Clinical Pharmacology Notes

Clinical Pharmacology Disciplines

Knowledge of statistics is crucial for proper interpretation of clinical research results.

Ars Longa, Vita Brevis

Clinical pharmacology exemplifies the Latin proverb "Ars longa, vita brevis" (Knowledge is vast and life is short), emphasizing continuous learning.

Adverse Events vs. Adverse Effects

• Adverse Event: Any unfavorable occurrence during drug administration, which may or may not be related to the drug.

• Adverse Effect: A proven cause-and-effect relationship between a drug and an adverse event.

• Pharmacovigilance: The scientific discipline for diagnosing and interpreting adverse drug effects.

Adverse Drug Reaction (ADR)

An ADR is a harmful and unintended response to a drug at normal doses used for prophylaxis, diagnosis, treatment, or physiological function changes. Includes:

• Unfavorable drug interactions.

• Absence of therapeutic effect.

• Adverse changes after discontinuing a previously well-tolerated drug.

Side Effects of Drugs

• All drugs have side effects with varying severity.

• Side effects should always be considered to predict and avoid unwanted effects.

• Early signs of adverse effects should be recognized.

  • Example: Red spots after lamotrigine application require immediate discontinuation to prevent progression to Steven-Johnson syndrome.

Impact of Adverse Effects

• ADRs significantly burden the health system.

• Approximately 6% of hospital admissions are due to ADRs.

• 10-20% of patients experience unwanted drug effects during hospitalization.

• Simultaneous administration of multiple drugs is a major cause.

• About 50% of side effects are preventable through careful consideration.

Classification of ADRs

• Type A: Predictable ADRs based on the drug's mechanism of action (e.g., dry mouth with tricyclic antidepressants due to antimuscarinic effect).

• Type B: Bizarre ADRs that are unpredictable, rare, dose-independent, and usually serious (e.g., agranulocytosis with beta-lactam antibiotics).

• Type C: ADRs that imitate diseases (e.g., systemic lupus erythematosus-like syndrome with procainamide or hydralazine).

Frequency of Side Effects

• Very common: >10% of patients

• Common: 1-10% of patients

• Not common: 0.1-1% of patients

• Rare: 0.01-0.1% of patients

• Very rare: <0.01% of patients

Identifying Causes of Adverse Events

When a patient experiences an adverse event while taking multiple drugs, suspect the drug with the highest frequency of causing that effect.

Serious Side Effects

Serious side effects result in:

• Death

• Hospitalization

• Prolonged hospitalization

• Disability

• Life-threatening conditions

• Malignant disease

• Congenital anomalies

Preventing Adverse Events

For each drug, know the seriousness of potential side effects, warn the patient, and provide preventive measures and monitoring guidelines.

• Example: Patients taking sulfonamides should drink plenty of fluids to prevent crystallization in kidney tubules.

• Patients on clozapine require regular neutrophil checks to prevent agranulocytosis.

Establishing Cause-and-Effect Relationship for ADRs

When determining the cause-and-effect relationship between a drug and an adverse event, consider:

1. Time interval from drug administration to ADR occurrence

2. Dechallenge - What happens after stopping the drug?

3. Rechallenge - What happens after re-administration of the drug?

4. Alternative causes of ADR?

5. Has such an adverse effect been described before?

6. Is there a laboratory confirmation?

7. Is there a suitable biological explanation for the occurrence of the adverse effect of the drug, i.e., can we guess the mechanism of side effects?

Reporting Adverse Drug Reactions

• Pharmacists and doctors should report observed adverse reactions to the National Center for Adverse Drug Effects.

• Suspicion of an unwanted effect is sufficient for reporting.

• All side effects for new drugs are reported within the first 5 years.

• For older drugs, only serious and previously unknown side effects are reported.

• The National Center provides assessments of cause-and-effect relationships.

• Patients can also report suspected adverse drug effects.

Importance of Reporting

Regular reporting is crucial for drug safety, enabling the detection of dangerous drugs and their removal from the market.

