Pharmacology: Dynamics & Kinetics

General Pharmacology

• Pharmacodynamics studies the effects of drugs on the body.
• Pharmacokinetics studies how the body affects drugs.

Pharmacodynamics: Qualitative Aspects

• Qualitative aspects include receptors, enzymes, and selectivity.
• Quantitative aspects include dose response, potency, therapeutic efficacy, and tolerance.

Pharmacokinetics: Time Course of Drug Concentration

• Pharmacokinetics considers the time course of drug concentration.
• Factors include drug passage across cell membranes and the order of reaction.
• Plasma half-life and steady-state concentration are key considerations.
• Therapeutic drug monitoring is part of pharmacokinetics.
• Individual processes include absorption, distribution, metabolism, and elimination.
• Drug dosage involves dosing schedules; chronic pharmacology involves prolonged drug administration and drug discontinuation syndromes.

Pharmacodynamics: Mechanisms

• Mechanisms involving ligand-gated ion channels are examined.
• Receptors are coupled directly to membrane ion channels.
• Neurotransmitters act on these receptors in the postsynaptic membrane of nerve or muscle cells.
• This process gives a response within milliseconds.

G-Protein-Coupled Receptor Systems

• Receptors are bound to the cell membrane and coupled to intracellular effector systems by a G-protein.
• Catecholamines activate β-adrenoceptors through a coupled G-protein system.
• This increases the activity of intracellular adenylyl cyclase.
• It increases the rate of cyclic AMP formation, which is a modulator of enzyme activity.
• The process of G-protein-coupled receptor systems takes seconds.

Protein Kinase Receptors

• Protein kinase receptors incorporate a protein kinase in their structure.
• They're targeted by peptide hormones involved in cell growth, differentiation, and inflammatory mediator release.
• Inflammatory mediators are released over hours.

Cytosolic (Nuclear) Receptors

• These receptors are located within the cell and regulate DNA transcription and protein synthesis.
• Steroid and thyroid hormones use cytosolic receptors.
• The process takes hours or days.

Drug Action Within or Near Cells

• Drugs act by enzyme inhibition, like platelet cyclo-oxygenase inhibition by aspirin.
• Other examples include cholinesterase inhibition by pyridostigmine or xanthine oxidase inhibition by allopurinol.
• Drugs can inhibit or induce transporter processes that carry substances into, across, and out of cells.
• Probenecid blocks anion transport in renal tubule cells, protecting against cidofovir's nephrotoxic effects.
• Cidofovir is used for cytomegalovirus retinitis.

Incorporation Into Larger Molecules

• Some drugs, like 5-fluorouracil (an anticancer drug), incorporate into larger molecules.
• 5-fluorouracil is incorporated into messenger RNA in place of uracil.
• Effective antimicrobial agents alter metabolic processes unique to microorganisms.
• Penicillin interferes with bacterial cell wall formation; trimethoprim inhibits folic acid synthesis.

Drug Action Outside the Cell

• Drugs act through direct chemical interaction, like chelating agents and antacids.
• Osmosis is involved with purgatives like magnesium sulfate and diuretics like mannitol.
• These drugs are active because neither they nor the water in which they are dissolved is absorbed by the cells lining the gut and kidney tubules.

Pharmacodynamics: Receptor Interactions

• Considerations include receptors with agonists, antagonists, partial agonists, and inverse agonists

Agonists

• Drugs that activate receptors resemble natural transmitters or hormones.
• The extended effects result in greater resistance to degradation than natural compounds.
• Albutamol-induced bronchodilation lasts longer than that induced by epinephrine.

Partial Agonists

• Some drugs block access of the natural agonist to the receptor.
• Partial agonists are capable of a low degree of activation, having both antagonist and agonist actions.
• Pindolol and oxprenolol are β-adrenoceptor antagonists with partial agonist activity, also called intrinsic sympathomimetic activity (ISA).
• Propranolol lacks agonist activity and is a pure antagonist.

Partial Agonist Effects

• Propranolol and pindolol can produce extensive β-blockade like eradication of exercise tachycardia.
• However, resting heart rate may be lower on propranolol, indicating clinically significant differences.

