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434 Cards in this Set
- Front
- Back
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What is pharmacodynamics?
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Mechanism (ex—anti inflamm)
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What is pharmacotherapuetics?
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Effect (ex--improves lung funct)
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What is pharmicokinetics?
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Dose (ex--250mg)
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What is Advair?
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Long term oral med for COPD
2 meds: ---Corticosteroid (3 dif doses) ---Beta 2 agonist (only 1 dose) …work better in combo than alone Pharmacokinetics--oral vs. inhaled B-2 agonist Pharmacotherapeutics--dif pt responses to corticosteroid Pharmacodynamics--drug interactions |
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What is the "occupational theory"?
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Drug + receptor --> Drug-Receptor Complex
The max effect results when receptors are fully occupied Effect= ( max effect x [D] ) / ( K(D) + [D] ) K(D) is K2/K1… the greater the affinity the drug, the larger the K1… the smaller the K(D)… the larger the effect! |
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What other equation is the "Occupational Theory" mathematically similar to?
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Michaelis-Menton Equation
K(D) and K(m) are similar… the smaller the value, the higher the affinity! |
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What is the difference between Km and KD?
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Km represents a concentration term
KD is a unit-less ratio that shows Drug-Receptor affinity |
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What do the Km and KD graphs have in common?
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The max effect occurs when finite # of receptors become fully occupied
(assuming--finite # of receptors and direct relationship) |
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What graph form is used to express drug activity?
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Sigmoidal plot (dose in log form)
--> gives good visual comparison b/w drugs |
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What are factors that affect drug activity and may vary between drugs?
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Binding affinity
Intrinsic activity |
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What is intrinsic activity?
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Max ability to produce an effect
(full agonist vs. partial agonist) |
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What controls the smooth muscle in vasculature, gut, and airway?
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Autonomic NS
(Ach, Epi, NorEpi) |
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How are rings of smooth muscle often used in pharmacologic studies?
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(gut or blood vessel smooth muscle)
Mount ring of musc in bath with known/stable drug concentration --> measure contraction w/pressure transducer |
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What is EC(50)?
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Concentration where 50% of max response is seen
10 fold range--25-75% of max response 10,000 fold range--1-99% of max response |
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What are the assumptions (limitations) of the Occupation Theory?
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One drug molec reversibly combines with single receptor
Binding is independent of other drug receptor interactions Receptors are identical and equally accessible to the drug Only small portion of total drug is involved in forming complex with receptor Bio response is proportional to degree of receptor occupancy and independent of time |
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What drugs usually target cytosolic receptors?
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Steroid hormones
Spironolactone Tyroxine Vit D |
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What drugs usually target Ion channels?
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Local anesthetics
Neurotransmitters Paralytics |
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What drugs usually target G-protein coupled receptors?
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Approx half of non-microbial prescription drugs
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What drugs usually target enzyme linked receptors?
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-Insulin
-EPO |
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What type of bond between drug and receptor is very rare?
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Covalent--would be irreversible
[Most drugs have a combo of chem moities that bind to specific receptor sites to give specific binding--> allows design of drugs w/ varying affinity and intrinsic activity] |
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How many transmembrane domains does a Beta 2 adrenergic receptor have?
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7, with specific aa's that contribute to binding (extracellular face)
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How many potential binding sites does epi have?
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5
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What is the structural difference between Epi and Norepi?
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Epi has a methyl off the amino group
Norepi does not |
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What is the active form of epi?
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L-epinephrine (not D)
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What are Beta adrenergic receptors coupled to?
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Gs proteins
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What happens when a drug binds a Beta adrenergic receptor?
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Activation of receptor
--> stim GTP binding to alpha subunit -->dissociates --> stim adenylyl cyclase to catalyze the formation of cAMP |
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What does cAMP do?
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Bind PKA--> cAMPK --> dissociates --> phosphorylates proteins on serine or threonine (OH groups)
[this may activate or inhib regulatory enzymes] |
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What do Beta 2 receptors do?
