Pharmacokinetics: ADME Processes

Pharmacokinetics

• Pharmacokinetics describes how the body affects a drug after administration, encompassing absorption, distribution, metabolism, and excretion (ADME).

Absorption

• Absorption is the process by which a drug moves from the site of administration to the systemic circulation.
• Bioavailability refers to the fraction of an administered dose of drug that reaches the systemic circulation unchanged.
• Intravenous administration has 100% bioavailability.
• Factors affecting absorption include route of administration, drug formulation, blood flow, and gastrointestinal (GI) physiology.
• First-pass metabolism can significantly reduce the bioavailability of orally administered drugs.

Distribution

• Distribution is the process by which a drug reversibly leaves the bloodstream and enters the tissues.
• Factors affecting distribution include blood flow, tissue binding, drug lipophilicity, and capillary permeability.
• Volume of distribution (Vd) is a pharmacokinetic parameter that relates the amount of drug in the body to the plasma concentration.
• A high Vd indicates extensive distribution into tissues.
• Plasma protein binding can affect distribution by limiting the amount of free drug available to reach tissues.

Metabolism

• Metabolism (biotransformation) is the enzymatic alteration of a drug within the body.
• The liver is the primary site of drug metabolism.
• Phase I reactions (e.g., oxidation, reduction, hydrolysis) introduce or expose a functional group on the drug molecule.
• Cytochrome P450 (CYP) enzymes are a major family of enzymes involved in Phase I metabolism.
• Phase II reactions (conjugation) attach a polar molecule to the drug, increasing its water solubility.
• Glucuronidation, sulfation, and acetylation are common Phase II reactions.
• Prodrugs are inactive compounds that are metabolized to active drugs.
• Enzyme induction increases the synthesis of CYP enzymes, potentially increasing drug metabolism.
• Enzyme inhibition decreases the activity of CYP enzymes, potentially decreasing drug metabolism.

Excretion

• Excretion is the process by which drugs or their metabolites are removed from the body.
• The kidneys are the primary route of excretion.
• Glomerular filtration, active tubular secretion, and passive tubular reabsorption are the renal processes involved in drug excretion.
• Liver via bile is another significant route of excretion.
• Clearance (CL) is a pharmacokinetic parameter that describes the rate at which a drug is eliminated from the body.
• Half-life (t1/2) is the time required for the plasma concentration of a drug to decrease by 50%.
• In first-order kinetics, a constant fraction of drug is eliminated per unit time.
• In zero-order kinetics, a constant amount of drug is eliminated per unit time.

Pharmacodynamics

• Pharmacodynamics describes the effects of a drug on the body, including its mechanism of action, therapeutic effects, and adverse effects.

Receptors

• Receptors are cellular macromolecules with which drugs interact to produce a pharmacological effect.
• Ligand-gated ion channels, G protein-coupled receptors (GPCRs), enzyme-linked receptors, and intracellular receptors are major receptor families.
• Agonists bind to receptors and activate them, producing a biological response.
• Antagonists bind to receptors but do not activate them, blocking the effects of agonists.
• Competitive antagonists bind reversibly to the same site as the agonist.
• Noncompetitive antagonists bind irreversibly or to a different site than the agonist.
• Partial agonists produce a submaximal response, even when occupying all available receptors.
• Inverse agonists bind to receptors and produce an effect opposite to that of agonists.

Dose-Response Relationships

• Efficacy is the maximum effect a drug can produce.
• Potency is the amount of drug required to produce a given effect.
• ED50 is the dose that produces 50% of the maximal effect.
• TD50 is the dose that produces a toxic effect in 50% of the population.
• Therapeutic index (TI) is a measure of drug safety, calculated as the ratio of TD50 to ED50.
• A higher TI indicates a safer drug.

Signal Transduction

• Signal transduction is the process by which a drug-receptor interaction leads to a cellular response.
• Second messengers, such as cAMP, IP3, and DAG, play a role in signal transduction.
• G proteins (Gs, Gi, Gq) mediate the effects of GPCRs.

Drug Interactions

• Drug interactions occur when the effects of one drug are altered by the presence of another drug or substance.
• Pharmacokinetic interactions affect ADME.
• Pharmacodynamic interactions occur at the receptor level or through shared signaling pathways.
• Additive effects occur when the combined effect of two drugs is equal to the sum of their individual effects.
• Synergistic effects occur when the combined effect of two drugs is greater than the sum of their individual effects.
• Antagonistic effects occur when the combined effect of two drugs is less than the sum of their individual effects.

Adverse Drug Reactions

• Adverse drug reactions (ADRs) are unintended and undesirable effects of drugs.
• Type A reactions are predictable and dose-dependent.
• Type B reactions are unpredictable and not dose-dependent (e.g., allergic reactions).
• Idiosyncratic reactions are rare and unpredictable ADRs.
• Teratogenic effects are drug-induced birth defects.

Autonomic Pharmacology

• The autonomic nervous system (ANS) regulates involuntary functions.
• The sympathetic nervous system (SNS) is responsible for the "fight or flight" response.
• The parasympathetic nervous system (PNS) is responsible for "rest and digest" functions.
• Acetylcholine (ACh) is the primary neurotransmitter in the PNS.
• Norepinephrine (NE) is the primary neurotransmitter in the SNS.
• Adrenergic receptors (alpha and beta) mediate the effects of NE and epinephrine.
• Cholinergic receptors (muscarinic and nicotinic) mediate the effects of ACh.