Underreporting of Side Effects

Side effects are often underreported due to:

• Belief in drug safety

• Fear of lawsuits

• Desire to avoid communicate persons in charge of pharmacovigilance

• A feeling of guilt

• Desire not to publicize side effects

• Not knowing how to report

• Reluctance to report mere suspicion

• Disinterest

Research Methods for Adverse Drug Reactions

Available research methods include: Stimulated reporting, active methods (monitoring, sentinel studies, registries), observational studies (cross-sectional, case/control, cohort), and experimental clinical studies.

Suitable Methods for Clinical Pharmacologists

Sentinel and observational studies are feasible due to limited resources: a small number of patients ( < 200), focus on quick-onset adverse effects, non-interventional design, and low costs.

Special Considerations for Elderly Patients

• The term 'elderly' refers to people over 65 years of age.

• Polypharmacy (taking 5+ drugs simultaneously) is common but risky.

• Polypharmacy increases risk of side effects and drug interactions.

• Prescribe the fewest drugs necessary to treat health disorders.

Interactions Between Medicines

Two or more drugs in the body at the same time can affect each other by changing their pharmacokinetics or pharmacodynamics.

Pharmacodynamic interactions

Drugs that change the effect of each other, usually by affecting the same receptor or by acting on the same tissue in the same or opposite way.

• Agonism: Enhancement of the effect of one or both drugs

• Antagonism: Weakening of the effect of one or both drugs

Both agonism and antagonism can be:

• Pharmacological: The result of the effect of drugs on the same receptor

• Physiological: The drugs act on the same tissue, but through different receptors

Pharmacokinetic interactions

Influence of drugs on each other at the level of absorption, distribution, metabolism or excretion

The most significant pharmacokinetic interactions take place at the level of drug metabolism, namely in liver cells, on cytochromes, where some drugs can induce the formation and activity of cytochromes, while others inhibit them.

• Induction of cytochromes results in acceleration of the elimination of drugs that are metabolized by them

• Inhibition slows down the elimination

In addition to cytochromes, interactions can occur on other enzymes that metabolize drugs, or on membrane transporters by means of which drugs either enter cells or are expelled from them.

• ABC superfamily: The largest superfamily of membrane transporters, transfers drugs across the membrane. Includes glycoprotein P, a breast cancer resistance protein, protein responsible for drug resistance. Medicines can compete for the same transporter and thus interfere with each other's exit or entry into cells, or in some other way stimulate or inhibit the functioning of membrane transporters.

Basic Pharmacokinetic Parameters

Basic parameters describing drug movement include volume of distribution ($V<em>d$), drug clearance (Cl), and elimination constant ($K</em>e$).

Volume of Distribution ($V_d$)

Vd is the extent to which the drug penetrates the tissues and cells
$V = binom{D}{Cp}$, where D is drug administration and Cp is drug concentration in the blood.

• $V_d$ ≈ 5 L drug distributes only in the intravascular space (plasma-expander dextran 70).

• $V_d$ ≈ 15 L, drug distributes within the extracellular fluid, not liposoluble, and does not penetrate inside the cells or into the central nervous system.

• $V_d$ ≈ 40 L, the drug has penetrated into all cells of the body.

• $V_d$ > 40 L, which means that the drug is somewhere deposited in the organs

Clearance (Cl), Elimination Constant ($K<em>e$) and Half-Life ($T</em>{1/2}$)

drug clearance and the elimination constant express the same thing in different ways: the rate at which the drug is eliminated from the body. All three quantities can be calculated from the curve that describes the serum drug concentration in time after oral administration.

$K<em>e = binom{Cl}{V</em>d}$
Drug clearance represents the amount of blood plasma that is cleared from the drug in a unit of time.

The total clearance of the drug includes all routes of elimination and can be expressed as the sum of renal, hepatic, pulmonary and other clearances.

