Pharmacology: Key Concepts & Case Study

General Pharmacology

• General pharmacology studies the effects of drugs and their mechanisms of action.
• Key areas include pharmacokinetics, pharmacodynamics, adverse drug reactions, and special considerations for dental patients.

Case Scenario

• A 38-year-old heavy smoker presents to the dental clinic with severe facial pain and swelling from a dental abscess.
• Her medical history includes epilepsy (treated with phenytoin) and gastroesophageal reflux disease (treated with lansoprazole).
• Consideration should be taken on her medical history when determining management.

Definitions

• Pharmacoepidemiology studies the uses and effects of drugs in populations.
• Pharmacoeconomics describes and analyzes the costs of drug therapy.
• Pharmacogenomics (PGx) studies the role of the genome in drug response.
• Pharmacotherapeutics studies the selection and use of drugs for diagnosis, prevention, and treatment of disease.
• Pharmacokinetics studies the movement of a drug over time through the body or what the body does to the drug.
• Pharmacodynamics studies the pharmacological actions of drugs and their mechanisms of action or what the drug does to the body.

Pharmacokinetics (ADME)

• Pharmacokinetics is the study of how drugs move through the body over time.
• ADME stands for Absorption, Distribution, Metabolism, and Excretion.

Absorption

• Absorption is the transfer of a drug from its administration site to systemic circulation.
• Intravenous (IV) drug delivery results in complete absorption, while other routes may lead to partial absorption.
• Drugs must traverse cellular barriers (e.g., gastrointestinal mucosa, renal tubule, blood-brain barrier, placenta) to reach their site of action.

Factors Affecting Drug Absorption

• Solubility: Drugs require both water and lipid solubility. The higher the lipid/water partition coefficient, the faster the absorption rate.
• Ionization: Unionized drugs are more lipid-soluble and, therefore, better absorbed.
• Valency: Ferrous salts (Fe++) are better absorbed than ferric salts (Fe+++).
• Nature: Inorganic substances are better absorbed than organic ones.
• Drug Formulation: Aqueous solutions are absorbed more readily than solids or suspensions.
• Rate of disintegration e.g. Paracetamol has a rapid rate of disintegration leading to rapid absorption.

Factors Related to the Patient Affecting Drug Absorption

• Route of administration: The absorption rate varies as IV and inhalation > IM > SC, oral > intact skin (slow).
• Surface area and vascularity of the absorbing surface influence absorption.
• State of health of absorbing surface: Conditions like gastritis or inflammatory bowel can affect absorption.
• State of general circulation: Shock reduces drug absorption, so IV drugs are preferred.
• Specific factors: Intrinsic factor is essential for Vitamin B12 absorption in the stomach.

Factors Affecting Oral Absorption

• pH within the gut: Weak acids (e.g., aspirin) are better absorbed in an acidic medium (stomach), while weak bases (e.g., amphetamine, ephedrine) are better absorbed in an alkaline medium (intestine).
• Gut contents: Tetracycline absorption is decreased by calcium and iron due to chelation. Cholestyramine and charcoal decrease absorption of many drugs by adsorption.

First Pass Effect

• First-pass effect refers to the metabolism of a drug in the gut wall or liver before it reaches systemic circulation which occurs with oral route.
• Gut first-pass effect: Gastric acidity destroys benzyl penicillin (penicillin G). Digestive enzymes destroy insulin and Mucosal enzymes destroy chlorpromazine.
• Hepatic first-pass effect: Drugs extensively metabolized include Nitroglycerine – Lidocaine and Drugs metabolized to a large extent e.g. propranolol.
• Overcoming hepatic first-pass metabolism: Increase the oral dose or use alternative routes (NOT ORAL) like sublingual.

Bioavailability

• Bioavailability is the fraction of an administered drug that reaches systemic circulation in an unchanged form by any route.
• For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 (70%).

Factors Affecting Bioavailability

• First-pass metabolism impacts bioavailability: Hepatic metabolism effects nitroglycerine while Gut metabolism effects Benzylpenicillin, insulin.
• Solubility: A drug must have some water solubility in addition to lipid solubility.
• Nature of drug formulation: Particle size, salt form, and excipients influence dissolution.

Distribution

• Distribution refers to the movement of a drug to and from the blood and various tissues of the body

Patterns of Distribution

• One-compartment model (intravascular): e.g., high MW heparin or drugs highly bound to plasma proteins (warfarin).
• Two-compartment model (extracellular): e.g., quaternary ammonium compounds (neostigmine, Na Cl).
• Multicompartment model (extra and intracellular): e.g., propranolol.
• Other sites: e.g., tetracycline and calcium in bone and teeth.