Cardiovascular Pharmacology

• Antihypertensive drugs lower blood pressure.
• Diuretics increase urine output and decrease blood volume.
• ACE inhibitors block the conversion of angiotensin I to angiotensin II.
• Angiotensin II receptor blockers (ARBs) block the effects of angiotensin II at its receptors.
• Beta-blockers block adrenergic receptors in the heart.
• Calcium channel blockers reduce calcium influx into smooth muscle and cardiac cells.
• Antianginal drugs relieve chest pain.
• Nitrates dilate blood vessels and increase blood flow to the heart.
• Beta-blockers reduce heart rate and contractility.
• Calcium channel blockers reduce heart rate and contractility.
• Antiarrhythmic drugs suppress abnormal heart rhythms.
• Sodium channel blockers reduce the excitability of cardiac cells.
• Beta-blockers reduce heart rate and contractility.
• Potassium channel blockers prolong the refractory period of cardiac cells.
• Calcium channel blockers reduce heart rate and contractility.
• Cardiac glycosides (e.g., digoxin) increase the force of heart contraction.
• Anticoagulants prevent blood clot formation.
• Heparin activates antithrombin.
• Warfarin inhibits vitamin K-dependent clotting factors.
• Antiplatelet drugs inhibit platelet aggregation.
• Aspirin inhibits cyclooxygenase (COX).
• Clopidogrel blocks ADP receptors.
• Thrombolytic drugs dissolve blood clots.
• Tissue plasminogen activator (tPA) converts plasminogen to plasmin.
• Lipid-lowering drugs reduce cholesterol levels.
• Statins inhibit HMG-CoA reductase.

Central Nervous System Pharmacology

• Sedative-hypnotics depress the central nervous system (CNS).
• Benzodiazepines enhance GABA activity.
• Barbiturates enhance GABA activity.
• General anesthetics produce a reversible loss of consciousness.
• Inhaled anesthetics affect neuronal ion channels.
• Intravenous anesthetics affect neuronal ion channels.
• Antidepressants relieve symptoms of depression.
• Selective serotonin reuptake inhibitors (SSRIs) block the reuptake of serotonin.
• Tricyclic antidepressants (TCAs) block the reuptake of serotonin and norepinephrine.
• Monoamine oxidase inhibitors (MAOIs) inhibit the breakdown of monoamines.
• Mood stabilizers treat bipolar disorder.
• Lithium affects neuronal signal transduction.
• Antipsychotics treat psychosis.
• First-generation antipsychotics (FGAs) block dopamine receptors.
• Second-generation antipsychotics (SGAs) block dopamine and serotonin receptors.
• Antiepileptic drugs prevent seizures.
• Sodium channel blockers reduce neuronal excitability.
• Calcium channel blockers reduce neuronal excitability.
• GABA enhancers increase GABA activity.
• Analgesics relieve pain.
• Opioids activate opioid receptors.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX).
• Local anesthetics block sodium channels.
• Anti-Parkinson's drugs treat Parkinson's disease.
• Levodopa is converted to dopamine in the brain.
• Dopamine agonists activate dopamine receptors.
• MAO-B inhibitors inhibit the breakdown of dopamine.
• Alzheimer's drugs treat Alzheimer's disease.
• Cholinesterase inhibitors increase acetylcholine levels.

Endocrine Pharmacology

• Hypoglycemic drugs lower blood glucose levels.
• Insulin promotes glucose uptake into cells.
• Oral hypoglycemic agents include sulfonylureas, biguanides, thiazolidinediones, and DPP-4 inhibitors.
• Thyroid hormones regulate metabolism.
• Levothyroxine is a synthetic form of thyroxine (T4).
• Anti-thyroid drugs inhibit thyroid hormone synthesis.
• Corticosteroids have anti-inflammatory and immunosuppressant effects.
• Prednisone is a synthetic corticosteroid.
• Sex hormones regulate reproductive function.
• Estrogens and progestins are female sex hormones.
• Androgens are male sex hormones.

Chemotherapeutic Agents

• Chemotherapeutic agents kill or inhibit the growth of cancer cells.
• Alkylating agents damage DNA.
• Antimetabolites interfere with DNA synthesis.
• Antibiotics inhibit DNA or RNA synthesis.
• Mitotic inhibitors interfere with cell division.
• Targeted therapies target specific molecules involved in cancer cell growth.
• Immunotherapies stimulate the immune system to attack cancer cells.

Immunopharmacology

• Immunosuppressants suppress the immune system.
• Calcineurin inhibitors (e.g., cyclosporine) inhibit T cell activation.
• mTOR inhibitors (e.g., sirolimus) inhibit T cell proliferation.
• Cytotoxic drugs kill immune cells.
• Antibodies neutralize immune mediators or kill immune cells.
• Immunostimulants stimulate the immune system.
• Vaccines induce immunity to infectious diseases.
• Cytokines stimulate immune cell activity.

Toxicology

• Toxicology is the study of the adverse effects of chemicals on living organisms.
• Dose-response relationships are used to assess toxicity.
• LD50 is the dose that is lethal to 50% of the population.
• Toxicokinetics describes the ADME of toxins.
• Toxicodynamics describes the effects of toxins on the body.
• Antidotes counteract the effects of toxins.