review of basic pharmacology. describe the different branches of pharmacology discuss the...
DESCRIPTION
Is the science that deals with the mechanism of action, uses, adverse effects, and fate of drugs in animals and humans It provides the basis for the understanding of body function and the subsequent treatment of diseaseTRANSCRIPT
Dennis S. Flores, MD
REVIEW OF BASIC PHARMACOLOGY
OBJECTIVES
Describe the different branches of pharmacology
Discuss the important concepts and mechanisms of Pharmacodynamics Pharmacokinetics
Exercise on pediatric drug dosing
PHARMACOLOGY
Is the science that deals with the mechanism of action, uses, adverse effects, and fate of drugs in animals and humans
It provides the basis for the understanding of body function and the subsequent treatment of disease
BRANCHES OF PHARMACOLOGY PHARMACODYNAMICS
The study of what the drug does to the body
PHARMACOKINETICS The study of what the body does to the
drug Absorption, Distribution, Metabolism,
Excretion PHARMACOTHERAPEUTICS
The study of drugs in the treatment and prevention of disease
Pharmacodynamics + Pharmacokinetics
BRANCHES OF PHARMACOLOGY CLINICAL PHARMACOLOGY
The study of the clinical pharmacological evaluation of drugs in human use
Concepts and principles underlying approach to rational therapeutics
PHARMACOGENETICS The study of genetic variation in
response to drug efffects
BRANCHES OF PHARMACOLOGY PHARMACOVIGILANCE
All scientific and data gathering activities that relate to detection, assessment, understanding, and prevention of adverse events
PHARMACOECONOMICS The study of economic use and management of
disease Cost effectivity of drugs
TOXICOLOGY The study of adverse effects of drugs
PHARMACODYNAMICS
The action of a drug on the body Includes receptor interactions, dose-
response phenomena, and mechanisms of therapeutic and toxic action
PHARMACODYNAMICS
A drug will exert its activity through interactions at one or more molecular targets The macromolecular species that control
the functions of cells May be surface-bound proteins like
receptors and ion channels Species internal to cells, such as
enzymes or nucleic acids
PHARMACODYNAMICS
Other sites of drug binding: Proteins (in patient or microbes) Genome (cyclophosphamide) Microtubules (vincristine)
PHARMACODYNAMICSMECHANISMS AND SPECIFICITY OF DRUG BINDING
Majority occurs through non-covalent interactions
These govern The folding of proteins and DNA The association of membranes Molecular recognition ▪ Interaction between an enzyme and its
substrate or the binding of an antibody
PHARMACODYNAMICSMECHANISMS AND SPECIFICITY OF DRUG BINDING
They are generally weak and operate only over short distances
So for an effect to occur, you need: Large numbers of interactions for
stability High degree of complementarity
PHARMACODYNAMICSEFFECTS OF BINDING
CONFORMATION EFFECTS Binding also locks a mobile, flexible molecule into a
restricted conformation CONFIGURATION EFFECTS
Differences in configuration (e.g. stereochemistry) can lead to startling differences in the biological effect
E.g. the L-enantiomer of penicillamine is highly toxic and only the S-enantiomer of indomethacin acts as an anti-inflammatory agent
Wrong configuration either no reaction or a toxic effect
PHARMACODYNAMICSNON-RECEPTOR MEDIATED INTERACTIONS
Acid base reaction Outcome does not need a receptor, just a simple
acid-base equilibrium Ex. antacid
Counterfeit incorporation mechanism A form of poisoning Utilized in cancer chemotherapy Mechanism: feed the patient/cell with false
nucleotides to cheat the cancer cells Colligative mechanism
This elicits effect by means of numbers Ex. Acetylcysteine, Mannitol
PHARMACODYNAMICSDRUG RECEPTOR
A macromolecular component of a cell with which a drug interacts to produce a response
