Pharmacokinetics and Absorption

Pharmacokinetics

• Describes what the body does to a drug, including absorption, distribution, metabolism, and excretion (ADME).
• Pharmacodynamics describes what the drug does to the body through interactions with molecular targets and pharmacological responses.

Absorption

• The process by which a drug moves from its administration site into the bloodstream.
• Most drugs must enter systemic circulation to be distributed to their site of action.
• IV administration is an exception, as it directly introduces the drug into systemic circulation.
• Orally administered solid drugs must disintegrate and dissolve before absorption.
• Absorption rate: liquids > suspensions > powders > capsules > tablets > coated tablets > enteric-coated tablets.

First Pass Metabolism

• Orally administered drugs are absorbed from the gastrointestinal tract and pass through the portal system to the liver before entering systemic circulation.
• The liver extracts a portion of the drug, reducing the concentration of the active drug.
• Bioavailability is the proportion of the administered dose that reaches systemic circulation intact.
• It is determined by the amount of drug absorbed from the GI tract and the amount escaping hepatic extraction.
• The first-pass effect is the hepatic metabolism of a drug, resulting in a reduced concentration of the active drug.
• Oral drug doses are calculated to compensate for the first-pass effect.
• Bioavailability example: 30mg of oral morphine ≈ 10mg of morphine administered IM/IV/SC,

Absorption Across Biological Membranes

• Passive diffusion and carrier-mediated transport facilitate ADME processes.
• Drugs must cross cell membranes and enter blood vessels to reach their target site.
• Lipid-soluble drugs pass through the lipid bilayer membrane more easily than ionized or charged drugs.
• Movement across membranes occurs through passive diffusion, facilitated transport, active transport, and aquaporins.

Variables Affecting Drug Absorption

• Surface area of the absorption site: larger surface area = greater absorption = rapid effects (e.g., pulmonary epithelium, small intestine).
• Blood circulation to the administration site: determines the rate and extent of drug absorption (e.g., sublingual route vs. subcutaneous route).
• Drug solubility: more soluble drugs are more rapidly absorbed (lipid solubility enhances absorption in GIT).
• Ionization: Non-ionized forms are more lipid-soluble and easily cross cell membranes; ionized forms are water-soluble and do not diffuse readily.
• Blood-brain barrier: lipid-soluble drugs can cross, while strongly ionized/water-soluble drugs cannot.
• Drug formulation: enteric coatings allow controlled release for drugs with short elimination half-lives, prevent decomposition, or reduce gastric irritation, dissolving in the alkaline pH of the small intestine
• Route of drug administration: oral, parenteral (subcutaneous, intramuscular, intravenous, intrathecal, epidural), inhalation, topical, or rectal.

Routes of Drug Administration

• Oral: most common, safe, convenient, and economical; slow absorption due to GIT environment.
  • Stomach: not a major site of absorption; administer drugs on an empty stomach with sufficient water to ensure dissolution and rapid passage into the small intestine.
  • Small intestine: highly vascular with many villi with a larger surface area. MAJOR ABSORPTION SITE
  • Oral cavity: sublingual route allows drugs to directly enter systemic circulation. Bypassing the liver and escaping first-pass metabolism allows rapid absorption (e.g., glyceryl trinitrate).
  • Buccal route places some hormones and enzyme preparations between the teeth and mucous membrane of the cheek for rapid absorption.
• Rectal: absorption occurs through extensive vascularity; avoids first-pass metabolism to some degree; useful for unconscious, fasting, or vomiting patients but has erratic absorption.
• Parenteral: drug administration by injection.
  • Intravenous (IV): most rapid with immediate pharmacological response; 100% bioavailability. Higher risk of adverse effects when given as a small bolus dose or constant infusion to prevent adverse effects.
  • Subcutaneous (SC): slow absorption rate; use for non-irritating drugs to tissue.
  • Intramuscular (IM): more rapid absorption than subcutaneous due to greater tissue blood flow.
  • Intrathecal: bypasses the blood-brain barrier, rapid CNS effect (e.g., spinal anesthesia, acute CNS infections).
  • Epidural: provides pain relief during childbirth and surgery.
• Inhalation: drug delivery via the lungs, bypasses first-pass extraction by the liver, large surface area with a rich capillary network
• Topical: applied to skin or mucous membranes, bypasses first-pass metabolism, generally rapid absorption; skin aided by capillaries in the dermis.
  • Topical drugs need to be lipid-soluble for systemic effects.

Distribution

• The reversible transfer of a drug between locations in the body, e.g., from the bloodstream.
• Unionized/lipid-soluble drugs are distributed more readily.