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Relax smooth muscles in airway
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What deactivates cAMP?
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Phosphodiesterase
(cAMP-->AMP) |
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What are alpha 1 adrenergic receptors?
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In smooth muscle of many arterioles
Mediate vasoconstriction when stim by norepi from post gang symp neurons Epi (in local anesthesia) binds alpha 1 receptors--> restrict blood flow Alpha 1 agonists found in cold remedies to reduce blood flow to the nasal area--> treat runny nose |
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What are Alpha 1 receptors coupled to?
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Gq proteins
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What happens once a drug binds to an alpha 1 receptor?
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Gq proteins activate phospholipase C
--> PLC catalyzes breakdown of phosphadidyl inisitol --> inositol triphosphate (IP3) --> IP3 stims release of Ca2+ from ER --> Ca2+ binds calmodulin --> activate myosin light chain kinase --> Stim smooth muscle contraction |
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What 2 types of receptors does Acetylcholine (Ach) bind?
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Nicotinic and muscarinic receptors
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What is a nicotinic receptor?
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Ligand gated ion channel
4 subunits (2 a, B, y) Ach binds to each a subunit--> opens channel for conductance of Na into cell |
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What does Ach activation of nicotinic receptors promote?
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Neurotransmission between pre and post synaptic cells of ANS and between motor neurons and skeletal muscles
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What is Alzheimer's disease associated with?
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Loss of Ach-mediated synapses
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What parasympathetic cells release Ach?
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Post ganglionic parasympathetic cells
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What is a muscarinic receptor?
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Ach binds this GPCR
--> activate phospholipase C -->activate DAG-IP3 path |
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How is Phospholipase C (PLC) activated?
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By the alpha subunit of Gq
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What does the DAG-IP3 path activate?
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DAG --> activates protein kinase C (PKC) to give Protein and ATP
IP3--> promotes secretion of Ca2+ from ER |
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What does the parasympathetic realease of Ach and binding to muscarinic receptors cause?
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INC gut motility
Glandular secretion (SALIVARY GLANDS) |
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What is another function of Ach stimulation of muscarinic receptors?
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Constriction of smooth muscle in iris of eye --> constrict pupil
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What plant compound blocks the muscarinic receptor that constricts the iris?
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Atropine
(aka--belladonna b/c women with dilated pupils were more attractive) |
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How is the inhibition of these iris constricting muscarinic receptors a variation of the occupation theory?
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There are more receptors than needed for a max response
(receptor reserve) …so, even if you have a blocker…may still get max or at least some response! |
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How are differences in efficiency of coupling accommodated?
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The receptor occupancy equation!
Intrinsic activity is a function of the total # of receptors and what fraction of active receptors can give a max response. |
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How does agonist stimulation lead to reduced Beta adrenergic receptors?
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Activate cAMP synth and PKA
Activate beta adrenergic protein kinase--> phosphorylates receptor --> beta arrestin binds --> displace G protein |
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How do some cells reduce alpha adrenergic receptors in response to an agonist?
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Endocytosis of alpha receptors
Insertion of extra B1-receptors (after prolonged exposure to agonist) |
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What is the allosteric theory?
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Receptors have active and inactive states
When stimulation is present, equilibrium shifts towards active state and contributes to agonist effect The allosteric inhibition of the receptor inactivates the response and has inverse agonist effect --> shift to inactive form |
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What is the active state of a B2 receptor stimulated by?
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Epi (agonist)
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What is the difference between an antagonist and an inverse agonist?
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Antagonist neutralizes agonist
Inverse antagonist works exactly opposite of agonist |
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T/F--Epi is a weak, slow agonist.
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FALSE! It is powerful and fast.
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What does LABA stand for?
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Long Acting Beta-2 Agonists
(have additional hydrophobic residues that prolong receptor binding via Van der Walls but reduces potency) |
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What is an example of an LABA?
