Pharmacology
Pharmacology
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Note
Fundamentals of pharmacology
Summary
The action of a drug depends on multiple factors.
Pharmacokinetics concerns what the body does to the drug. = How does the drug concentration change as it moves trough the different compartments of your body
Pharmacodynamics, on the other hand, concerns what the drug does to the body. = How does the drug exert its effect on your body - potency, drug-receptor interactions
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.
Overview
- Pharmacokinetics (what the body does to the drug)
- LADME is an acronym for the important phases of pharmacokinetics:
- Liberation
- Absorption = in
- Distribution
- Metabolism =out
- Excretion
- LADME is an acronym for the important phases of pharmacokinetics:
- 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 )
Before clinical trials begin, drugs are first tested in preclinical studies. Preclinical studies do not include human subjects!
- Pharmacokinetics (what the body does to the drug)
- What is the difference between PK and PD?
1. Pharmacokinetics
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Note
Pharmacokinetics is concerned with the drug absorption, distribution, metabolism, and excretion!
- What are the 4 major components of PK?
- Define these 4 components?
- Where in the body do each of thse predominantely occut?
Phase
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Phase
Liberation
- What is liberation?
1.1 Absorption
- What is Absorption?
- Absorption depends on what?
- Describe what a drug given P.O. has to go trough compared to I.V.?
- Visualize the graph comparing I.V. absorption vs P.O.?
- What is the equation for concentration?
- What is the differect between blood, plasma, and serum?
- What is the approximately volume of blood compared to plasma?
- Biovailability
1.2. Distribution (pharmacology)
- What is distribution?
- Where it starts and end?
- What are the factors of distribution? (4)
- Vd
1.3. Metabolism (biotransformation). Elimination A
- Overview
- Chemical reaction that metabolize drugs? (2)
- Phases of biotransformation
- Types of drug kinetics
EliminationExcretion- Overview
Dose
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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
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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]
2. Pharmacodynamics
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what is it?
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!
Drug-receptor interaction
- Overview?
- What is drug receptor?
- Depends on?
- Receptors
- types (4)
- Ligand (Drug)
- Agonist
- Antagonist
Dose-response relationship
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Terms
The following terms are used to describe dose-response relationships:
- Potency (ED): 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 both drug affinity and drug efficacy.
- Lethal dose (LD50): The dose that is lethal in 50% of the test population. LD50 is determined through animal experiments.
- Therapeutic index: = LD50/ED; i.e., the greater the therapeutic index, the safer the drug
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Decrease with?
The effect of a drug can decrease with repeated dosing:
- Drug tolerance
- Tachyphylaxis
Pharmacogenetics
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note
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
- 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.
- If the enzyme in question is responsible for the breakdown of a drug, the following effects are possible:
Drug interactions and the cytochrome p450 system
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note
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:
- 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!
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