Plasma Protein Binding

• Proportion of free drug molecules bind to proteins and lipoproteins in the bloodstream to form drug-protein complexes
• Only the free/unbound drug exerts a pharmacological effect.
• Drug-protein complexes are too large to diffuse through blood vessel membranes and exert effect.
• Decreased protein binding increases free drug concentration and limits tissue distribution.
• Clinical Example: Warfarin, a highly protein-bound drug, has only 1% of the drug available for distribution at any given time which means that 99% of the drug will be bound to plasma proteins.
  • Hypoalbuminemia (low albumin levels): caused by hepatic dysfunction, liver dysfunction and limited synthesis of plasma proteins. Results in increased free drug available for distribution to tissue sites and may result in toxicity, thus a dose reduction is needed.

Tissue Binding

• Adipose tissue: lipid-soluble drugs have a high affinity for adipose tissue, where they can accumulate = a reservoir for certain drugs = prolonged half-life
• Clinical Example- lipid-soluble barbiturate anesthetic thiopentone is initially rapidly distributed to brain = continued administration leads to accumulation in adipose tissue = delayed wake up =used only during an induction.
• The Blood-Brain Barrier (BBB) consist of a tight junction that restrict the passage of water-soluble drugs but allows lipid soluble drugs to pass and penertate the brain and CSF more readily.
• Clinical example: Meningitis causes the BBB to become leaky due to the inflammatory process, which allows drugs like penicillin to enter the CSF and treat the infection.

Metabolism

• Chemical modification of a drug, mainly by enzymes.
• The liver is the primary site of drug metabolism.
• Decreased lipid solubility and increased water solubility enhance urinary excretion
• Prodrugs require activation in the liver to elicit a therapeutic action (e.g., antirheumatic - leflunomide, analgesic - codeine, antiplatelet - clopidogrel).

Inter-individual variability in drug metabolism

• Drug interactions: drug-drug, herb-drug, and food-drug interactions can result from induction or inhibition of enzyme activity.
  • Reactions result from either INDUCTION or INHIBITION of enzyme activity
  • Two drugs compete for metabolism by same enzyme = Decreased metabolism of one or both of drugs = decreased rate of elimination. = Increased plasma concentration = risk of toxicity
  • Example: Inhibition of warfarin metabolism by amiodarone = increased risk of bleeding. Inhibition of azathioprine metabolism by allopurinol = increase risk of severe bone marrow toxicity and death. Inhibition of ciclosporin by erythromycin = increased risk of nephrotoxicity. Inhibition of Diazepam by Cimetidine = Prolonged CNS depression.
• Disease states:
  • Cardiac failure causes decreased liver perfusion or oxygenation = reduced activity of drug-metabolizing enzymes.
  • Liver disease, such as severe cirrhosis or viral hepatitis, influences drug metabolism, decreasing the clearance of metabolized drugs.

Excretion

• Loss of the parent molecule or metabolite in urine or bile.
• The kidneys are the main organs of excretion.
• Lipid-soluble drugs are reabsorbed into the tubular fluid back into systemic circulation, while water-soluble drugs are not reabsorbed and excreted into the urine.
• The first step is the drug reaches hepatocyte in liver Once in hepatocyte, drug becomes available for metabolism by enzymes for excretion into bile Metabolites formed within hepatocyte Diffuse, Be transported across back into blood for excretion in urine or Be transported into bile, passed to duodenum, excreted in faeces
• Lipid Soluble= reabsorbed into tubular fluid back into systemic circulation. Water soluble drugs are not reabsorbed and excreted into urine. Reabsorption depends on whether the drug is lipid or water soluble

Renal Excretion

• Influenced by glomerular filtration rate, tubular secretion (transfer of drugs and metabolites from blood to urine), and reabsorption.

Pulmonary excretion

• Gases and volatile drugs are inhaled and excreted via the lungs
• Depends on RR.

Excretion in sweat and saliva

• Only a minor proportion, unimportant clinically, but can still be an occupational hazard for HCP.

Half-Life

• The time taken for blood or plasma drug concentration to fall by 50%.
• Major determinant of time to reach steady state with chronic dosing and dosing frequency avoids fluctuations in plasma drug concentration during dosing.
• It takes 3-5 half-lives for the plasma drug concentration to reach a desired steady state.
• Determinants of half-life: volume of distribution and clearance.
  • Small volume of distribution = shorter half life, Higher clearance = shorter half life.
  • For Example: liver/kidney disease = impaired clearance = longer half life

Pharmacodynamics

• The study of the interaction between a drug and its molecular target.
• The pharmacological effect depends on the nature of the interaction with the target, the affinity of the drug for the target, and the concentration of the drug at the site of action.

