (e.g., metabolism of isoniazid), sulfates, amino acids (e.g., glycine), or glutathione
• Clinical significance
  • Detoxification: In most cases, the drug is inactivated and modified into a hydrophilic metabolite → allows the drug to be excreted by the kidneys or in bile
  • Activation; : Certain drugs are transformed in the liver from their inactive prodrug state into active forms.
  • Formation of toxic metabolites

Excretion

• Drug clearance: a measure of the rate of drug elimination. It is defined as the plasma volume that can be completely cleared of the drug in a given period of time (e.g., creatinine clearance)
• Half-life (T½): the time required for the plasma concentration of a drug to reach half of its initial value

After 4 half-lives, more than 90% of the drug will be eliminated!

Drugs and/or their metabolites are excreted from the body in one or more of the following ways:

• Renal elimination: mostly hydrophilic drugs
  • Glomerular filtration
  • Tubular secretion
  • Tubular reabsorption
• Biliary elimination: lipophilic and hydrophilic substances
  • Lipophilic substances that have undergone biliary elimination may be reabsorbed from the gut and then secreted again in bile (enterohepatic circulation)
• Pulmonary elimination: primarily in inhaled anesthetic drugs

Loading dose

• Definition: The amount of an initial dose of a certain drug needed to reach a target plasma concentration.
• Formula: loading dose = (Cp x Vd) / F
  • Cp = target peak plasma concentration (mg/L or units/L)
  • Vd = volume of distribution (L/kg)
  • F = bioavailability

Maintenance dose

• Definition: The amount of a certain drug needed to achieve a steady target plasma concentration.
• Formula: maintenance dose = (Cp x Cl * τ) / F
  • Cp = target plasma concentration at steady state (mg/L)
  • Cl = clearance (L/h)
  • τ = dosing interval (hours)
  • F = bioavailability

References:^[2]

Pharmacodynamics is concerned with the effect of a drug at its site of action, the dose-response relationship of the drug, and the influence of other factors on the drug effect!

Types of receptors

Every functioning molecule in an organism is a potential site of action for a drug. Means through which drugs act include:

• Interaction with receptors
  • Cell membrane receptors
    • G-protein coupled receptors
    • Ion channels
    • Protein kinase receptors
  • Intracellular receptors
• Interaction with enzymes
• Interaction with DNA
• A physical/chemical effect

Drug-receptor interactions

Basic principles

• Drug affinity: a measure of the tendency of a drug to bind to its receptor
  • Most drug-receptor bonds are reversible
  • Covalent drug-receptor bonds, which are less common, are almost always irreversible (e.g., the binding of aspirin to cyclooxygenase enzyme).
• Drug efficacy: the degree to which a drug activates receptors after binding and triggers a cell response
• Residence time: : the lifespan of a drug‑receptor complex

Antagonists have zero efficacy, agonists have maximum efficacy, and partial agonists (see below) have submaximal efficacy.

Types of drug-receptor interactions

• Agonist: a drug that has a similar effect to that of the endogenous receptor activator (e.g., β2 agonists)
• Antagonist: a drug that binds to a receptor and prevents its activation. Types of antagonism include:
  • Competitive antagonist; : The agonist and the antagonist compete to bind to the same receptor; . Inhibition of the effect of the agonist in a dose-dependent fashion → higher concentration of the agonist is needed to achieve same efficacy (e.g., there is a decrease in potency)
    • Reversible competitive antagonists
    • Irreversible competitive antagonists
  • Non-competitive antagonist: The drug binds at a site other than the agonist-binding site; (also called allosteric site), changes the structure of the agonist binding site, and decreases the affinity of the agonist. As a result, the efficacy of the agonist is decreased
  • Functional (physiological) antagonist; : In this type of antagonism, two different molecules working through separate receptors produce physiologically opposite effects.
• Partial agonist: a substance that has some agonistic action at a receptor but does not elicit the complete response of a true agonist.
• Inverse agonist: Binds to the same receptor as an agonist, but not to the same active site. It elicits a response that is opposite to the agonistic response and has a negative efficacy.
• Allosteric regulation
  • Allosteric modulator: Binds at a different site than the agonist and initiates conformational changes that induce modulation of ligand-binding.
  • Allosteric activator: Binds at a site other than the agonist-binding site (also called allosteric site) and changes the structure of the active binding site to increase affinity to the substrate For more information on enzyme kinetic, see also enzymes and biocatalysis.

