Pharmacokinetics Flashcards
What does ADME stand for? Outline what ADME is.
A successful drug must be able to cross the physiologic barriers that limit the access of foreign substances to the body. Drug absorption may occur by a number of mechanisms that are designed to either to exploit or breach these barriers. After absorption, the drug uses distribution systems within the body, such as the blood and lymphatic vessels, to reach its target organ in an appropriate concentration. The drug’s abiliy to act on its target is also limited by several processes within the patient. These processes fall broadly into two categories: metabolism, in which the body typically inactivates the drug through enzymatic degradation (primarily in the liver), and excretion, in which the drug is eliminated from the body (primarily by the kidneys and liver, and in faeces).
How can drugs transverse membranes?
Small nonpolar molecules, such as steroid hormones, are able to diffuse easily through membranes. However, passive diffusion is ineffective for the transport of many large polar molecules and drugs.
Som transmembrane proteins in the human solute carrier (SLC) superfamily allow transport of polar drugs and molecules across the membrane. Transmembrane carrier proteins may be specific for a drug and related endogenous molecules; upon binding of the drug to the extracellular surface of the protein, the protein undergoes a conformational change that may be energy independent (facilitated diffusion) or require energy (active transport). This conformational change allows the bound drug access to the interior of the cell, where the drug molecule is released from the protein.
Alternatively, some drugs bind to specific cell surface receptors and trigger endocytosis, a process in which the cell membrane involutes around the molecule to form a vesicle from which the drug is subsequently released into the cell interior.
Outline pH trapping.
Net diffusion of acidic and basic drugs across lipid bilayer membranes may be affected by a charge-based phenomenon known as pH trapping, which depends on the drug’s acid dissociation constant (pKa) and the pH gradient across the membrane. For weakly acidic drugs, such as aspirin, the protonated, electrically charged neutral form of the drug is predominant in the highly acidic environment of the stomach. The uncharged form of the drug can pass through the lipid bilayers of the gastric and duodenal mucosa, speeding the drug’s absorption.
Define bioavailability.
The fraction of administered drug that reaches the systemic circulation. Defined quantitatively as:
Quantity of drug reaching systemic circulation / Quantity of drug administered
What non-specific defense mechanisms of the body may limit a drug’s bioavailability?
The integument has keratinised outer layer and defensins in the epithelium. Mucous membranes are protected by mucociliary clearence in the trachea, lysozyme secretion from lacrimal ducts, acid in the stomach, and base in the duodenum.
What factors can affect the bioavailability of a drug?
- Host defences (pH extremes, clearance)
- Route of drug administration
- Chemical form of the drug
- Patient-specific factors (GI and hepatic transporters and enzymes)
Name some routes of drug administration.
- Enteral (oral): simple, inexpensive, convenient, painless,exposes drugs to stomach and duodenal pHs, first-pass metabolism (liver first), e.g. aspirin.
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Parenteral: drug introduced directly to systemic circulation, CSF, or vascularised tissue, rapid delivery, high bioavailability, avoids first-pass metabolism, irreversible, risk of infection, pain.
- Subcutaneous: slow onset, small volumes, e.g. lidocaine.
- Intramuscular: intermediate onset, can affect lab tests (creatine kinase), painful, e.g haloperidol.
- Intravenous: rapid onset, controlled drug delivery, peak-related toxicity, e.g. morphine.
- Intrathecal: delivers to CSF, bypasses blood-brain barrier, risk of infection, skiller personnel required, e.g. methotrexate.
- Mucous membrane: rapid delivery to site of action, avoids first-pass metabolism, simple, convenient, direct delivery, few drugs allow for this route, e.g. nitroglycerin.
- Transdermal: simple, convenient, painless, continous/prolonged administration, requires a lipophilic drug, slow delivery, e.g. nicotine.
Outline drug distribution.
Absorption of a drug is a prerequisite for establishing adequate plasma drug levels, but the drug must also reach its target organ(s) in therapeutic concentrations to have the desired effect on pathophysiologic processes. Drug distribution is achieved primarily through the circulatory system; a minor component is contributed through the lymphatic system. Once a drug has been absorbed into the systemic circulation, it is then capable of reaching any target organ (except sanctuary compartments, e.g. CNS).
Organs and tissues vary widely in their capacity to take up different types of drugs and the systemic blood flow they receive. In turn, these factors affect the concentration of the drug that must be administered to achieve the desired plasma drug concentration.
Define volume of distribution (Vd).
The volume of distribution (Vd) describes the extent to which a drug partitions between the plasma and tissue compartments. In quantitative terms, Vd represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a concentration equivalent to that in the plamsa at steady state.
Vd = Dose / [Drug]plasma
Drugs primarily retained within the vascular compartment have a low Vd and drugs highly distributed into adipose and other non-vascular compartments have a high Vd.
What plasma protein is most abundant and responsible for the most drug binding?
Albumin
How does plama protein binding affect delivery of a drug to its target?
Many drugs bind with low affinity to albumin through both hydrophobic and electrostatic forces. Plasma protein binding tends to reduce the availability of a drug for diffusion or transport into the drug’s target organ because, in general, only the free or unbound form of the drug is capable of diffusion across membranes. Plasma protein binding may also reduce the transport of drugs into nonvascular compartments such as adipose tissue.
Outline metabolism of drugs.
The kidneys, GI tract, lungs, skin, and other organs all contribute to systemic drug metabolism. However, the liver contains the greatest quantity and diversity of metabolic enzymes, and the majority of drug metabolism occurs there. The ability of the liver to modify drugs depends on the amount of drug that enters the hepatocytes. Highly hydrophobic drugs can generally enter cells readily (including hepatocytes), and the liver preferentially metabolises hydrophobic drugs. However, the liver contains a multitude of transporters in the human solute carrier (SLC) family that allows for entry of some hydrophilic drugs.
Hepatic enzymes chemically modify a variety of substituents on drug molecules, thereby either rendering them inactive or facilitating their elimination. These reactions are collectively referred to as biotransformation, which are classified into two types: oxidation/reduction reactions (Phase I) and conjugation/hydrolysis reactions (Phase II).
Outline phase I metabolism.
Oxidation/reduction (phase I) reactions modify the chemical structure of a drug: typically, a polar goup is added or uncovered. Phase I exists to expose or create an active site, and phase II adds a conjugate to make the metabolite more water soluble. Some drugs and toxins do not require phase I to prime for adding a conjugate in phase II, as they are ready for conjugation straight away.
Phase I metabolism is split into two major groups: cytochrome p450-mediated metabolism, and flavin mono-oxygenase (FMO)-mediated metabolism.
Outline phase II metabolism.
Conjugation/hydrolysis (phase II) reactions hydrolyse a drug or conjugate a drug to a large, polar molecule in order to inactivate the drug, or more commonly, to enhance the drug’s solubility and excretion in the urine and bile. Phase II needs to happen at the same speed, or faster, than phase I metabolism. The most commonly added groups include glucuronate, sulfate, glutathione, and acetate.
Outline drug excretion.
Phase I and phase II reactions enhance the hydrophilicity of a hydrophobic drug and its metabolites, enabling such drugs to be excreted along a final common pathway with drugs that are intrinsically hydrophilic. Most drugs and drug metabolites are eliminated from the body through renal and biliary excretion, and it relies on the hydrophilic character of a drug or metabolite.