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Salmeterol (one of meds in advair)
--> associated w/adverse rxns and death |
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T/F--Not all B2 agonists are catecholamines.
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TRUE!
Epi=catecholamine, but Salmeterol is NOT |
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What effect do LABA drugs have?
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Weak agonists, bund longer
Prolonged therapeutic effect BUT may result in prolonged receptor inactivation because they stay bound… so if there is an acute asthma attack, there are less active receptors to respond to epi |
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Is salmeterol most dangerous in its bound active or bound inactive state?
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Bound inactive --> inverse agonist
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What is the mechanism of "blockers"?
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Bind competitively to active site and prevent normal binding
--> INC EC50, but not Ecmax Ex) B1-blockers reduce symp stim of heart |
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What is the mechanism of allosteric inhibitors?
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May bind allosterically and prevent binding of hormone/neurotransmitter
--> DEC Ecmax, no effect on EC50 Essentially, the end goal is lowered by allosteric binding |
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How do statin drugs work?
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Competitively block HMG-CoA from binding catalytic site of HMG-CoA reductase
--> can't do committal step in cholesterol synthesis because HMG-CoA can't access active site of enzyme |
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What is the inhibitory mechanism of aspirin?
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Aspirin inhibits cyclooxygenase (COX 1) by acetylation of serine resiue and modification of protein conformation.
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T/F--Aspirin is the only COX inhibitor that covalently modifies the protein.
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True!
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What are some drugs that do NOT bind specific receptors?
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Chelating agents (dimercaprol-Hg)
Antacids Bad-nasty chemicals (Na Hypochlorite) Osmotic agents (mannitol as diuretic or to reduce tissue swelling) Counterfeit biochem compounds (5-Bromouracil --> incorporates into DNA--> induce chrom damage… used to treat neoplasms) |
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What is Pharmacokinetics?
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Absorption, distribution, and fate of drugs
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How do in vitro pharmacodynamic studies work?
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-Usually isolated tissue in glass container
-allows stable concentrations of drug to be presented to receptors on a tissue and produce dose-responsive curves predicted by the Occupation Theory -Early studies |
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How studies of drugs taken in vivo differ?
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-Subject to a number of factors that limit accessibility to the site of action
(variable between drugs and patient) |
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What is the difference between a lab study and a drug taken by a patient with respect to dose?
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-In a real patient, Effective Concentration (EC50) becomes Effective Dose (ED50)
-Need to adjust the dose to maintain an effective concentration at the site of action |
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T/F—Except for topical application, drugs MUST be absorbed into the plasma and be carried to the site of action.
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TRUE!
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What are the various modes of delivering a drug?
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-Oral
-IV -Transdermal/subcutaneous -Inhalation -Sublingual/buccal -Rectal |
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What is bioavailability?
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-A measure of how efficiently a drug enters the plasma
-Calculated relative to a drug given intravenously |
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Does an intravenous drug dose become more or less bioavailable over time?
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Less (because already in the plasma)
--metabolized and excreted over time (direct route--more immediate action) |
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Does an oral, subcutaneous, or intramuscular drug dose become more or less bioavailable over time?
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-Bioavaiability INC at 1st as the plasma volume INC
-At a certain point (in time at a certain plasma concentration) bioavailability maxes out -Bioavailability DEC from there (indirect route--slower action) |
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How is bioavailabilty determined?
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-Under very carefully controlled conditions in the clinical laboratory
-Total amount that reaches plasma is evaluated as area under the curve [AUC] for a given drung--compared to IV administration or other routes or other drugs -Values may be fraction or percentage |
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What is absolute bioavailability?
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(Fraction)
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What is relative bioavailability?
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Compares drugs A and B
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What is usually the absolute bioavailability of a drug when administered extravascularly?
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F < 1
--physiologic factors reduce availability of drugs prior to their entry into the blood |
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What are some factors that may reduce the availability of drugs administered EV before they enter the blood?