Drug-Target Interactions

• Agonists and antagonists are drugs that bind to receptors.
• Receptor agonists bind and activate receptors, producing the same response as endogenous ligands (e.g., hormones, neurotransmitters, catecholamines).
• Receptor antagonists bind to receptors with high affinity but without eliciting a response. They prevent the binding of agonists and block activation (e.g., naloxone for opioid overdose).

Respiratory System

Obstructive Airway Diseases

• Characterized by airflow obstruction or limitation that causes difficulty during expiration.
• Asthma: reversible.
• COPD: irreversible.
• Common manifestations include dyspnea and increased work of breathing, decreased FEV1 and decreased FEV1/FVC ratio.

Asthma

• Evaluation and treatment involve spirometry, which measures lung function, including FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), and FEV1/FVC ratio.
• Asthma is a hypersensitivity reaction leading to inflammation.
• Requires triggers such as airway inflammation, mucus production/muscle tightening/swollen bronchial membranes = narrow breathing passages = wheezing/cough/shortness of breath.

Pathophysiology of asthma

• Airway inflammation (oedema)
• Airway hyper-responsiveness (bronchial smooth muscle spasm, thickening of airway walls)
• Mucus hypersecretion (thick, impaired mucociliary function)
• Episodic and reversible physiological changes
• Long term = remodeling of airway structures: thickening of basement membrane airway smooth muscle hypertrophy, mucous gland hypertrophy

Clinical Manifestations

• Bronchoconstriction, expiratory wheezing, dyspnea, cough, prolonged expiration, tachycardia, tachypnea.
• Well-controlled asthma has pulmonary function tests within limits, but if not, there is a risk of acute exacerbations from exposure to triggers (allergens, infections, smoke).
• Acute asthma episodes = life threatening.
• Manage through maintain patent airway/Administer oxygen/Rapid acting bronchodilators/Systemic steroids for moderate/severe attacks = decrease inflammatory response in lungs.
• Arterial blood gas abnormalities include hypoxemia, hypocapnia (low CO2), and respiratory alkalosis (pH above 7.45).

Pulmonary circulation

• May be altered by increased intra-alveolar pressure (caused by hyperinflation) = decreased perfusion of alveolar caps (increase alveolar volume = compressed pulmonary capillary). Regional hypoxic vasoconstriction (intrapulmonary arteries constrict in response to alveolar hypoxia, divert better oxygenated lung segments, optimize systemic o2 delivery.

Respiratory Failure:

• Late stage progression: Acute CO2 retention from air trap (hypercapnia) + hypoxemia . Respiratory acidosis (decreased pH).
• Impending respiratory/cardiac arrest = LIFE THREATENING

Management Goal

• Long Term: maintain asthma control and lung function through education, trigger avoidance, and pharmacotherapy (inhaled corticosteroids, bronchodilators = SABA LABA, anticholinergic BD’s). Reducing inflammation = most important
• Short Term: Prevent morbidity and mortality. Category function examples
  • Reliever: relax smooth muscle rapid bronchodilation actue releif : salbutamol ipratopium
  • Symptom controllers: long acting bronchodilator decreases symptoms daily not for raid: salmeterol tioptropium
  • preventers: daily treat and control fluticasone beclomethasone
  • combined: combo contain symptom and preventer enable signle administration: fluticasone and sameterol.

COPD

• Preventable and progressive chronic disease characterized by IRREVERSIBLE obstruction of airways due to immunological processes leading to inflammation and lung damage.
• Main cause is exposure to NOXIOUS particles or GASESS such as cigarette smoke and air pollution.
• Mechanism of disease via air trapping in inspiration and difficulty exhaling.
• Exacerbations in COPD lead to progressive decline in lung function. accelerating the decline, reducing the quality of life faster.
  • Emphysema losses the ELASIC recoil causing a difficult expiration and trapping air = stimulating inflammation from irritants which causes Alveolar destruction: increased breathing workload, hypoventilation, and hypercapnia.
  • Bronchiectasis is a chronic inflammation of airways that cause abnormal permanent dilation or distortion which causes progressive destruction of bronchial walls and lung tissue

management GOALS

• reduce symptoms and reduce risk of exacerbation.
• Inerventions include life sycle changes = Stop smoking, Influena vac, O2 therapy, pum rehab.
• Pharmaco therapy= SABA Inhale glucs Oxygen long term pum rehab.

