Clinical Pharmacology Introduction
- Drug metabolism that varies on a genetic basis is often called polymorphic drug metabolism.
- Pharmacogenetics: It is the study of individual gene-drug interactions, usually one or two genes that have a dominant effect on drug response.
- Pharmacogenomics is the study of genomic influence on drug response.
Read And Learn More: General Medicine Question And Answers
Adverse Drug Reaction
Definition: An unwanted or harmful reaction experienced following the administration of a drug or a combination of drugs under normal conditions of use and suspected to be related to the drug.
Adverse drug reactions (ADR) could be trivial or serious or fatal.
Classification of Adverse Drug Reaction
Severity of Adverse Drug Reaction
- Minor: No need for therapy, antidote, or hospitalization.
- Moderate: Requires drug change, specific treatment, and hospitalization.
- Severe: Potentially life-threatening, permanent damage, and prolonged hospitalization.
- Lethal: Directly or indirectly leads to death.
Types of Adverse Drug Reactions
- Side effects:
- Unavoidable, predictable, decreased dose results in amelioration.
- Occurs as an extension of the same therapeutic effect, For Example, atropine as antisecretory in pre-anesthetic medication → dry mouth, mucositis induced by the anticancer drug.
- Occurs as a distinctly different effect, Examples: promethazine as antiallergic—sedation, phenytoin-induced gum hyperplasia, and zidovudine-induced nail pigmentation.
- Estrogen as anti-ovulatory → nausea.
- Side effects exploited for therapeutic use, for Example codeine (antitussive) constipating action used in diarrhea.
- Sulfonylureas (tested as antibacterial) were found to decrease blood glucose.
- Secondary effects: Indirect effect of therapy. For example, intestinal microflora killed by tetracycline cause
superinfection, and corticosteroids decrease immunity causing oral candidiasis. - Toxic effects: Overdose or prolonged use. Examples of toxic effects, overdosage, or prolonged use include atropine
delirium, paracetamol → hepatic necrosis, barbiturates → coma, and morphine → respiratory failure. - Intolerance: It is the opposite of tolerance and is characterized by increased sensitivity to low doses. Examples are few doses of carbamazepine → ataxia, a single dose of triflupromazine → muscular dystonia.
- Idiosyncrasy: Genetically determined atypical or bizarre effect. Examples are barbiturate → excitement and mental confusion, and streptomycin → deafness with a single dose.
- Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially life-threatening, drug-induced
hypersensitivity reaction that includes skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and internal organ involvement (liver, kidney, lung). Common drugs associated are phenytoin, olanzapine, sulfonamides, febuxostat, dapsone, and vancomycin. - Drug allergy or hypersensitivity: Immunologically mediated, independent of dose, and occurs in a small proportion
of patients. Prior sensitization is required and occurs after 1–2 weeks after the first dose. The drug acts as an antigen or hapten. Chemically-related drugs may show cross-sensitivity. The same drug can cause different allergic reactions in different individuals. Types of allergies include:- Type 1: Urticaria, angioedema, asthma, anaphylactic shock.
- Type 2: Thrombocytopenia, agranulocytosis, aplastic anemia, systemic lupus erythematosus (SLE).
- Type 3: Arthralgia, lymphadenopathy, Stevens-Johnson syndrome.
- Type 4: Contact dermatitis, fever, photosensitization, Example: penicillin, sulfonamides, carbamazepine, and methyldopa.
- Photosensitivity:
- Phototoxic: Drug accumulates in skin → absorbs light → photochemical reaction → photobiological reaction → tissue damage. Examples are erythema, edema, and blistering with tetracyclines.
- Photoallergic: Drug → cell-mediated immune response → contact dermatitis on exposure to light, e.g., sulfonamides, griseofulvin.
- Drug dependence: This can be psychological and physical dependence.
- Teratogenicity: Drug use in pregnancy affects the fetus. Examples are thalidomide → phocomelia, phenytoin → cleft palate.
- Carcinogenicity and mutagenicity: For example, anticancer drugs, estrogens.
- Drug-induced diseases/iatrogenic diseases: Examples, salicylates → peptic ulcer, phenothiazine → Parkinsonism, isoniazid (INH) → hepatitis.