Factors Affecting Distribution

• Physicochemical properties: Molecular weight, degree of ionization, and lipid solubility affect drug distribution.
• Binding to plasma proteins: Extensive protein binding restricts drugs to the plasma as barbiturates, benzodiazepines, warfarin, and NSAIDs. Free form is active, metabolized and excreted.
• Passage across barriers: Drugs need to be able to cross certain barriers. If it's non-ionized, and lipid-soluble drugs it can cross the blood brain barrier (BBB). e.g. physostigmine can stimulate the Central nervous system, while neostigmine (quaternary ammonium) cannot because it cannot penetrate into the brain.
• Passage of drugs across barriers: Inflammation as in meningitis, increases BBB permeability therefore penicillin can pass the BBB in sufficient amount only if there is inflammation.
• Passage across barriers: Non-ionizable, lipid-soluble drugs pass from mother to fetus effecting tetracyclines which may cause malformation and morphine which may cause neonatal asphyxia.
• Passage of drugs through breast milk: Most drugs administered to lactating women are detectable in breast milk. Milk has a more acidic pH so basic drugs ionize and accumulate in milk (ion trapping) e.g diazepam, morphine.

Metabolism (Biotransformation)

• Drug metabolism aims to change lipid-soluble drugs into water-soluble metabolites for easy excretion.
• Hepatic microsomal enzymes are present in endoplasmic reticulum while non-microsomal enzymes are present in cytoplasm mitochondria of liver-kidney -lung -GIT plasma.
• Cytochrome P450 is important for metabolism as it is responsible for most oxidation, reduction, hydrolysis of phase I and only glucuronide conjugation of Phase II.
• Lipid soluble drugs and water soluble drugs are affected by factors affected later and are Not induced by drugs. Not affected by starvation, liver disease but affected by age, sex., respectively.

Factors Affecting Hepatic Microsomal Enzyme Activity

• Hepatic microsomal enzyme inducers: increase metabolism of another drugs which cause tolerance, e.g., Androgens, Phenytoin, Phenobarbitone, Rifampicin, Smoking, tea and Coffee.
• Hepatic microsomal enzyme inhibitors: decrease metabolism of another drugs, e.g Estrogens, Chloramphenicol, Erythromycin, QuinolonesKetoconazole -Sulphonamides, Omeprazole and Grape fruit juice.
• Age: Lowering of drug metabolism occurs in extremities of age. Therefore drug doses has to be reduced.
• Sex: Androgens stimulate while estrogen and progesterone inhibit drug metabolism.
• Starvation: Enzyme activity is decreased.

Factors Affecting Hepatic Microsomal Enzyme Activity

• Pathological conditions: In liver diseases, drug metabolism is reduced leading to increased drug toxicity.
• Genetic factors: Genetic polymorphism is responsible for variation in drug toxicities, e.g. Succinylcholine is metabolized by pseudocholinesterase and deficiency of this enzyme leads to succinylcholine apnea.

Excretion

• Drug removal from the body occurs through the kidney into the urine primarily, and also GIT, skin glands, and lungs.
• Glomerular filtration: The drug must be free and water-soluble.
• Passive reabsorption: Concentration of the drug increases as it moves towards the distal tubules. If sufficiently lipid soluble and unionized, re-absorption occurs.
• Active secretion: Occurs in the proximal tubules which requires a carrier. Probenecid competes with penicillin to prolong the action of penicillin.
• Changes in urine pH affect drug excretion: Alkalization of urine by bicarbonate increases excretion of acid drugs and Acidification of urine by NH4Cl excretion of base drugs.
• Other routes of excretion: Saliva, Stomach, Bile, feces, milk and sweat.

Pharmacodynamics

• Pharmacodynamics is the study of the pharmacological actions of drugs and their mechanisms of action.
• It describes what the drug does to the body and drugs act by affecting specific molecules in the cells or the body called target molecules.

Drug Target Molecules

• Most drugs act by affecting specific molecules in the cells or the body called target molecules which include: receptors, ion channels, Enzymes and carrier molecules.
• Receptors are protein macromolecules specifically interacting to initiate signaling mechanisms and that result in a biological response.

Types of Receptors

• Ligand-gated ion channels - Nicotinic receptor (influx of sodium with depolarization and stimulation) i.e. AcH, carbachol and GABA receptor (influx of chloride with hyperpolarization and inhibition) i.e. benzodiazepines
• G-protein-coupled receptors (GPCRs) - transmembrane receptors coupled to intracellular G-protein to affect enzyme or ion channel i.e. muscarinic acetylcholine receptor and adrenoceptors (alpha & beta)
• Kinase-linked receptors - Receptors for insulin and for various cytokines and growth factors.
• Nuclear receptors (intracellular) - binding with the ligand occurs, activated and regulates gene transcription, producing slow but prolonged response for steroid hormones, thyroid hormone and vitamin D.

Classification of Drugs

• Classification of Drugs based on efficacy (effect) for agonists, partial agonists and antagonists.