Usually a protein which requires translation to have an effect
AGONISTA drug that triggers the same events in the receptor as the native ligandANTAGONISTA drug that stops the binding of the native agent without eliciting a response
PHARMACODYNAMICSRECEPTOR TYPES
TYPE 1: ionotropic receptors (ligand-gated channels)
TYPE 2: metabotropic receptors (G-protein coupled)
TYPE 3: tyrosine kinase-linked receptors Ex. Insulin and growth factor receptors
TYPE 4: steroid receptors
PHARMACODYNAMICSENZYMES
Proteins that catalyze the reactions required for cellular function
Control a number of metabolic processes
PHARMACODYNAMICSENZYMES
INHIBITORS Molecules that restrict the action of enzyme on
its substrate REVERSIBLE (competitive or non-competitive)▪ A very common mode of action of many drugs▪ E.g. in the patient (ACE inhibitors)in microbes (sulfas, penicillins)in cancer cells (5-FU, 6-MP)
IRREVERSIBLE▪ Enzyme inhibitors might be seen to allow very fine
control of cellular processes ▪ E.g. 6-methylpurines death of CA cells
PHARMACODYNAMICSNUCLEIC ACIDS
Potentially the most exciting and valuable of the available drug targets
May be used in gene therapy BUT designing compounds that can
distinguish target nucleic acid sequences is not yet achievable
PHARMACODYNAMICSNUCLEIC ACIDS
ACTION: generally inhibit the processes of DNA manipulation required for protein synthesis and cell division
Suitable as drugs for applications where cell death is the goal of therapy – such as treatment of cancer
PHARMACODYNAMICSDRUG-RECEPTOR INTERACTION
DOSE-RESPONSE RELATIONSHIP Most important concept in
pharmacodynamics “Dose of a drug translates to an
effective response”
PHARMACODYNAMICSDRUG-RECEPTOR
CONCEPT OF A RECEPTOR For most drugs, the site of action is at a
specific macromolecule, termed as RECEPTOR Not all drug actions and effects are mediated
through receptors. An average of 10% of them is not
For most drugs, the magnitude of pharmacological response increases as the drug concentration (dose) increases at the site
PHARMACODYNAMICSTHEORY AND ASSUMPTIONS OF DRUG-RECEPTOR INTERACTIONS
Combination or binding of drug to receptor leads to response
Response to a drug is graded or dose-dependent
Drug-receptor interaction follows simple mass-action relationships. Only one drug molecule occupies each receptor site and binding is reversible
PHARMACODYNAMICSTHEORY AND ASSUMPTIONS OF DRUG-RECEPTOR INTERACTIONS
For a given drug, the magnitude of response is directly proportional to the number of receptor sites occupied by drug molecules (occupancy assumption)
The number of drug molecules is assumed to be much greater than the number of receptor sites
PHARMACODYNAMICSSIGNIFICANCE OF KD (DISSOCIATION CONSTANT)
Represents the drug concentration at which half maximal binding occurs
The smaller the KD, the greater the affinity the drug has for the receptor
The smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding
PHARMACODYNAMICSOTHER TERMS
SAFETY No drug is 100% safe
QUALITY Tests bioavailability How much of the drug will enter the
system VARIABILITY
Changes from patient to patient, drug to drug, and time to time
LOG DOSE RESPONSE CURVE
EFFICACY Maximal ceiling effect Drug effect irrespective of the dose
POTENCY Does not refer to the strength of the drug Drug effect with respect to the dose Location of the drug response curve along the
horizontal axis The nearer the dose to the y axis, the greater
the potency The farther the dose, the lesser potency
Log dose response curve
Log dose response curvecomparison of drugs
PHARMACODYNAMICSAGONISTS
AGONIST DURGS Drugs that interact with and activate
receptors Possess both affinity and efficacy
2 TYPES FULL – an agonist with maximal efficacy PARTIAL – an agonist with less than
maximal efficacy
PHARMACODYNAMICSAGONISTS