Inverse Agonists

• Some substances produce effects specifically opposed to those of agonists.
• Benzodiazepines produce sedation, anxiolysis, muscle relaxation, and control convulsions by agonist action.
• B-carbolines cause stimulation, anxiety, increased muscle tone, and convulsions and are inverse agonists.
• Both types act by modulating the effects of γ-aminobutyric acid (GABA).

Antagonists

• Antagonists block receptors but do not activate a response.
• Instead, they prevent agonists from exerting effects.
• Drugs with no activating effect are termed pure antagonists.
• A low-efficacy agonist can act as an antagonist if it occupies a receptor, preventing access by a high-efficacy agonist.
• This can occur with opioids.

Physiological (Functional) Antagonism

• Drugs can oppose effects through different mechanisms, not just by acting on the same receptor.
• Atropine counteracts bradycardia from β-adrenoceptor blocker overdose by accelerating the heart.
• The parasympathetic (vagal) tone slows the heart.
• Adrenaline/epinephrine and theophylline counteract histamine-induced bronchoconstriction by relaxing bronchial smooth muscle.
• Antagonism results from different physiological mechanisms.

Enzymes

• Interactions between drugs and enzymes are similar to drug-receptor interactions.
• Drugs can alter enzyme activity by resembling a natural substrate, competing with it for the enzyme.

Examples of Enzyme Alteration by Drugs

• Enalapril reduces hypertension by structurally resembling angiotensin I.
• Enalapril competitively inhibits angiotensin-converting enzyme (ACE).
• Carbidopa reduces levodopa's metabolism to dopamine in the blood, treating Parkinsonism.
• This combination reduces metabolism of levodopa to dopamine in the blood without affecting the brain (carbidopa does not cross the blood-brain barrier).

Relevance of Drug Selectivity

• Doctors and pharmacologists aim for selective drug actions, which prevent adverse effects and simplify patient management.
• Approaches to achieve selectivity include modification of drug structure and selective delivery or drug targeting, and stereoselectivity.

Quantitative Aspects of Selectivity

• Dose-response relationships show wanted and unwanted effects and can quantify selective and non-selective drug action.

Dose-Response Curves

• Drug A's maximum wanted effect occurs at a lower dose than the lowest dose producing unwanted effects.
• The ratio ED50 (unwanted effect) / ED50 (wanted effect) indicates a large therapeutic index, meaning high selectivity.
• Drug B causes unwanted effects below doses producing maximum benefit.
• The ratio ED50 (unwanted effect) / ED50 (wanted effect) indicates a small therapeutic index, meaning low selectivity.

Potency vs. Efficacy

• Potency is the amount of drug needed for an effect.
• If drug A has a greater effect than drug B weight-for-weight, drug A is more potent, even if both drugs have similar maximum efficacy.
• Therapeutic efficacy is the drug’s capacity to produce a maximum effect and refers to the maximum possible therapeutic effect.

Clinical Importance: Efficacy vs. Potency

• Differences in therapeutic efficacy are more clinically important than differences in potency.

Tolerance

• Repeated drug administration can lead to tolerance.
• A state of tolerance requires increased doses to achieve effects previously obtained at lower doses, indicating reduced sensitivity.

Tachyphylaxis

• Tachyphylaxis is a phenomenon describing progressive lessening of effect in response to frequent administration.

Rapid Tolerance

• Rapid tolerance is common with nitrates for angina.
• It is possibly because of free radical generation from nitric oxide.
• It can be avoided by removing transdermal nitrate patches for 4-8 hours.

Pharmacokinetics: Drug Processes and Time Course

• Drug passage across cell membranes is a factor.
• This includes the order of reaction or process involved.
• Plasma half-life and steady-state concentrations are also important.
• Individual processes include absorption, distribution, metabolism, and elimination.

Lipid and Water Solubility

• Lipid solubility is promoted by benzene rings, hydrocarbon chains, steroid nuclei, and halogens (-Br, -Cl, -F).
• Water solubility is promoted by alcoholic (-OH), amide (-CONH2), or carboxylic (-COOH) groups.
• Water solubility is also promoted by the formation of glucuronide and sulfate conjugates.

