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any chemical that affects living processes
pharmacodynamics + pharmacokinetics
(study of drugs and interactions with living organisms)
study of drugs in humans
use of drugs to diagnose, prevent, treat diseases or prevent (induce) preganancy.
Properties of an ideal drug
- effective (FDA regs)
other: reversible, predictable, ease of administration, min. drug interactions, low cost, chemically stable.
provide maximum benefit with minimal harm
Intensity of drug response
the concentration of the drug at the site of the action in the body (receptors)
Determined by: administration, pharmacokinetics, pharmacodynamics, individual variations
Federal Pure Food and Drug Act (1906)
- drug free of unnecessary components
- (safety and efficacy not considered)
Food, Drug and Cosmetic Act (1938)
- tested for safety (not for drugs marketed before 1938)
- due to deaths: sulfonamide solubilized with diethylene glycol (antifreeze)
- FDA evaluates for safety
Kefauver-Harris Amendments (1962)
drugs be proven effective (retroactive 1938)
Controlled Substances Act (1970)
5 schedules of drugs in decreasing order of potential for addiction and abuse
- I-more addicting, no medical use
- II, III, IV, V= medical use but potential abuse
(↓ addiction with higher number)
FDA "fast track" (1992)
- FDA allowed acceleration of approval process
- (cancer and HIV drugs)
Prescription Drug User Fee Act (1992)
- drug manufactures pay fee for product applications
- FDA hire reviewers to assess applications (process applications faster)
FDA guidelines during 1990's
increased requirement to include women and children from minority populations in clinical studies.
Food and Drug Administration Modernization Act (1997)
- -Plan for manufacturer discontinuation of drug (6 months)
- -"off label" promotion
- -renewed PDUFA
- "fast track" for other drugs (not just AIDS and cancer)
Best Pharmaceuticals for Children Act (2002)
- improve use and safety of drugs in children
- 6 months patent extension on drugs already on the market for peds research on safety and efficacy
Pediatric Research Equity Act (2003)
- FDA require research on peds for certain drugs
- improve use and safety of drugs in kids.
FDA Amendments Act (2007)
- Extend FDA authority over surveillance of drugs safety in the post-market phase
- Post marketing studies (Phase IV)
Family Smoking Prevention & Tobacco Control Act (2009)
- FDA regulate cigarettes
- Advertisement restriction
- mandate nicotine content, to non-addictive levels
- Preclinical testing: before tested in humans. Test for toxicity, pharmacokinetics, useful biologic effect.
- Clinical Testing: Phase I: healthy volunteers, drug metabolism, pharmacokinetics, biologic effects.
- Clinical Testing: Phase II: tested in patients, determine therapeutic effect, dose ranges.
- Clinical testing: Phase III: patient safety and effectiveness
- Clinical Testing: Phase IV: post marketing surveillance. use drug general public, new side effects may be discovered.
Types of Drugs by regulatory authority
- Over the counter-FDA
- Behind the counter (nicotine, emergency contraceptives, pseugoephedrine)-FDA
- Nutritional/dietary supplements: DSHEA
Dietary Supplements Health and Education Act (DSHEA)
- ♨no proof of efficacy and safety required.
- ♨The manufacturer of a dietary supplement or dietary ingredient is responsible for ensuring that the product is safe before it is marketed.
- ♨FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market.
☠Federal Register: supplement manufacturers may make "truthful, non-misleading health claims as long as they do not expressly or implicitly suggest an effect on a disease" (helps, supports, promotes)
- ☁ Generic Name: by US adopted names Council
- ☁ Trade: by company
Investigational number, chemical name, generic, abbreviation, trade name
☁usually generic products are equivalent to brand name products: very few exceptions
Therapeutic effect (TE) begins with letter "A"- no problems with bioequivalence.
- ☑ what the body does to the drug
- ☑ absorption, distribution, metabolism, excretion.