Types of Antagonists

• Competitive antagonists bind reversibly and are displaced by agonists (e.g., atropine, propranolol, naloxone).
• Non-competitive antagonists are not displaced by agonists.
  • Reversible: Binds reversibly, effect ends by its metabolism, short duration e.g. Succinylcholine
  • Irreversible: Binds covalently, ends by re-synthesizing a new receptor & usually of long duration e.g. organophosphates

Drug Dosage

• Therapeutic dose: Average dose required to produce therapeutic effect in adult male.
• Minimal effective dose: The lowest dose to produce therapeutic effect.
• Maximal tolerated dose: The largest dose without toxic effect.
• Paracetamol example: the usual dose is one or two 500mg tablets at a time, up to 4 times in 24 hours with a maximum dose of eight tablets in 24 hours (4g).

Factors Affecting Action and Dosage

• Biological variations, Gender and Age affect action and dosage. Biological variations: Affected by Race, nutritional state & genetic variation. Age: dose is for adult male (20-60 years) and decreased for the extremes of age.
• Pediatrics: Infants (<2y.) formula is (Infant dose = adult dose X infant's surface area / 1.73) and Children (4-12 y) teenager: 13 to 19 formula is (Child dose = adult dose X Age in Y. / Age + 12)
• Geriatrics (Elderly > 60 y.): percentage method: Use ¼ (>60y.) or 2/3 (>70y.) of the young adult dose.
• Females should avoid some drugs at certain periods as well as needing smaller doses (estrogens inhibit HME) than males.

Contraindicated Drugs for Females by Period

• Menstruation: Avoid aspirin (bleeding risk).
• Pregnancy: Avoid oxytocics, teratogenics (abortion & fetal anomalies).
• Labour: Avoid morphine, barbiturates (neonatal asphyxia).
• Lactation: Avoid antihistaminics, anticoagulants, tetracyclines, purgatives (excreted in milk).

Factors Affecting Action and Dosage of Drugs

• Route of administration: Affects bioavailability and the amount of dose.
• Time of administration: relation to different meals.
• Psychological factors & Pathological state
• ADR: Adverse drug reactions
• Allergic reaction & Idiosyncrasy

Adverse Drug Reactions

• Are harmful effects of a drug at doses used in therapy.
• decrease dosage / stop drug / immediate treatment are required.
• Due to patient-related (age, sex, atopy, disease) and drug-related factors (nature, dose, drug interactions).

Types of Adverse Drug Reactions

• Type A (Augmented or predictable adverse effects): Exaggerated predictable effects of the normal pharmacological actions of the drug.
  • Side effects: Undesirable unavoidable effects produced by therapeutic doses of the drug.
  • Overdose toxicity: Toxic effects due to high blood levels of the drug.
  • Super-sensitivity (Intolerance): Exaggerated effects to a small dose of the drug.
  • Secondary effects: Effect secondary to the drug action.

Types of Adverse Drug Reactions Cont.

• Cytotoxicity: Toxic effects on specific organs like the heart, liver, bone marrow, and nerves.
• Type B (Bizarre or unpredictable adverse effects): Unpredictable abnormal responses to the drug. Drug allergy (Hypersensitivity:) due to immune reaction. Idiosyncrasy: abnormal response to drugs.

Types of Adverse Drug Reactions Cont..

• Type C (Chronic adverse Effects): Due to prolonged drug use. – Tolerance & Dependence – Iatrogenic (drug-induced) diseases: e.g., Parkinsonism, peptic ulcer, Cushing
• Type D (Delayed Effects): Effects appearing after long period of using the drug. – Carcinogenicity: tobacco smoking & lung cancer – Teratogenicity (drug-induced fetal malformations) e.g. phenytoin and aspirin.

Types of Adverse Drug Reactions Cont...

• Type E (End of use Effects): Effects of sudden stopping of drug use (Drug Withdrawal), include:
  • Abstinence syndromes: Morphine, cocaine, barbiturate.
  • Acute Addisonian crisis: chronic steroid therapy.
  • Worsening of existing disease: stopping B-blockers (MI).

Drug Allergy (Hypersensitivity)

• Due to Ag/Ab reaction, not all drugs, not all patients.
• Avoided by: History taking, Intradermal sensitivity tests.
• Treated by: SC adrenaline, IV corticosteroids, antihistaminic.
• Example: Penicillin

Drug Idiosyncrasy

• Is abnormal response to drug due to genetic variations affecting drug metabolism and the excretion i.e. Hemolytic anemia, Succinylcholine apnea, and MAlignant hyperthermia

Special Considerations in Dental Patients

• The dentist must take critical factors into consideration prior to the drug administration or prescription of a drug
• Involves medical health questionnaires, consulting with physician, physical assesment. Factors:
• The prescribing physician(s) should be involved in the determination of the patient's ability to tolerate specific dental procedures, particularly those categorized as American Society of Anesthesiologists' Physical Status Classification III or IV.

Special Considerations in Dental Patients Cont...

• The adverse effects of medically prescribed drugs must be monitored and managed appropriately.
• Vital signs should be consulted to obtain detailed information about the management of patients with special needs
• Also involves the management and consideration of patients with special healthcare needs along with pregnancy and lactation.