Exam 1 Flashcards
Schedule I
- highest potential for abuse
- NO accepted medical use in US or lacks safety for use in tx in US
- eg) heroin, marijuana
Schedule II
- high potential for abuse
- HAS a currently accepted medical use
- abuse may lead to severe psychological or physical dependence
- eg opiates (morphine, oxycodone, methadone), amphetamines (ritalin, adderall), cocaine
Schedule IV
- currently accepted medical use in US
- abuse may lead to limited physical or psychological dependencies relative to III
- benzos
Schedule III
- less abuse potential than I or II
- accepted medical use
- abuse may lead to moderate/low physical dependence or high psychological dependence
Schedule V
- low potential for abuse
- some can be sold in limited amounts without rx
Where to look for Drug Information
lexi-comp, MICROMEDEX, package, URI pharm library
Where do drugs come from (4)?
-plants/natural products, synthetic, semi-synthetic, human pool
Drug Testing Phases (7)
- compound discovery/”bench”
- animal phase
- Human phase I, II, III
- FDA approval with patent
- human phase IV (post-marketing phase)
Human Phase I
- determine effects, safe dosage, pharmacokinetics
- small number (<1 year
Human Phase II
- assess drugs effectiveness in treating a specific disease/disorder
- limited number (200-300) with target disorder
- 2 years
Human phase III
- assess safety and effectiveness in larger pt population
- large number (1000-3000)
- double/single blinding, placebo controls
- 3 years
Human phase IV (post-marketing phase)
- monitor any problems after NDA approval
- general pt population
- indefinite
Pharmacotherapeutics
-area of pharm that refers to use of specific drugs to prevent, treat, or diagnose a disease
Pharmacokinetics
-how body deals with drugs in terms of absorption, distribution, metabolism, excretion
Pharmacodynamics
- what the drug does to the body
- biochemical and physiological effects and mechanism of action
Enteral methods
-oral, sublingual/buccal, rectal
Parenteral methods
-inhalation, injection, topical, transdermal
Drug Absorption
entrance of drug into bloodstream
Drug factors affecting absorption (5)
-dosage form, drug water solubility, drug lipid solubility, drug particle size, drug concentration
Physiologic factors affecting absorption
-biologic/cell membranes, body “compartments”, cell membrane phospholipid bilayer
Lipid Bilayer
- hydrophilic tails, hydrophobic tails
- SMALL, UNCHARGED particles will pass
- small/charged and large/uncharged will not
Bioavailability
percentage of administered dose that is absorbed into systemic circulation
Factors affecting bioavailability (5)
- how administered
- where administered
- drug properties
- properties of the environment
- additional barriers
ADME
Absorption
Distribution
Metabolism
Excretion
Distribution
-after drug gains access to bloodstream, it is distributed to the organ/tissues of the body
Factors affecting Drug distribution (4)
- tissue permeability
- blood flow
- binding to plasma proteins
- binding to subcellular components
BBB
- additional lipid barrier that protects the brain by restricting the passage of electrolytes and similar water soluble substances
- drugs must have a certain degree of lipid solubility to penetrate
Most likely to penetrate BBB?
- small, uncharged, lipophilic
- eg) heroin, alcohol, benzo, meth
Plasma protein binding
- plasma proteins (esp albumin) assist in transport of hormones and vitamins
- only the UNBOUND portion of the drug is able to exert pharmacologic activity. remainder will continue to circulate
- 80% of most drugs will bind at some level
Blood Flow
- diff parts of body receive diff amounts of blood
- liver, kidney, heart, and brain have largest blood supply, therefore exposed to largest amount of drug
Volume of Distribution (Vd)
- Vd = amount administered / plasma concentration
- not physical volume, refers to size of compartment necessary to account for total amount of the drug in the body if it were present throughout in the same concentration found in plasma
Drugs that are activated with metabolism are called ______.
Pro-drugs
Kidney prefers ___ , _____ molecules
ionized, water soluble
Biotransformation
chemical aleration of drugs and foreign compounds in the body (phase I)
DMMS function
takes lipid-soluble drugs and prepares for excretion via renal system
First-pass effect
- drugs taken orally are absorbed through GI tract into portal circulation. Drug goes to liver BEFORE body. many drugs are inactivated by liver
- if drug is significantly metabolized, can reduce amount of active drug that reaches circulation
enzyme induction
when used repetitively, some drugs may increase enzyme activity. This may lead to faster metabolism of the drug and shorter duration of action (eg barbituates)
enzyme inhibition
will slow metabolism of all other drugs metabolized by the enzyme system and increase duration and intensity of drug
common pathways of drug excretion
-kidney/renal, liver/hepatic, lungs/pulmonary
Clearance (CL)
- ability of the body to remove drug from blood or plasma
- expressed as volume per unit time (eg ml/min)
- amount of drug removed depends on plasma concentration as well as clearance
entero-hepatic recirculation
- drug secreted into bile, may go into feces
- some drugs reabsorbed, process may be repeated
periodic measurements of plasma levels can help establish ________ for the drug
therapeutic range
plasma half-life (t 1/2)
time required for the plasma concentration of a given drug to fall to 1/2 its original level
-dependent on CL and Vd
Why is establishing half-life important?