Passage of drugs across membrane
- phospholipid bilayer (hydrophilic head)
- Passage mechanisms:
- ☁ channels/pores (for small molecules)
- ☁ pumps (requires ATP)
- ☁ direct penetration through membrane (lipid soluble)
- Note: lipid soluble-not charged, water soluble-charged
- Note: polar molecules (uneven distribution of charge) dissolve into polar solvents (water) but not in lipid
Ions and membrane transport
- ☃ Ions (net electrical charge + or -)
- ☃ Quaternary ammonium compounds: too polar, not lipid soluble pass through membrane poorly
- ☃ pH-dependent ionization: acid (proton donor) or base (proton acceptor); when proton given up or taken=ionized
- electrical charge
- ionized=charged=polar=not lipid soluble=pass through membrane poorly
Ion Trapping (pH partitioning)
Cell membrane separate to acidic and basic, drugs accumulate in higher concentration on the side in which they are MORE ionized.
Factors affecting drug absorption
- rate of dissolution
- surface area
- blood flow
- lipid solubility
- pH partitioning
Routes of drug administration
- Enteral: via gastrointestinal (epithelial cells, p-glycoprotein, enterohepatic)
- Parenteral: all other (injection, IV, SubQ)
drugs carrier in blood bound to carrier protein.
- Bound: stay in vascular space
- unbound: pharmacologically active, pass membrane more readily.
Cytochrome P450 enzyme
- Found in several organs.-most importantly GI tract and liver.
- Metabolize endogenous substances, and xenobiotics.
Cytochrome 450 =CYP3A4=drug metabolism
St. Johns Wort-CYP3A4 inducer
First Pass Effect
- rapid hepatic inactivation of certain oral drugs.
- lose large percent of drug before get to system circulation.
- By pass first pass effect administer drug parentally.
- Therapeutic consequences:
- accelerated drug excretion
- drug inactivation
- changed therapeutic action
- activation of produgs
- toxicity variations
☃ NOTE: increased effectiveness of drug: codeine to morphine (more effective)
considerations: age, enzymes, nutritional status (protein, acid-base balance, competition between drugs)
- Remove drug from body
- kidney: glomerular filtration, passive tubular reabsorption, active tubular secretion (urine)
- Other: GI (biliary tract-stool, into gut lumen), lungs, breast milk, sweat
Drug Excretion: Glomerular Filtration
- filtration moves drugs from blood to urine
- protein-bound drugs are not filtered
Drug Excretion: Passive Reabsorption
- Lipid-soluble drugs move back into the blood
- Polar and ionized drugs remain in the urine.
Drug Excretion: Active Transport/Secretion
Tubular "pumps" for organic acids and bases move drugs from blood to urine.
Minimum effective concentration (MEC)
least amount of drug that will give effect
- between MEC and toxic concentration
- enough drug to produce therapeutic response but not to toxicity.
Drug Half Life
- the time for the amount of drug in the body to decrease by 50%
- Maintenance give dosage at every half life, plateu
- more than maintenance
- given initially to create a therapeutic effect, then use maintenance
- Biochemical and physiologic effects of a drug and the molecular mechanism by which they are produced.
- what the drug does to the body.
- intensity of response of a drug at different/various dosages
- Determines max effective dose
- Largest effect that a drug can produces
- Height of dose response curve
- most benefit a drug can produce.
- amount of drug that is needed to a elicit a specific response.
- consider side effects.
Activate receptor (off → on), mimic normal physiological response (increase or decrease response)
- inactivate receptor that is usually always in active state.
- i.e. histamine receptor, so use antihistamine.
- Prevent activation, block receptor
- block normal physiological response
- need agonist present (otherwise no normal response)
- Noncompetitive Antagonist: reduce maximal response/efficacy
- Competitive Antagonist: compete with normal physiological transmitter or other agonist. ↓ potency
- Agonist and antagonist effect
- lower maximal efficacy
- may act as antagonist if receptor is already occupied by full agonist (equal or high affinity)
- continuous, long term, exposure of a drug/transmitter to receptor can change number of receptors and/or sensitivity to exposure.
- agonist: desensitization, ↓ regulation=tolerance
- antagonist: hypersensitivity, ↑ regulation
ED50 Effective Dose
- average effective dose
- define therapeutic response.
- will elicit the expected response in 50% of patients given the drug
- LD50/ED50Safety factor
- higher therapeutic index=safer drug
- interactions with another substance
- Beneficial, detrimental, neutral
- Potentiative: increase therapeutic effect or increase side effects
- Inhibitory: decrease therapeutic effects, decrease side effects
- Unique response: Disulfiram + alcohol.