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-poor absorption
-degradation or metabolism -hepatic first pass effect |
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What are some things that may alter drug absorption?
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-Taken with or without food
-Other drugs taken at same time -Intestinal motility -Disease (liver or GI) |
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What else might taking different drugs concurrently alter?
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Hepatic first pass
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Why does intestinal motility alter absorption?
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-Alters dissolution of drug
-may affect degree of chemical degredation fy intestinal microflora |
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What is enteral administration?
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Oral
(--gut--either liver and into circulation OR excreted) |
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What is parenteral administration?
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Intramuscular, Intravenous, subcutaneous, inhaled
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Once a drug is in the blood stream, what can happen to it?
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-Can be stored bound to plasma components
-Can be stored bound to tissue -Can go to site of action -Can be metabolized -Can be excreted/reabsorbed |
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What is the most common, convenient, and economical route of drug administration?
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Enteral
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What affects the rate of absorption and bioavailability in the Enteral route?
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-drug formula
-concentration of drug -pH of GI tract -Food in stomach -Gastric motility -Splanchnic blood flow -1st pass metabolism |
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How are most enteral drugs absorbed?
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Passive diffusion across the epithelium lining in gut
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What drugs are more readily absorbed?
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Hydrophobic! (lipid soluble)
--more easily cross phospholipid bilayer |
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T/F—Absorption is NOT pH dependent.
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FALSE! It can be. Want molecules to be neutral.
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What is an example of a drug that is a weak acid?
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Aspirin
--non-dissociated form is neutral and more permeable |
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What is an example of a drug that is a weak base?
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Lidocaine
(quarternary ammonium qroup has positive charge) --dissociated form is neutral and more permeable |
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How does the association of aspirin in the stomach compare to the plasma?
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-Aspirin (weak acid) is more associated (1/100) and more permeable in the stomach because it’s an acidic environment
-In the plasma, aspirin is 10,000/1 dissociated |
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Is codeine a weak acid or base?
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Weak base
Opposite of aspirin! Absorption more favored in alkaline environment of intestine |
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Why do some medicines tell you not to take them with fruit juice?
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Fruit juice is Acidic!! --will reduce absorption
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How do you determine association and permeability?
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pH-pKa = log[A-]/[HA]
Ex) Aspirin Stomach pH=1.4 Aspirin pKa=3.4 -- 1.4-3.4 = -2 = log 1/100 = 0.01 --undissociated and permeable form HA is 100x’s more concentrated in the stomach |
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What is the pH of the plasma?
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Plasma pH = 7.4
--7.4-3.4= 4 = Log 10,000/1 -- aspirin is mostly dissociated in plasma |
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What other than permeability (P) is important in absorption?
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Surface area available for Drug absorption (A)
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Is aspirin absorbed more in the stomach or the intestine?
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INTESTINE! (even though less perm at basic pH)
Transit time through stomach can affect delivery of drug to intestine |
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What can slow gastric emptying?
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Fat in the diet
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What was the name of the cholesterol drug that was found to be ineffective?
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Zetia
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What happens to drugs absorbed across the brush border cells of the intestine?
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Diffuse into interstitial fluid of villi
--taken up by capillaries inside villi --blood from small and large intestines flow into mesenteric veins-- become hepatic portal vein |
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Is splanchnic blood flow less or greater after a meal?
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Greater! (blood flow to intestines)
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T/F—Drugs are absorbed across the apical membrane and diffuse into capillaries across the basal membranes.
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TRUE!
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What is carried from the small intestine to the liver via the hepatic portal circulation?
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DRUGS!
Sugars, amino acids, electrolytes, water |
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Once blood is delivered to the liver by the portal vein, what happens?
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Blood is carried to liver sinusoids which have a very large surface area for drug uptake and detox by hepatocytes
--Drug metabolites may be returned to venous circulation (vena cava and heart) OR to the bile |
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What is significant about hepatocytes?