Dose-response relationship

The following terms are used to describe dose-response relationships:

• Potency (ED₅₀): The potency of a drug is measured as the dose required to produce a pharmacological response of a specified intensity. Potency is a property that is dependent on affinity but not related to efficacy
  • E_max = the maximum drug response that can be achieved
  • ED₅₀ = the dose required to produce 50% of the maximum possible response (E_max)
• Lethal dose (LD₅₀): The dose that is lethal in 50% of the test population. LD₅₀ is determined through animal experiments.
• Therapeutic index: = LD₅₀/ED₅₀; i.e., the greater the therapeutic index, the safer the drug
  • High therapeutic index: e.g., glucocorticoids, penicillin
  • Narrow therapeutic index: e.g., lithium, theophylline, warfarin, digoxin, antiepileptic drugs

To remember Therapeutic Index: = LD₅₀/ED_50, think: TILE

The effect of a drug can decrease with repeated dosing:

• Drug tolerance
  • The mechanisms responsible for the development of drug tolerance include:
    • Down-regulation of receptors
    • Increased synthesis of enzymes that metabolize the drug
  • Drug tolerance develops slowly over a few weeks.
  • Drug tolerance can be overcome by increasing the dose.
• Tachyphylaxis
  • The underlying mechanism responsible for the decreased effect of a drug involves depletion of the body's stores of an endogenous mediator. and downregulation of receptors
  • Tachyphylaxis develops quickly (within a few hours of dosing).
  • Tachyphylaxis cannot be overcome by increasing the drug dose.
  • Examples include nitrates, indirect sympathomimetic drugs (e.g. ephedrine), direct sympathomimetic drugs (e.g., phenylephrine) niacin, LSD, MDMA.

Pharmacogenetics deals with genetic variation in the expression of enzymes that metabolize drugs. These genetic differences can cause a drug response to deviate from the expected response and/or increase the risk of side effects:

• If the enzyme in question is responsible for the breakdown of a drug, the following effects are possible:
  • A hyperactive variant of the enzyme decreases the drug response.
  • A hypoactive variant of the enzyme can cause cumulative drug effects and thus increase the risk of side effects.
• The reverse is true if the enzyme is responsible for the activation of a drug.

Examples of clinically relevant variations

• CYP2D6 polymorphism
  • There are hyperactive and hypoactive variants.
  • CYP2D6 is involved in the metabolism of many drugs
  • Gender-specific differences in CYP2D6 have been observed.
• N-acetyltransferase polymorphism
  • There are hyperactive (rapid acetylators) and hypoactive (slow acetylators) variants.
  • N-acetyltransferase breaks down isoniazid, sulfasalazine, and hydralazine.
• Atypical pseudocholinesterase
  • Pseudocholinesterase is responsible for the breakdown of succinylcholine through ester hydrolysis.
  • Atypical pseudocholinesterase breaks down succinylcholine slowly and thus prolongs the duration of muscle relaxation during anesthesia from a few minutes to a few hours; this may cause respiratory depression.
• Thiopurine-methyltransferase polymorphism (TPMT)
  • TPMT is involved in the breakdown of azathioprine.

Drug interactions

• Drug interactions can cause an increase or decrease in the potency of a drug or result in additional side effects.
• The greater the number of coadministered drugs, the greater the chance of drug interaction
• The most common form of drug interaction results from the induction of the cytochrome P450 enzyme system. Interactions as a result of drug inhibition are less common.