Drug-Drug Interactions: Mechanisms
- Direct chemical/physical interactions: IV solution (in vitro). If precipitate appears when mixed=discard. In vivo: interactions less likely because mixed with water.
- Pharmacokinetcs interactions (ADME): altered GI absorption (binding, pH, GI transit time, blood flow for injections) Absorption, distribution, metabolism, excretion
- Pharmacodynamics: interactions at same receptor, or different sites
- Toxicity: additive or synergistic (2 sedatives, liver toxicity, loss of potassium)
Drug-Drug Interactions: Pharmacokinetics: Absorption
- Altered GI tract absorption: physical/chemical binding/absorption, influence of pH, GI transit time (laxatives decrease time-increase speed), meds for diarrhea decrease peristalsis
- altered absorption of injection: deceased regional blood flow.
Drug-Drug Interactions: Chemical/Physical Interactions
- Direct chemical/physical interactions: IV solution (in vitro).
- If precipitate appears when mixed=discard.
- In vivo: interactions less likely because mixed with water
Drug-Drug Interactions: Pharmacokinetics: Distribution
- Competition for protein binding
- Alteration of extracellular pH
Drug-Drug Interactions: Pharmacokinetics: Metabolism
- Involves CYP 450
- Drugs are substrates for CYP450=metabolize
- Drugs induce CPY450=increase activity
- Drugs inhibit CPY450=decrease activity
Grapefruit juice inhibits CYP3A4= inhibit metabolism.
Drug-Drug Interactions: Pharmacokinetics: Excretion
- Glomerular Filtration: decrease renal blood flow (decreased cardiac output)= decrease filtration
- Reabsorption: can be decreased by pH (aspirin)
- Tubular Secretion: affected by drug competition (penicillins)
Drug-Drug Interactions: Pharmacodynamics
- Interacting at same receptor: inhibitory (narcan for morphine)
- Interacting at different sites: potentiating, inhibitory, or neutral: 2 drugs with sedative properties, etc.
Drug-Drug Interactions: Toxicity
- additive or synergistic
- Examples: two sedative drugs, two drugs with kidney toxicity (aminoglycoside antibiotic+vanomycin), two drugs with liver toxicity (TB drugs: INH+PZA), two or more drugs that cause potassium (corticosteroids+thiazide diuretics).
Drug-Drug Interactions: foods
- Alters rate of absorption (Calcium binding TCN= fats increase absorption SQV)
- Impact of drug metabolism: Grapefruit juice (inhibit CYP3A4).
- Impact of Food on drug toxicity/action (vitamin K and warfarin.
- Timing of drug administration: before/after/with
Adverse Drug Reactions
A noxious, unintended, and undesired effect that occurs at normal drug dosages
Identification: may not be obvious, other drugs, diseases etc may be causing ADR. Time relationship with drug
Prevention: know ADR of every drug, know patient (diseases, organ dysfunction, allergy, intolerance), educate patient
- secondary effect of a drug produced at therapeutic dose, unavoidable
- predictable, known, intensity is dose dependent
- ADR due to excessive dose
- Severe ADR (overdose not required)
- Immunologic Reaction: antibody (from body) exposed to antigen=immunologic response
- prior exposure required
- reaction independent of dosage.
- Uncommon drug response from a genetic predisposition
- Enzyme for codeine to morphine
- G6PD risk for hemolytic reaction to drugs
- disease produced by physician, or caused by treatment/therapy
- example: antipsychotic and disease similar to PD disease
- Expected consequence of long term use of some drugs
- Withdrawal signs and symptoms
- Opioids, alcohol, amphetamines
- Does not indicate addiction, dose not predict abuse
- Present when increasing dosage required to elicit same response (created by lower dose previously)-need to increase dose administered
- decreased response to a drug due to a repeated administration
- For both analgesia and side effects
- Three types:
- Parhmacodynamics: repeated dosage increases MEC
- Metabolic (pharmacokinetic): stimulate enzyme, accelerated drug metabolism-1/2 shorter (no change in MEC)
- Tachyphylaxis: decrease responsiveness with repeated dosing over short time
- NOT addiction
- Constellation of maladaptive behaviors
- loss of control of use of opioids, preoccupation with use despite adequate pain relief, continuation despite adverse effects
- Abuse is use other that that intended,
- despite harm.