- Drug withdrawal reaction: Examples, propranolol → hypertension, acute adrenal insufficiency following withdrawal of corticosteroids.
The management of ADR has been shown.
The ways of preventing ADR are listed
Drug Interaction
Definition: A measurable modification (in magnitude and/or duration) of the action of one drug by prior or concomitant administration of another substance, including prescription, nonprescription (including complementary medicines) drugs, food, alcohol, cigarette smoking, or diagnostic tests. Outcomes of drug interaction are listed.
Prevention of adverse drug reactions.
- Avoid inappropriate drugs in the
- context of clinical condition
- Use the right dose, route, and frequency based on patient variables
- Elicit medication history; consider
- untoward incidents
- Elicit history of allergies (higher chances in patients with allergic diseases)
- Rule out drug interactions
- Adopt the right technique, For Example, slow IV injection of aminophylline
- Carry out appropriate monitoring, For Example, prothrombin time (PT) with warfarin; drug levels
Outcomes of drug interaction
- Loss of therapeutic effect
- Toxicity
- Unexpected increase in pharmacological activity
- Beneficial effects, Example: additive and potentiation (intended) or antagonism (unintended)
- Chemical or physical interaction, for example, intravenous incompatibility in fluid or syringes mixture
Mechanism of Drug Interaction
Pharmacokinetic Interaction
Altered gastrointestinal tract (GIT) absorption:
- Altered pH: The nonionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. For example, antacids and H2 blockers change gastric pH and decrease the dissolution of ketoconazole which requires acidic pH. Therefore, these drugs must be separated by at least 2 hours at the time of administration of both.
- Altered intestinal bacterial flora: In patients receiving digoxin, 40% or more of the administered dose is metabolized by the intestinal flora. If patients simultaneously take antibiotics which destroy the intestinal flora, digoxin toxicity can occur.
- Complexation or chelation: Tetracycline interacts with iron preparations → unabsorbable complexes. Decrease absorption of ciprofloxacin by 85% due to chelation, if given along with antacids.
- Drug-induced mucosal damage: Antineoplastic agents, Example: cyclophosphamide, vincristine, procarbazine → mucosal damage and inhibit the absorption of several drugs, Example: digoxin.
- Altered motility: Metoclopramide (antiemetic) → increase absorption of cyclosporine due to the increase of stomach emptying time.
Displaced protein binding:
- It depends on the affinity of the drug to bind to plasma protein.
- Phenytoin is highly bound to plasma protein (90%), tolbutamide (96%), and warfarin (99%). Drugs that displace these agents are aspirin, sulfonamides, and phenylbutazone.
Altered metabolism:
- The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism
- but other organs can also be involved, Example: white blood cell (WBC), skin, lung, and GIT.
- The CYP450 family is the major metabolizing enzyme in phase 1 (oxidation process).
- Therefore, the effect of drugs on the rate of metabolism of others can involve the following examples:
- Enzyme induction:
- A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself, Example:
carbamazepine (antiepileptic drug) increases its own metabolism. - Phenytoin increases the hepatic metabolism of theophylline → leading to a decrease in its level, reducing its action and vice versa.
- A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself, Example:
- Enzyme induction:
- Enzyme inhibition:
- It is characterized by a reduction of the rate of metabolism of a drug by another drug. This leads to increased concentration of the target drug and thereby increases its toxicity.
- Inhibition of the enzyme may be caused by the competition on its binding sites. This shortens the onset of action (maybe within 24 hours).
- For example, erythromycin inhibits the metabolism of astemizole and terfenadine → raises the serum concentration of the antihistaminic, and thereby increases cardiotoxicity which may be life-threatening.
First-Pass Metabolism
- Administration of drugs by oral route increases their metabolism in the liver and GIT. This causes the loss of a part of the drug dose and decreases its action.
- This is more evident when such a drug is an enzyme inducer or inhibitor.
- By increasing its first-pass metabolism, rifampin reduces the serum concentration of verapamil level. Also, rifampin induces the hepatic metabolism of verapamil.
Renal Excretion
Active tubular secretion:
- It occurs in the proximal tubules (a portion of renal tubules).
- The drug combines with a specific protein and reaches the proximal tubules.
- When drug X has a competitive reactivity to the protein responsible for the active transport of drug Y, drug X will cause toxicity of Y due to a decrease in drug excretion of Y (increased concentration of Y).