Cytochrome-P450 system

• Basic principles
  • Cytochrome P450 is a superfamily of heme-containing, primarily oxidative enzymes; that take part in phase 1 reactions.
  • They are divided into families and subfamilies based on the similarity of amino acid sequences.
  • Nomenclature: the prefix "CYP" (which stands for cytochrome P450)- + family number + a letter representing the subfamily + isoenzyme number
  • There are 200 cytochrome P450 enzymes, which are classified into 43 subfamilies and 18 families. Of these 200, only 12 are involved in drug metabolism. They belong to the first three families:
    • CYP1 family; (CYP1A1, CYP1A2),
    • CYP2 family; (CYP2A6, CYP2B6, CYP2C8, CYP2C9; , CYP2C19; , CYP2D6; , CYP2E1)
    • CYP3 family; (CYP3A4, CYP3A5, CYP3A7)
  • The highest concentration of CYP enzymes is found within the centrilobular hepatocytes
  • CYP induction increases the rate of metabolism of the substrate, while CYP inhibition decreases it.
    • The effects of drugs that are activated by CYP enzymes are increased by enzyme induction and decreased by enzyme inhibition.
    • The effects of drugs that are broken down by CYP enzymes are decreased by enzyme induction and increased by enzyme inhibition.
    • Ultrarapid metabolizers: The activity of CYP2D6 is increased in individuals with a duplication on chromosome 22. Such individuals require a significantly higher dose for the desired effect to be achieved!
• Role in carcinogenesis
  • Metabolic activation of certain pro-carcinogens (e.g., aflatoxin, sterigmatocystin) → induction of cancer (e.g., hepatocellular carcinoma)

Carbamazepine acts as both substrate and inducer of CYP3A4!

Rifampicin and carbamazepine are some of the strongest inducers of cytochrome P450 enzymes and can thus interact with many drugs!

CYP		Substrate
			CYP 450 inhibitors	CYP 450 inducers
CYP1A2		Caffeine Theophylline Acetaminophen Some psychotropic drugs	Ciprofloxacin Fluvoxamine	Smoking
CYP2C	CYP2C19	Proton pump inhibitors (PPI) Other drugs, including: Clopidogrel Indomethacin Escitalopram	Antifungals (azoles such as itraconazole) Cimetidine Proton pump inhibitors (PPI) Isoniazid	Prednisolone Carbamazepine Rifampicin St. John's Wort
	CYP2C9	NSAIDs Other drugs, including: Oral antidiabetic medications (e.g., rosiglitazone) Warfarin Angiotensin II antagonists	Amiodarone Antifungals (azoles such as itraconazole) Sulfamethoxazole	Rifampicin Griseofulvin St. John's Wort
CYP2D6		Several beta‑blockers (e.g., metoprolol) Several antipsychotics (e.g., haloperidol) Caution: Haloperidol is also metabolized by CYP1A2 and CYP3A4! Several SSRIs, SNRIs, and SSNRIs (e.g., fluoxetine, fluvoxamine, venlafaxine) and some antidepressives Antiarrhythmics (e.g., flecainide) Several other drugs	Amiodarone Several antipsychotics and antidepressives Metoclopramide	Rifampicin Dexamethasone
CYP2E1		Ethanol	Ethanol (acute consumption) Disulfiram Metronidazole	Ethanol (chronic consumption) Isoniazid Nicotine
CYP3A4		Statins (except pravastatin) Steroid hormones (e.g., estrogen, glucocorticoids, testosterone) Oral contraceptives Immunosuppressives Cyclosporin Tacrolimus Macrolides Carbamazepine Haloperidol Benzodiazepine Oral anticoagulants Warfarin Phenprocoumon Anti-HIV medication Calcium channel blockers	Amiodarone Antifungals (azoles, e.g., itraconazole) Macrolide (erythromycin, clarithromycin) Several anti-HIV medications Grapefruit juice Cimetidine Isoniazid (weak inhibitor)	Carbamazepine Rifampicin St. John's Wort Glucocorticoids Barbiturates Several anti-HIV medications Griseofulvin Phenytoin (also a CYP substrate)

References:^{[3][4][5][6][7][8][9][10]}