- perception on part of caretakers of apparent "drug-seeking behavior
- Real problem: inadequate pain relief.
- Pain relief causes drug-seeking behavior to stop.
Cancer producing (chemicals, environment, pollutants, drugs-even chemo)
- Cause birth defect
- Drugs act at specific time frame during development in utero
- Avoidance: simply medication use, avoid unnecessary and new drugs, extreme care with women in reproductive age
- Consider drug categories.
- Many drugs cause ADRs in specific
- Liver: hepatotoxicity (common)
- Kidney: nephrotoxicity (common)
- Other: cardiac, bone marrow, skin, nervous system
Types: wrong pt, drug, route, time, dose, etc. Causes: human (performance-most common, knowledge, miscalculation), communication, name confusion, packaging, label.
Individual variation in drug response: contributing factors
- Age- organs deteriorate, funciton
- Body weight, composition
- Drug Interactions
Renal Disease: effect excretion=therapeutic levels are longer (drug levels rise), side effects are longer. Effect on acid base balance as well and protein binding.
Liver Disease: affect metabolic rate decreased (levels rise)
- Component of drug response that can be attributed to psychologic factors, rather than to direct physiologic actions of the drug.
- lacking research
- ability of a drug to reach the systemic circulation from its side of administration.
- important for drugs with small therapeutic range
Drug Therapy during Breast Feeding
- ☑ consider physiological changes:
- ☑ kidney: ↑ renal blood= ↑ excretion
- ☑ liver: ↑ metabolic rate of drugs
- ☑ GI: ↓ tone/motility/rate (↑ transit time) = ↑ absorption (↑ efficacy/side effects)
Most drugs cannot maintain significant concentration in milk to cause effect, but best to take drugs after breast feeding, avoid drugs with long half-life.
Placental Drug Transfer
- almost all drugs pass placenta (or safe to assume they do reach the fetus)
- ↑ for lipid soluble
- ↓ for ionized/polar
Adverse Reactions during Pregnancy
- Teratogenesis: birth defects
- Osteoporosis: long term use of heparin
- Uterine stimulation: prostaglandins
- Uterine suppression: NSAIDS/ASA
- Drug-dependent infant
- Neonatal respiratory suppression (opioids, CNS depressants)
some drugs (thialidomide) cause birth defect with just on dose, other drugs (alcohol) require prolonged exposure.
Stages of Fetal Development
- Preimplantation/presomite: conception to 2 wks. all or none (abortion-fetal loss)
- Embryonic Period: wk 3-8: major malformation of organs and limbs
- Fetal Period: organs already formed so get behavioral/developmental problems.
FDA pregnancy Risk Categories
- A=safe, B, C, D (↓'ing safety)
- X=known tetratogen
Drug Therapy in Peds: overview
- Organ system immaturity, body composition-more sensitive.
- More intense and prolonged responses
- IM absorption in neonates is lower than adults, Absorption in infants is more
- Protein-biding capacity is limited in early life
- Blood-Brain barrier not fully developed, more sensitive
Drug Therapy Peds: absoprtion
- GI tract: slow, irregular transit, decreased gastric acid secretion=increased absorption.
- IM: irregular blood flow-neonates slow absorption time; infant-faster IM absorption
- Cutaneous: more rapid and complete for infants (thinner skin)
Drug Therapy Peds: Distribution
- Protein Binding: lower levels of albumin=higher concentration of drug. consider nutrition, liver function. Compete with endogenous substances.
- Blood-Brain Barrier: incomplete development, drugs have easier access=more sensitive
Drug Therapy Peds: Metabolism
Enzyme system (mostly from liver) poorly developed at birth, then increase by one month, normal by 1 year.
Drug Therapy Peds: Excretion
- Excretion is low during infancy, give reduced dosage and/or at longer dosing intervals.
- at 1 year -normal adult function.