kidney and liver disease
Loading dose
- try to get the person into therapeutic range quickly
- many drugs require loading dose to do this effectively
- a large initial dose of a substance or series of such doses given to rapidly achieve a therapeutic concentration in the body
Maintenance Dose
- the amount of drug required to keep a desired mean steady-state concentration in the tissues
- usually drop from loading dose to maintenance dose
Median Effective Dose (ED50)
-dose required to produce a specific therapeutic response in 50% of a group of patients
Median Lethal Dose (LD50)
-the dose that causes lethality in 50% of a group of animals
Therapeutic Index (TI)
TI = LD50/ED50
Potency
- measure of strength
- more potent drug requires lower dose to produce same effect as a higher dose of the second drug
Maximal Efficacy
-point at which there is no further increase in response even if dosage continues to be increased
Factors that influence drug response
-age, height, weight, gender, body fat, genetics, emotional state, placebo effect, presence of disease, patient compliance
Pregnancy and drugs
- fetus is exposed to drugs taken during pregnancy
- placenta is NOT a drug barrier
- harmful drugs = teratogens
Passive exposure
-drugs passed from breast milk to infant
Difference in Pediatric populations
-thinner skin, less skeletal muscle, higher % body water, lower body fat, higher percentage of unbound drug due to reduced plasma protein levels
Physiology of Aging
–decreased CO –> decreased blood flow
-reduced gastric acid secretion, motility, and intestinal absorption
-lean body mass and total body water decrease, % body fat increases
-decreased renal blood flow
-increased bioavailability of oral drugs
= reduced rate of metabolism, increase in duration of drug action
SNS origin
T1-L2/3
PSNS origin
Midbrain, medulla, sacral spinal cord
Autonomic Ganglia
contain synapses between pre- and post-ganglionic neurons
ACh
- in ALL autonomic ganglia
- in effector junction of PSNS
ACh synthesized in the _____ from ____ and ____ by _____
in the NEURON from ACETYL CoA and CHOLINE, by CHOLINE ACETYLTRANSFERASE
*one step synthesis, synthesized as needed, choline reabsorbed. not used as a drug
ACh broken down in the ____ or ______ by ______
in the GANGLIONIC JUNCTION or NEURO-EFFECTOR JUNCTION by ACETYLCHOLINE ESTERASE
NE is the neurotransmitter at _______
NEUROEFFECTOR JUNCTION OF SNS
NE belongs to group of endogenous chemicals called ______, which also include ____ and _____
CATECHOLAMINES which include EPINEPHRINE and DOPAMINE
NE is re-uptaken by the ______, a process mediated by pre-synaptic _______.
PRE-SYNAPTIC FIBER, mediated by A2 RECEPTORS (receptor gives signal to decrease NE synthesis = feedback inhibitor)
Other mechanisms of inactivation of NE (2)
- breakdown by monoamine oxidase (MAO)
- breakdown by catechol-O-methyltransferase (COMT)
M receptors – location
-at neuro-effector junction of PSNS
N receptors – location (2)
-autonomic ganglia (SNS and PSNS) and neuro-muscular junction
A1
arteriolar smooth muscles –> vasoconstriction
A2
pre-ganglionic synapse and in CNS
-activation leads to decrease in SNS flow from CNS (decreased NE production)
Parasympathomimetics
mimic effects of PSNS nerve stimulation
Direct acting parasympathomimetics
=muscarinic receptor agonists
- stimulation of M receptors at neuro-effector junction with little or no N receptor stimulation
- eg) metacholine, carbachol, bethanchol, pilocarpine
Indirect Acting parasympathomimetics
=prolong action of endogenous ACH by inhibiting ACh esterase (prevent breakdown of ACh)
- Carbamates eg) -stigmines
- all are REVERSIBLE inhibtors of esterase -used for same reasons as direct acting, also – myasthenia gravis, paralytic ileus, dementia (aricept)
Irreversible ACh esterase inhibitors
- insecticides, nerve gas
- NO therapeutic use
- intoxication sx increased secretions, tremors, respiratory collapse
- atropine, pralidoxime given to counteract
Toxic reactions to muscarinic agonists
- treated with atropine sulfate
- epinephrine can help overcome cardiovascular or bronchoconstrictor response
Parasympatholytics: Muscarinic Receptor Antagonists
- competitive blocking of M receptors at neuro-effector sites on smooth muscle, cardiac muscle, gland cells, and in CNS
- little effect on ACh at N receptors
- given when poisoned by agonists to stimulate heart, bronchodilators
M Antagonists - heart
increased heart rate by blocking vagal nerve effects on M2 receptors on SA nodal pacemaker
M Antagonists - vessels
- only work with choline esters
- block vasodilation
M Antagonists - respiratory
- induce bronchodilation
- inhibit secretions of nose, pharynx, and bronchii thus drying mucous membrane of the respiratory tract