Restrictive Airway Diseases = Infections of the pulmonary system

Infections of the Pulmonary System

• Infections mostly involve the upper airways (common cold, sore throat, laryngitis).
• Infections of the lower respiratory tract are frequent in immunocompromised patients and cause serious alterations to the pulmonary system.
• Pneumonia: Group of infections of pulmonary parenchyma caused by various organisms (bacteria, virus, fungi, parasites)
• Tuberculosis: Infection caused by Mycobacterium Tuberculosis (affects lungs, sometimes other body systems)
• Influenza: Common respiratory viral infection june-sept. Higher risk groups: Elderly Adults/children >6mo with chronic pulm/circ disorders Nursing home/longtermcare residents.

Clinical MANIFESTATIONS

• Dyspnea
• Fever
• Chlls
• Malaise
• Productive or dry cough, hemoptysis, pleural pain
• Symptoms or signs of systemic disease and sepsis

Management

• Bacterial: antibiotics. Viral: supportive therapy, antivirals for severe cases. Polymicrobial: multiple drugs, antifungals; Other: hydration, pulmonary hygiene.

Pediatrics and pulmonary disorders

• Croup and pertussis are the 2 main diseases in paediatrics.

Cause

• Croup: Virus bacteria atypical agents
  • Pertusiss: bacterium bordatella pertussis

Pathophysiology

• Croup: Airways obstruction in trachea from mucosal oedema and secretions related to viral infection, Subglottic mucous membrane more loosely attached/vascular in children, Airways more susceptible to compromise
  • Pertussis thick secretions chronic cough.

Manifestations

• Croup: Rhinorrhea, sore throat, low grade fever, seal-like barking cough -Purtussis coughing fits whoop sound.

Management:

• Croup; resolve 24 to 48, inspiratory stridor resp distress = hospitalization
• Pertussis vacines lethal for new borns and under 2 dosage.

Conditions caused by pulmonary alterations Pulmonary edema

Excess water in lungs water free bc lymphatic drainage capillary surfactant lining repels water stops enter

Management

• Compresseion and aborption prevention and treatment frequent postion early ambulation

Pheumothorax

Presence of Air Gas ruptures in visceral and walls Causes ruptures.

Comprizes pressure equal disrupt elastic recoil forces.

AUTONOMIC and NEURO-MUSCULAR pharmacology Sympathomimetic Medications.

Action

• Beta2-adrenergic receptors smooth muscles stimulant -Short acting= saba rapid relief= saalbitamol -Long acting= Laba controls symptoms=salmeterol
  • non selective adrenergic agents= ephedrine are hazardous to cdop annd heart conditions Anticholinergic agents Control bronchial muscles= bronchodilation

Cardiovascular System Disorders

Aneurysm

• Localized dilation or outpouching of vessel wall usually as a result of atherosclerosis or hypertension.
• Treatment Smoke BP stop the dialtin with surgical.

Thrombous and embolism

Forms on wall vessel or hear cells stick to= gether Path physiology intra vascular flow risks. Diagnosis docter ultrasonic graphy Angiography Ant coagulance antithimbs and thrombo.

Arteriosclorois and Atherosis

Arteriosclerosis= Chronic disease abnormal hardening. Atherosis= plaquebuild up inside inflammation plays LDL levels smoking DM.

Peripheral Vascular Disorder

Perfuse limbs severe lack pain. Thromboli prevent treatment. ##Phomaciology. Anticoagulants- prevents no form. Antiplelaets anti arthousis suppress enzymes for platets. Thymboytic convert plassminogwn to plasmin.

hypertension

consistent elevation above 140/90. Primary= essential no causes secondary = underlying disese causes kidney and hormone.

Primary factors

• sympathetic system= increase HR
• Natriuretic peptides.
• renonin aldosterone. Lifestyle. Phamocy drugs Vasodilaters and diuretic. Beta Adrenoreceptors block. Calcium channel slow and lower HR. Renin Block. ACE INHIBITORS AND ANGINOTENSIO RECEPTOR are given to patient as an alternative treatment. Loop Thiazide potassium. Electrocardiogram(EKG)= is a P qrs is a measure that uses electro to asses cardiac. Arrhythmias: Are various severity that intervere causes hard failure and deAth. Common: atrual deadly ventricle fibrillation. Electrical impules not conducted to vent causes hypomkemia.

Myocardial Infaction

Ishemia result in O2 causes tissue infract and no functioning. Evaluation by ECG biomarkers and enzyme. Pain like anginas and severe vomiting is a key sign. Treatment by asprin+ clopidgreol gtm fentanyl OXYGEN Structural function Abnormal failure decrease contantions

Heart Failure

In adequate perfusion and systolic diastolic is an inadequate contraction. Contractility= Contraction force heart volume and stroke ejection and pre load. Increased load causes renal failure reduces urine output. Echo test is needed Decreased C decrease rejection