Drug Classification Based on Physicochemical Properties

• Drugs are classified as variably ionized, non-ionizable, or permanently ionized.
• Variability depends on environmental pH or lipid/water solubility.

Ionization and Diffusibility

• Acidic groups are less ionized in acidic environments; basic groups are less ionized in basic environments.
• The ionization state influences drugs’ diffusibility.
• Un-ionized drugs are lipid soluble and diffusible; ionized drugs are lipid insoluble and non-diffusible.

Order of Reaction or Process

• Drug molecules reach action sites in the body after crossing cell membranes and cells.
• Many are metabolized during this process.
• The rate of these movements is subject to order of reaction or process.

Reaction Orders

• First-order processes involve a constant fraction of the drug being transported or metabolized per unit time.
• Zero-order processes involve a constant amount of the drug being transported or metabolized per unit time.

First-Order (Exponential) Processes

• The rates of absorption, distribution, metabolism, and excretion of a drug are directly proportional to its concentration in most instances.
• Transfer of drug across a cell membrane or metabolite formation is high at high concentrations, falling in direct proportion to low concentrations.
• There's an exponential relationship.

Zero-Order Process

• Zero Order happens when the amount of drug in the body rises.
• Metabolic reactions or processes with limited capacity become saturated.
• The rate of the process reaches a maximum level.
• There is limited enzyme activity - increased dose will not change rate.
• The reaction rate is no longer proportional to dose and is dose-dependent.

Time Course of Drug Concentration and Effect

• Plasma half-life and steady-state concentrations are important parameters.
• The t½ (half-life) is a key pharmacokinetic value.
• The time to reach steady state is also important.
• Maintaining the same dosing schedule ensures a steady drug amount, preventing toxicity.

Steady State

• The time to reach steady state depends on the t½.
• After about 5 t½ periods, the drug amount in the body and plasma concentration becomes constant.
• State depends on the t½, and 5 t½ periods will result in leveling.

Time to Reach Steady State: Percentages

• At ultimate steady state (100%):
  • In 1 t½, the concentration reaches 50%.
  • In 2 t½, it reaches 75%.
  • In 3 t½, it reaches 87.5%.
  • In 4 t½, it reaches 93.75%.
  • In 5 t½, it reaches 96.875%.

Pharmacokinetic Equations

• Equations for amount of drug in the body, volume of distribution, loading dose, and elimination rate

Amount of Drug in Body Equations

• Xb = Vd * C, where each term is defined as:
  • Xb is the amount of drug in the body (mg)
  • Vd is the volume of distribution (mL).
  • C is the plasma drug concentration (mg/mL).

Volume of Distribution Calculations

• Vd = Div / Co, where each term is defined as:
  • Vd is the volume of distribution (mL/kg)
  • Div is the IV dose (mg/kg), and
  • Co is the plasma drug concentration (mg/mL).

Loading Dose, Maintenance Dose Equations

• Loading dose=CpxVd/F
• Maintenance dose= CpxCL /F x Time Interval

Elimination Rate Equations

• kel = km + kex, where
  • kel is the drug elimination rate constant,
  • km is the elimination rate constant due to metabolism.
  • kex is the elimination rate constant due to excretion

Half-Life Equation

• t1/2 = ln 2 /kel = 0.693/kel is the equation:
  • t1/2 is the elimination half-life.

Clearance Equations

• CL = rate of elimination/C
• Rate of elimination = CL * C d
• CL = Vd * kel where Vd is volume of distribution and kel is elimination rate constant.
• CL = Vd * (0.693/t1/2) where 0.693 = ln 2 and t1/2 is the drug elimination half life.

Plasma Clearance components

• Note that plasma clearance CLp includes renal (CLr) and metabolic (CLm) components.