- For example, probenecid → decreases tubular secretion of methotrexate.
Passive tubular reabsorption:
- In the tubules, excretion, and reabsorption of drugs is by passive diffusion and are regulated by concentration and lipid solubility.
- For example, sodium bicarbonate—increases lithium clearance and decreases its action.
Pharmacodynamic Interaction
- It indicates that there is an alteration of the drug action without a change in its serum concentration by pharmacokinetic factors.
- For example,
- synergism means = 1 + 1 = 3,
- additive means = 1 + 1 = 2,
- potentiation means = 1 + 0 = 2, and antagonism
- means = 1 + 1 = 0 or 0.5.
Prevention of Drug Interaction
- Monitoring therapy and making adjustments.
- Monitoring blood levels of some drugs with narrow therapeutic indexes, Example: digoxin, anticancer agents, etc.
- Monitoring of some parameters may help to detect the early events of interaction or toxicity. For example, with warfarin treatment, it is necessary to monitor the prothrombin time to adjust drug dosages.
- Increase the interest in case report studies to report different possibilities of drug interaction.
Drugs And Liver
Common drugs metabolized in the liver are mentioned in
Cirrhotic Patients with Portosystemic Shunts
- Blood from the intestines bypasses the liver, delivering much more orally administered drugs to the systemic
circulation. Thus, the systemic bioavailability of orally administered high-clearance drugs is much greater. - Hepatic impairment:
- Research has shown reduced drug-metabolizing enzyme (CYP and conjugation reactions) in cirrhotics which worsens disease severity (ChildPugh score), but with large variability!
- Preferentially recommend conjugatively metabolized agents in cirrhotics
- In the absence of recommended doses:
- Child-Pugh 1: Reduce maintenance to 50%
- Child-Pugh 2: Reduce maintenance to 25%
- Child-Pugh 3: Use drugs proven safe, or drugs with level monitoring available.
Drugs And Kidney
Dosing of Drugs in Renal Failure
- Without careful dosing and therapeutic drug monitoring in patients with renal dysfunction, accumulation of drugs/toxic metabolites can occur. Drug dosing has to be adjusted to the calculated glomerular filtration rate (GFR).
- Renal disease affects the pharmacokinetic as well as pharmacodynamic (PD) effects of drugs.
- Uremia can alter drug disposition, protein binding, pharmacokinetics (PK), and PD and can also increase sensitivity to drugs.
Effect of Renal Failure on Bioavailability
- Absorption of drugs in patients with renal disorders could be inhibited by gastrointestinal disturbances seen in uremia (nausea, vomiting, and diarrhea), uremic gastritis, and pancreatitis.
- Edema of GIT can occur with nephrotic syndrome and impair absorption.
- Gastric motility can be impaired by uremia.
- Uremia can also increase gastric ammonia and lead to increased gastric pH thus affecting drugs that require acidic pH for absorption (Example: ferrous sulfate).
- The first-pass effect is reduced in patients with renal disease (therefore, absorption of drugs with high first-pass effect is increased, Example: propranolol).
Effect of Renal Failure on Protein Binding and Volume of Distribution
- The effect of a drug is related to the amount of free or unbound drug available to target tissues.
- Also, hypoalbuminemia is common in patients with renal failure. Therefore, highly protein binding drug has fewer albumins to cling to. This is especially important with phenytoin.
Elimination
- As kidney disease progresses, the kidney’s ability to excrete uremic toxins decreases as does its ability to eliminate certain drugs.
- The kidney eliminates primarily through filtration or active secretion.
- Drugs with low protein binding are filtered more readily.
- Large molecules (molecular weight > 20,000 daltons) are not readily filtered due to their size.
Drug Removed by Dialysis
- Removal by dialysis is specific to each drug.
- Factors affecting removal: Type of machine, membrane surface area, pore size, flow rates.
- Dialysis is sometimes used to remove excess drugs in an overdose situation.
Drug Usage In Pregnancy
- The safety of approximately 50% of medications for the mother and fetus remains unknown.
- Pharmacokinetics are profoundly affected by pregnancy-associated physiological changes and dose adjustments are sometimes necessary for optimal clinical outcome.