PARTIAL AGONISTS A partial agonist is one that produces
less of a response when all receptors are occupied than does a full agonist
Can compete with and can displace a full agonist for binding sites the maximal effect of the full agonist will be less
PHARMACODYNAMICSANTAGONISTS
COMPETITIVE
Reversible Maximal effect of the
agonist drug will not be affected, but larger concentrations of the agonist drug will be required to achieve maximal effect
Dose-effect curve is shifted to the right
NON COMPETITIVE Irreversible Antagonist will prevent the
agonist from producing a maximal effect, at any agonist concentration
Maximal effect of the agonist drug will be decreased, and this cannot be overcome by increasing the concentration of the agonist drug
Dose-effect curve flattened out
PHARMACOKINETICS
Action of the body to the drug COMPONENT PROCESSES ABSORPTION
The transfer of a drug from its site of administration to the blood stream
DISTRIBUTION The process by which drug reversibly
leaves the blood stream and enters the interstitium and/or other tissues
PHARMACOKINETICS
COMPONENT PROCESSES METABOLISM
Process by which drug structure is altered for removal from the body
Liver is the major site of drug metabolism
EXCRETION Usually through feces, urine, or bile
PHARMACOKINETICSABSORPTION
PASSIVE DIFFUSION Aqueous or Lipid diffusion Most common
ACTIVE TRANSPORT Important for some drugs, particularly
larger molecules
PHARMACOKINETICSABSORPTION
AQUEOUS DIFFUSION Within large aqueous compartments (e.g.
interstitial space, cytosol) Driving force: drug concentration
gradient (described by Fick’s Law) …. Molecules will tend to move from a higher concentration to a lower concentration
Plasma protein bound drugs cannot permeate through aqueous pores
PHARMACOKINETICSABSORPTION
LIPID DIFFUSION Most important barrier for drug
permeation due to many lipid barriers separating body compartments
Lipid-soluble drugs readily move across biological membranes
Ionization state of the drug is an important factor: charged drugs diffuse through lipid environments with difficulty
PHARMACOKINETICSABSORPTION
SPECIAL CARRIERS Peptides, amino acids, glucose Active transport, facilitated diffusion Saturable (unlike passive diffusion)
because of limited number of carrier sites
PHARMACOKINETICSABSORPTION
ENDOCYTOSIS/EXOCYTOSIS Entry into cells by very large substances E.g. iron, vit B12
PHARMACOKINETICSABSORPTION
PHYSICAL FACTORS INFLUENCING ABSORPTION Blood flow to the absorption site
Blood flow to intestine > blood flow to stomach Absorption from the intestine is favored
Total surface area available for absorption Intestines: rich in microvilli, surface area about
1000-fold that of the stomach Absorption from the intestine is favored
Contact time at the absorption surface E.g. Diarrhea – drug moves through the GI tract
very quickly, thus it is not well absorbed
PHARMACOKINETICSBIOAVAILABILITY
The fraction of administered drug that reaches the systemic circulation
Example 100 mg of a drug administered orally If 70 mg of this drug is absorbed
unchanged, bioavailability is 70%
PHARMACOKINETICSBIOAVAILABILITY
HOW TO TEST FOR BIOAVAILABILITY Get plasma levels of a drug after a particular
route of administration (e.g. oral administration)
Compare the plasma levels obtained with plasma levels achieved by IV injection
By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC)
AUC – reflects the extent of absorption of the drug
PHARMACOKINETICSBIOAVAILABILITY
FACTORS THAT INFLUENCE BIOAVAILABILITY First pass hepatic metabolism Solubility of the drug
Very hydrophilic drugs cannot cross cell membrane lipid component, thus, may not be well absorbed
Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body fluids, thus, cannot gain access to the surface of cells