M Antagonists - GI
- ihibit GI motility and secretions
- inhibit gastric acis secretion
M Antagonists - Urinary
-decrease tone and amplitude of contractions of ureter and bladder
M Antagonists - Sweat glands
- inhibition of sweating, skin becomes hot and dry
- high doses may raise body temp
M Antagonists - CNS (atropine and scopolamine)
- only effect if drug crosses BBB
- Atropine at higher doses (>10mg) causes central excitation, leading to restlessness, hallucinations, delerium. followed by CNS depression - drowsiness, anemia, fatigue
- Scopolamine - therapeutic doses case SN depression - drowsiness, anemia, fatigure
M Antagonist - eye
mydriasis and cycloplegia
M Antagonist - Principal Use
-bronchodilator in COPD, asthma (atrovent)
Sympathomimetic Agents
- direct stimulation of adrenergic receptors
- endogenous ones: NE, E, dopamine
E - cardiac
-through B1, stimulates heart
E - respiratory
-through B2 - bronchodilate
Rapid intravenous injection of E can cause
cerebral hemorrhage from sharp rise in BP
-also, tremor, palpation, anxiety, restlessness
E - therapeutic uses
- rapid relief of hypersensitivity reactions including anaphylaxis
- restore cardiac rhythym in pt with cardiac arrest
NE - effects
- more powerful activator of A1 than E, but much weaker activator of B2
- increases BP much more than E (E doesn’t affect BP due to balance of A1/B2)
- not useful as bronchodilator
A1 major effect
vasoconstriction
A2 major effect
decreased SNS activity
B1 major effect
stimulate heart
B2 major effect
vasodilation, bronchodilation
NE – clinical use
limited, can be used for hypotension
Dopamine - effects
- central NT and can act as agonist on its own receptor
- Low doses: D1 receptors in renal, coronary, mesenteric beds can lead to vasodilation
- High doses: stimulates cardiac B2 - stim heart
Dopamine - therapeutic uses
- severe CHF
- dilates renal arteres, increased renal perfusion, increased urine output (= decreased fluid retention)
B-Agonists - non selective
- Isopretrenol, Isuprel
- increased cardiac output (contractility, HR) and dilation of muscle and mesenteric arteries
- used in emergencies to stimulate HR in pt with bradycardia or heart block
B2 selective Agonists
-asthma
B2 selective agonists - short acting
- rapid onset of action (15 min) and short duration (4-6 hours)
- albuterol, terbutaline
B2 selective agonists - long acting
-duration up to 12 hours (salmeterol)
A1 selective agonists
- nasal decongestants in pt with allergic rhinitis - constriction of blood vessels in nasal tissues
- chronic use bad - lost efficacy, worse sx
A2 selective agonists
- clonidine*
- stimulates a2 receptors in CNS – decreased CNS sympathetic outflow = tx of HTN
Miscellanious Adrenergic Agonists
- dexedrine, ritalin
- CNS stimulant - release NE in CNS
- ADHD
Beta-blockers main functions (3) and Alpha-blocker main function (1)
Bblocker – arrythmia, CHF, HTN
Ablocker – HTN
A-adrenoceptor blockers
- *Phentolamines and Tolazoline are non-selective reversible a-blockers
- Phentolamine used in short term to control HTN in pts with pheocromocytoma (tumor of adrenal glands)
- Tolazoline used to treat persistent pulmonary HTN in newborns
A1 Selective Blockers
- blocking of a1 receptors in vascular smooth muscles of arterioles and veins = decreased peripheral resistance
- less tachycardia than with non-selective a blockers
- caution with hypotension
- Used for treatment of primary systemic hypertension
A1 Selective Blockers - adverse effects
- first-dose phenomenon = marked postural hypotension and syncope 60-90 mins after first dose
- because of vasodilating effect, can promote water retention
B Blockers - heart
-blocking of B1 leads to slowing of HR and decreased contractility
B blockers - pulm
little effect in normal ppl
-in pt with asthma or COPD, can lead to life-threatening bronchoconstriction
B Blockers - peripheral vascular resistance
- blocking of B2 in arteriolar smooth muscle can lead to increase in vascular resistance
- long term effect of B1 blocker in HTN pt with high circulating renin levels is a reduction in peripheral vascular resistance
Non-Selective B-blockers
- reversibly block both B1/B2 with no selectivity
* *Propranolol - angina pectoris, arrthymia, HTN, prevent reinfarction, prevent vascular headache
B1 selective blockers
- higher selectivity to B1
- HTN, CHF, angina, MI
B1 selective blockers - adverse effects
- in pt w AV conduction defects, can cause life-threatening bradyarrythmias
- abrupt discontinuation can exacerbate angina, increase risk of MI
B2 selective blockers – adverse effects
-can worsen bronchoconstriction in asthmatic pt
B1 selective or nonselective produce less bronchoconstriction