Current Categories for Drug Use in Pregnancy (FDA)
Few drugs are contraindicated during pregnancy and those which have teratogenic effects are listed. Common problems in pregnancy and drugs that can be safely used in these cases are mentioned.
Clinical Trials Basic Concepts
A clinical trial is an experimental epidemiological method. It is an interventional study on individuals, usually on patients.
Objectives of Clinical Trials
- Intervention trials determine whether experimental treatments are safe and effective under controlled environments.
- Observation trials address health issues in large groups of people in natural settings.
Levels of Evidence
Levels of evidence (sometimes called hierarchy of evidence) are assigned to studies based on the methodological quality of their design, validity, and applicability to patient care. These decisions give the “grade (or strength) of recommendation”.
Features of observational and experimental studies are mentioned.
Types of Study
The types of studies have been shown.
Phases of Clinical Trials
- Most trials that involve new drugs go through a series of steps:
- Experiments in the laboratory.
- Once deemed safe, go through 1–4 phases.
- Phase 1: Small group (20–80) for 1st time to evaluate safety, determine safe dosage range and identify side effects.
- Phase 2: Treatment is given to a larger group (100–300) to confirm effectiveness, monitor side effects, and further evaluate safety.
- Phase 3: Treatment is given to an even larger group (1,000–3,000) to fulfill all of phase 2 objectives and compare it to other commonly used treatments and collect data that will allow it to be used safely.
- Phase 4 (postmarketing surveillance): Done after treatment has been marketed—studies continue to test treatment to collect data about effects in various populations and side effects from long-term use.
Informed Consent
An informed consent document will be obtained from the participants in the study population after explaining to them fully about:
- the purpose;
- duration;
- required procedures;
- expectations;
- risks and benefits;
- adverse effects of the trial if any, and
- participants’ rights.
It is a continuous process throughout the study of learning key facts by participants about a clinical trial. It also explains the rights of the participant. It is not a contract and the participant can withdraw from the trial at any time.
Ethical Aspects
- Participants are human beings with a motive to help the researcher and society.
- Researchers should never be overenthusiastic in their intervention to get results while dealing with participants.
- Informed consent is not legally binding on the patients. It is a communication document.
Random Allocation
The participants in the study population are randomly allocated into two groups (arms) using random number tables to avoid selection and confounding biases.
Purpose of randomization: This elimination of allocation bias will greatly enhance the validity of the trial.
Blinding
The investigator, the participant, and sometimes even the evaluator are all kept unaware (blinded) of the outcomes of the trial, and secrecy is maintained to improve the validity. Purpose of blinding: Blinding or masking is done to
eliminate
- investigator bias;
- evaluation bias and
- Hawthorne effect.
Types of Blinding
The types of blinding have shown.
Unblinding
In emergencies and life-threatening situations for participants, unblinding can be done.
Assessment Criteria
- Whether the outcomes or endpoints are single or multiple, subjective or objective, uniform and similar types of evaluation of endpoints for both groups are to be carried out.
- The subjectivity of the outcome, for example, the reduction of pain, may lead to observer error and poor assessment.
- Double blinding eliminates observer bias to a large extent.
Intention-to-Treat Principle
The whole of the experimental population including nonparticipants, once randomized, whether they are participating or not in the trial, have to be considered for evaluation as our intention is to treat all the people randomized.
Placebo Effect or Attention Bias
Psychological relief of symptoms, not true biological relief, is often reported. Neurophysiologically there is an increase in dopamine and opioids in people experiencing placebo effects.
Nocebo Effect
- These are adverse events produced by negative expectations. These are observed not only in everyday clinical practice but also in clinical trials.
- Neurophysiologically there is a decrease in dopamine, but an increase in cortisol and CCK in people experiencing the nocebo effect.
- These nonspecific side effects distress patients, add to the burden of their illness, and increase the costs of their care.
- They may lead to nonadherence, cause physicians to discontinue what is otherwise an appropriate therapy, or prompt attempts to treat these side effects with additional drugs.
Hawthorne Effect
- Sometimes the participants in the comparison group may exaggerate the effects/outcomes to please the investigator or when they like the study or for some other reasons. The investigator does a more frequent follow-up of an exposed group in order to establish the cause.
- This will affect the assessment unless controlled.
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