FOR GOOD ABSORPTION: The drug must be largely hydrophobic yet have some solubility in aqueous solutions
PHARMACOKINETICSBIOAVAILABILITY
FACTORS THAT INFLUENCE BIOAVAILABILITY
Chemical instability Ex. Penicillin G – unstable in the pH of
gastric contents Nature of the drug formulation
Unrelated to drug chemistry Ex. Enteric coatings
PHARMACOKINETICSABSORPTION
ROUTES OF ADMINISTRATION Enteral
Oral Sublingual
Parenteral IV, IM, SC
PHARMACOKINETICSABSORPTION
ORAL ADMINISTRATION Simplest, most convenient, most economical Disadvantages
Emesis (drug irritation of GI mucosa) Digestive enzymes/gastric acidity destroy the
drug▪ Enteric coating of the drug protects it from the acidic
environment Unreliable or inconsistent absorption due to food
or other drug effects Metabolism of drug by GI flora
PHARMACOKINETICSABSORPTION
ORAL ADMINISTRATION First-Pass Effect
Drugs absorbed from the GI tract passes through the portal venous system LIVER and systemic circulation
IMPORTANCE: Extensive hepatic metabolism/extraction results in minimal drug delivery to the systemic circulation
PHARMACOKINETICSABSORPTION
ORAL ADMINISTRATION First-Pass Effect
Therefore, drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target organ
Example: nitroglcerin▪ NOT given orally because 90% of the drug is
cleared during a single passage through the liver
PHARMACOKINETICSABSORPTION
SUBLINGUAL ADMINISTRATION Allows drug to diffuse into the capillary
network, and, therefore, to enter the systemic circulation directly
ADVANTAGES▪ Rapid absorption▪ Convenience of administration▪ Low incidence of infection▪ Avoidance of harsh GI environment▪ Avoidance of first-pass metabolism
PHARMACOKINETICSABSORPTION
PARENTERAL ADMINISTRATION Intravenous (IV)
Permits rapid effect and maximal degree of control over the circulating levels of the drug
May inadvertently introduce bacteria through contamination at the site of injection
Intramuscular (IM) Requires absorption Drug diffuses out of the muscle precipitates at
the site of infection dissolves slowly, providing a sustained dose over an extended period of time
PHARMACOKINETICSABSORPTION
PARENTERAL ADMINISTRATION Subcutaneous (SC)
Like IM administration, requires absorption
Slower than IV route but minimizes risks associated with intravascular injection
PHARMACOKINETICSABSORPTION
OTHER ROUTES: Inhalation Intranasal Intrathecal/Intraventricular Topical Transdermal Rectal
PHARMACOKINETICSABSORPTION
INHALATION Rapid delivery of a drug across the large
surface area of the mucous membranes of the respiratory tract and pulmonary epithelium, producing an effect as rapid as with IV injection
For patients with respiratory complaints Drug is delivered directly to the site of
action and systemic side effects are minimized
PHARMACOKINETICSABSORPTION
INTRANASAL Directly into the nose Ex. Nasal decongestants, Desmopressin
for DI
PHARMACOKINETICSABSORPTION
TOPICAL Used when a local effect of a drug is
desired Ex. Antifungal creams, cyclopentolate
eye drops (to dilate pupils)
PHARMACOKINETICSABSORPTION
TRANSDERMAL ADMINISTRATION Advantages: Sustained therapeutic plasma levels Avoids continuous infusion technique
difficulties Low side effect incidence (smaller
doses) Good patient compliance Examples of drugs: Fentanyl, Clonidine
PHARMACOKINETICSABSORPTION
RECTAL ADMINISTRATION Rectal mucosal irritation is possible Unpredictable pharmacological responses REASON: Proximal rectum administration
Absorption into superior hemorrhoidal veins then enters the portal venous system then to the liver (possible first pass hepatic effect) and finally into the systemic circulation
Low rectal administration Drug enters systemic circulation without passing
through the liver
PHARMACOKINETICSABSORPTION