$Half- life (T_{1/2}) = binom{0.693}{Ke}$ Half- life (T1/2) is the time during which half of the administered amount of the drug is eliminated from the body.

Drug Elimination

Knowing:$T_{1/2} = binom{0.693}{Ke}$, since Ke= slope of the descending part of the curve. So a large volume of distribution, the concentration of the drug in the blood is low, then elimination depends on the level of drug concentration in the blood: drugs with a large volume of distribution will be eliminated slowly.

Steady State

When it comes to drugs with linear elimination kinetics, after repeated administration of the same dose, the equilibrium state is established, in which the amount of drug that is eliminated between two doses of the drug is equal to that dose
After 4-5 dosing intervals (provided that they are approximately equal to the elimination half-life of the drug), an equilibrium state is established. Then the concentration of the drug in the blood is maintained at a constant level, oscillating around a certain value.

Loading Dose

Loading doses are not adjusted to possible disorders of liver or kidney function in patients, because with their one-time administration we will certainly not exceed the target concentrations in the blood that we expect in a steady state.

Individual Drug Dosing

Individualization of doses should first be based on the precise estimate of functional condition of vital organs of the patient, and then on our knowledge about how functional status of an organ affects on the key pharmacokinetic parameters of drugs (clearance, volume distribution, binding for proteins in plasma and biological availability).

Drug Adjustment

For dose adjustment of a number of drugs, the simplest one is based on target average steady-state plasma concentration of a drug and non-compartmental pharmacokinetic model.

$𝑀𝐷 = (𝐶𝑠𝑠 × 𝐶𝐿 × 𝜏) 𝐹 = (𝐶𝑠𝑠 × 𝑘𝑒 × 𝑉𝑑 × 𝜏) 𝐹$ where MD is maintenance dose, Css is the steady-state plasma drug concentration, CL is total drug clearance, τ is dosing interval, ke is the elimination rate constant, and Vd is the volume of distribution.

Calculation of loading dose should be made according to the formula: $𝐿𝐷 = (𝐶𝑠𝑠 × 𝑉𝑑) 𝐹$

MD should be adjusted based on expected changes of CL and F, and LD should be adjusted based on changes of Vd and F.

Therapeutic Drug Monitoring

Therapeutic drug monitoring is the process of measuring drug concentrations in the patient's blood, and based on the measured concentrations, adjusting the dose of those drugs in order to achieve the optimal therapeutic effect and reduce the possibility of toxicity.

Therapeutic monitoring is not carried out for all drugs, but only for those that meet the following conditions:

1. there is a correlation between the concentration of the drug in the blood and the effect;

2. the therapeutic effect of the drug is not easily measurable;

3. the drug has a narrow therapeutic range (i.e., the difference between the minimum therapeutic and the minimum toxic dose is small);

4. there is great variability between individual patients in terms of drug concentrations achieved in the blood after administration of the same dose;

5. the ratio of the concentration of the drug in the blood during the day and the minimum concentration that has a therapeutic effect is necessary to know in order to predict whether the therapy will be successful in life-threatening situations, e.g., when antibiotics are used to treat sepsis; and

6. there is a methodology available to measure drug concentration in the blood.

When to take a blood sample

After a time that is five times longer than the half-life of the drug being measured has passed. Within the dose interval, a blood sample can be taken at any time, but it is recommended that it should be taken immediately before the next dose of the drug.

Drug concentration

Drug concentrations are most often measured in the patient's serum, although it is also possible to measure them in plasma. Although the total concentration of the drug in the serum is usually measured, whenever possible both the total concentration and the concentration of the free drug, which is not bound to plasma proteins, should be measured.

Methods for therapeutic measuring

1. Immunological methods (reagent, result can already be read)

2. Chromatographic methods(HPLC double mess detection (LC-MS/MS), requires more extensive preparation)

3. Biological methods( antibiotics. Using the fact that a precisely defined concentration of the antibiotic standard leads to a precisely measurabledegree of inhibition of the growth of microorganisms)