Drug Compliance in the Elderly
- Altered phamacokinetics (more sensitive, organ system deterioration of organs
- Multiple Illnesses
- Multiple drug therapy
- Poor Compliance
Geriatric Therapy: Altered pharmacokinetics: Absorption
- GI: decreased acid secretions, decreased surface area, decrease blood flow, decreased motility/peristalsis
- Skin: thin skin=increased absorption
- IM & SC: decreased blood flow=reduced absorption and rate
Geriatric Therapy: Altered pharmacokinetics: Distribution
all changes = increased sensitivity
- Affected by:
- ☑ ↑ % body fat = storage for lipid soluble drugs)
- ☑ ↓ Lead body mass = ↓ dose
- ☑ ↓ total body water = water soluble drugs become distributed in smaller volume = ↑ effects
- ☑ ↓ concentration of albumin = ↑ amount of free, active drug
- ☑ ↓ cardiac output
Geriatric Therapy: Altered pharmacokinetics: Metabolism
- ↓ hepatic blood flow/mass
- ↓ activity/amount of metabolizing enzymes
- ↑ Half life of metabolism
Geriatric Renal Drug Excretion
- -↓ Renal function = drug accumulation = adverse effects
- -Creatinine Clearance for renal function test
-↓ Liver function may prolong drug effects
Adverse Reactions in Elderly
- More common
- why? , sever illness, multiple pathologies, tx with dangerous drugs.
- Monitor: drug hx, start low dose, plasma monitor, fewest drugs/#dose
- Promote compliance: simple drug regimen, verbal/written instruction, appropriate form, label, reminders, support system, monitor
- Medications considered more likely to cause ADR;s in elderly patients
- STOPP (screening tool of older person's Rx)
- START (screening tool to alert doctors to right tx)
study of drugs that alter processes controlled by the nervous system
Mechanism of neuropharmacology agents
- -Axonal conduction: Action potential down axon
- -Synaptic Transmission: carry info across neuron gap to nerve cell or an effector organ.
-Synaptic transmission is site of action (on receptors)-alter=selectivity.
Few act on axonal conduction (lose selectivity) (local anesthetics are not selective)
Synaptic Transmission: Steps and possible drug effect
NOTE: termination: reuptake of transmitter (restored), enzymatic breakdown of transmitter, diffusion of transmitter away from synaptic space.
- Purpose: create neurotransmitter to get electrical charge/rx
- Transmitter synthesis (↑ or ↓) either activate or shut down receptor depending on drug.
- Transmitter storage (only ↓= ↓ in action)
- Transmitter release (↑ or ↓)
- Transmitter binding (agonist/antagonist ø receptor activity)
- Termination of transmission (block reuptake/prevent degradation)
Selectivity is good - get desired response.
Parasympathetic Nervous System
- rest and digest
- ↓ HR
- ↑ Gastric secretions, bladder/bowel stimulate smooth muscle = empty
- Vision = miosis (constrict of pupil)
- Bronchial smooth muscle - contraction
Sympathetic Nervous System
- Fight or fligh
- ↑ HR/BP/distribution of flood to skeletal muscles
- Bronchial smooth muscle dilation to ↑ O2Vision = mydriasis (dilation)
- Glycogenolysis and gluconeogenesis (breakdown glycogen and make glucose)
Transmitters of PNS
- Dopamine (kidney-urine production and BP)
Receptors of the peripheral nervous system
- Cholinergic: Mediated by Ach
- Adrenergic: mediated by norepinephrine (mostly) some epinephrine
Cholinergic receptor: Nicotinic c (neuronal)
- promotes ganglionic transmission
- promotes release of epinephrine (from adrenal medulla)
Cholinergic receptor: Nicotinic m (muscle)
contraction of muscle
Cholinergic receptor: Muscarinic
activates organs- parasympathetic
functions: contract ciliary muscles (accommodate for near vision), miosis, ↓ HR, bronchi ↑ secretions and contract, GI ↑ secretions, sex organs erection, empty urinary bladder, sweating ↑
Adrenergic receptor: Alpha1
- Radial muscle contraction= mydriasis (dilation of pupil)
- vascular smooth muscle contraction = ↑ BP
- contract bladder neck and prostate
Adrenergic receptor: Alpha2
located in presynaptic junction
Adrenergic receptor: Beta1
- Heart: ↑ HR, force of contraction, velocity of conduction in AV node
- Kidney: renin release (maintain BP and fluid balance)
Adrenergic receptor: Beta2
- Bronchial dilation
- relaxation of uterine muscle
- glycogenolysis and gluconeogenesis
Adrenergic receptor: dopamine
Dilates renal blood vessels: ↑ renal production