Renal Clearance Equation

• CLr = (U * Cur) / Cp; where U is urine flow (mL/min).
• Cur is urinary drug concentration.
• Cp is plasma drug concentration

Steady-State Drug Plasma Concentration

• To determine steady-state plasma concentration, sensitivity must be known to drug and patient-specific factors. The overall form of the oral drug equation;
  • Css = 1/(ke*Vd) * (F*D)/T
• Css* = F · (D/t)/(kel * Vd)

Individual Pharmacokinetic Processes: Absorption

• Absorption may occur via enteral such as by mouth, rectally, or sublingual.
• Absorption may also occur parenterally, including via IV injection, IM injection, inhalation, topical applications, or transdermally.
• Other routes are intrathecal, intradermal, intranasal, intratracheal, and intrapleural

Distribution

• If a drug stays mostly in plasma, its distribution volume is small.
• If a drug is present mainly in other tissues, its distribution volume will be large.

Volume of Distribution

• The distribution volume of a drug is the volume in which it appears to distribute.
• The volume includes the concentration throughout body equal to single compartment plasma.

Selective Distribution

• Selective distribution occurs because of a special affinity between drugs and body constituents.
• Many drugs bind to proteins in the plasma. E.g. phenothiazines and chloroquine bind to melanin tissues.
• Drugs may also concentrate selectively in a particular tissue because of transport mechanisms.
• Iodine concentrates in the thyroid.

Metabolism

• Metabolism transforms chemicals within the body.
• It reduces lipid solubility and altering biological activity.

Phase I Metabolism

• Phase I metabolism alters the drug usually introducing a chemically active site.
• The new metabolite often reduces or alters biological activity and pharmacokinetic properties.
• A shorter t/2 is common.
• The oxidations occur by microsomal mixed function oxidases (cytochrome P450 enzymes).
• These enzymes metabolise chemicals from the environment, the diet, and drugs.
• They incorporate one atom of molecular oxygen (O2) to form one atom of (chemically hydroxyl.

CYP2E1 Enzyme

• CYP2E1 is an isoenzyme that catalyzes a reaction involved in the metabolism of alcohol, paracetamol, estradiol and ethinylestradiol

Phase I Oxidation and Epoxides

• Phase I oxidation of some drugs results in the formation of short-lived and highly reactive epoxides, which are toxic.
• Glutathione is a tripeptide that combines with epoxides and defends against hepatic damage by halothane and paracetamol.

Phase II Metabolism

• Phase II metabolism combines the drug with a polar endogenous molecule.
• The kidney eliminates water-soluble metabolite.
• Conjugates may occur with glucuronic acid. or derived from glucose, oral contraceptive.
• Conjugation is performed by isoniazid, penelzine and dapsone. Phase II metabolism terminates biological activity.

Clinical Relevence of Enzyme Induction

• Enzyme induction is relevant to drug therapy because:
• Clinically important drug–drug may result.
• Failure to achieve the expected repsonse to the expected dose of a certain drug.

Enzyme Inhibition

– The outcomes from inhibiting drug metabolism are prolongation of action of a drug or metabolite. – Enzyme inhibition offers more scope for therapy.

Substances that Cause Enzyme Induction in Humans

• Some substances include barbecued meats, nevirapine, barbiturates, phenobarbital, Brussels sprouts and phenytoin.
• Carbamazepine, primidone, DDT, Rifampicin and ethanol can cause enzyme induction.

Binding

• Many natural substances circulate free in plasma and bound to plasma proteins.
• Free and bound fractions are in equilibrium.
• If a drug is removed from plasma by metabolism, renal function, or dialysis is replaced by drug released from the bound fraction

Albumin

• Albumin is the main binding protein for drugs and other natural drugs.
• Albumin molecule is low affinity for basic drugs and high affinity for acidic.
• Other binding proteins in the blood include lipoprotein and carriers of specific hormones.

Diseases

• If the patient is in chronic renal failure, hypoalbuminaemia and retention of protein are increased. Increased unbound.
• Drugs are is used with special caution.

Drugs that act by enzyme inhibition

• These drugs include Acetazolamide, allopurinol, benserazide, and disulfiram.
• Also important Selegiline.

Elimination of Drugs

• Drugs are eliminated renally as wellas the glomerular level, bile, pulmonary and tubular