AVOIDING FIRST-PASS EFFECT Sublingual Transdermal Suppositories in the lower rectum Inhalation (however, there is first-
pass pulmonary loss)
PHARMACOKINETICSDISTRIBUTION
Is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues
DETERMINANTS: Blood flow Capillary permeability Degree of binding of the drug to plasma and
tissue proteins Relative hydrophobicity of the drug
PHARMACOKINETICSDISTRIBUTION
Volume of distribution (Vd) is the ratio between the amount of drug in the body (dose given) and the concentration of the drug measured in blood or plasma
FACTORS INFLUENCING (Vd) Drug pka Extent of drug-plasma protein binding Lipid solubility Gender, age, disease, body composition
PHARMACOKINETICSDISTRIBUTION
IMPORTANCE OF Vd If Vd is large, most of the drug is in the
extraplasmic space and is unavailable to the excretory organs half life of the drug is increased extended duration of action of the drug
NOTE: an exceptionally large Vd indicates significant sequestration of the drug in some organ or compartment
PHARMACOKINETICSMETABOLISM
BIOTRANSFORMATION REACTIONS more polar, hydrophilic, biologically inactive molecules that are more readily excreted
Comes in 2 phases Principal organ: liver Other organs: lungs, skin, kidney,
and GI tract
PHARMACOKINETICSEXCRETION
Clearance is important for ensuring appropriate long term drug dosing for steady state drug concentration
It is additive: a function of elimination by all participating organs such as liver or kidney
KIDNEYS – most important organs for elimination of unchanged drug/drug metabolites
PHARMACOKINETICSEXCRETION
Water soluble compounds exhibit more efficient renal excretion compared to lipid soluble compounds
FACTORS AFFECTING RENAL CLEARANCE Renal disease Rates of filtration depend on▪ Volume filtered in the glomerulus▪ Unbound drug concentration in plasma (plasma
protein bound drugs are not filtered)
PHARMACOKINETICSEXCRETION
FACTORS AFFECTING RENAL CLEARANCE Drug secretion rates Changes in plasma protein concentration Blood flow Number of functional nephrons
PHARMACOKINETICSEXCRETION
KIDNEY Nearly all drugs filtered at the glomerulus Most drugs in a lipid soluble form will be
reabsorbed by passive diffusion To increase excretion: change the urinary
pH to favor the charged form of the drug Weak acids are excreted faster in alkaline pH Weak bases are excreted faster in acidic pH
PEDIATRIC DRUG DOSING
All drugs administered to the pediatric age group should be meticulously computed
Based on the WEIGHT
PEDIATRIC DRUG DOSING
Example .. A child is brought to the emergency room with high-grade fever for the past 2 days. There were no other accompanying symptoms. An impression of Acute Viral Infection was given.
As in all viral infections, treatment is supportive
An antipyretic was prescribed
PEDIATRIC DRUG DOSING
Paracetamol dose: 10-15 mg/kg/dose Paracetamol stock dose for children:
100 mg/ml drops, 120 mg/5 ml susp, 250 mg/5 ml susp
If the child weighs 10 kg10 kg x 10-15 mg/kg = 100-150 mg using a stock dose of 100 mg/mlyou should prescribe 1-1.5 ml per dose
PEDIATRIC DRUG DOSING
If on history taking, you extracted the information that a drug was given, how do you determine if the dose given was adequate or not?
PEDIATRIC DRUG DOSING
If the child weighs 20 kg, and was given Paracetamol 250 mg/5 ml 3 ml every 4 hours, was the dose given adequate?
250 mg/5 ml 3 ml = 150 mg/dose Normal therapeutic dose (10-15
mg/kg/dose) == child (wt 20 kg) should receive 200-300 mg/dose
Therefore, dose given was inadequate
PEDIATRIC DRUG DOSING
QUIZ
PEDIATRIC DRUG DOSINGEXERCISE
CASE A child weighing 15 kg with
pneumonia1. Give a prescription for Amoxicillin2. Give a prescription for Coamoxyclav3. Give a prescription for Cefuroxime4. Give a prescription for
Clarithromycin5. Give a prescription for Paracetamol
Thank you