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They have an extensive smooth ER with enzymes that metabolize (oxidize) normal metabolites and drugs
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What hepatic enzymes are involved with many of the metabolic reactions?
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Cytochrome P450 (CYP)
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Are metabolites usually polar or non-polar?
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Polar! -- water soluble
--can be passed by the kidneys |
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What are Phase I transformations?
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Include microsomal oxidations, dehydrogenations, and reductions
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What are Phase II transformations?
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Include conjugations.
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What can inhibit Cytochrome P450?
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--Certain Drugs
--Normal food in diet Grapefruit* Insulin |
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What can induce Cytochrome P450?
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--Certain drugs--Benzo[a]pyrene
--Chargrilled meats |
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T/F—Metabolic transformations by the liver can be extremely variable.
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True!
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What are the routes of Parenteral drug administration?
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-Intravenous (IV)
-Subcutaneous (SC) -Intramuscular (IM) -Topical --sublingual -Inhalation |
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What are the advantages of IV administration?
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-Accurate and immediate delivery
-Dose can be adjusted to patient’s response |
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What are the disadvantages of IV administration?
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-Sterile formulations and aseptic technique required
-Once the drug is injected there no recall -Local irritation at site of administration |
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What are the characteristics of absorption in Subcutaneous administration?
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-Rate of absorption is slow and sufficiently constant
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What are the disadvantages of subcutaneous administration?
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-Many drugs are irritating
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What are the characteristics of absorption in Intramuscular administration?
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-Rapid absorption of aqueous solutions
-Slow, constant absorptions of oily |
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What is an advantage of IM administration?
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Substances too irritating to give SC may sometimes be given IM
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What are the 2 types of topical administration?
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-Transmucosal
-- sublingual -Transdermal |
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How is absorption characterized in topical administration?
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Absorption is proportional to drug’s concentration and lipid solubility
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What is significant about sublingual topical administration?
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Circumvents 1st pass metabolism in the liver, via superior vena cava
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How is absorption characterized in drug administration via inhalation?
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Rapid access of gaseous agents to circulation
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What happens with both the enteral and parenteral routes?
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Drugs bind in varying amounts to plasma proteins
--limits accessibility to tissues AND reduces amount of drug filtered by kidneys |
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What is Volume of distribution (Vd)?
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Vd= quantity given/plasma concentration
Large Vd indicates greater tissue distribution |
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What are 2 ways of finding the plasma volume?
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-Evans Blue
-Iodine 131-albumin (do not leave plasma in significant amounts—Vd=3) |
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What are 2 ways of measuring total extracellular fluid volume?
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-Mannitol
-Inulin (polysaccs that pass thru capillary wall--equilibrium, Vd=12,11) |
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How can total body water be measured?
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Urea
(freely permeable to capillaries and cell membranes-- equilibrates in intra and extracell fluid, Vd=41) --Dilution of isotopic water can also be used |
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What are the average plasma water, extracellular water, and total body water volumes in an average 70kg male?
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Plasma water—3L, 4% body weight
Extracell water—9L, 13% b.w. Total body water—29L, 41% b.w. |
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How does %body weight vary with age?
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--Infants and children have higher % body water
--Old people haave smaller percent body water |
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What happens in drugs that strongly bind to tissues?
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--May produce longer lasting effects
--BUT in non-specific binding--require much higher dose to reach target -- may produce undesirable side effects in other tissues |
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What is a pre-req for most drugs?
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To reach target organs in therapeutic concentrations
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What are some physiological barriers that drugs must overcome during distribution?
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-Blood-Brain barrier
-Blood-Placental barriers -Differing blood flow to various organs |
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What organs receive a lot of blood flow?
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Heart, liver, kidneys, CNS
…receive drug w/in minutes |
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What organs take longer for drugs to reach them?
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Muscle, most viscera, skin, fat
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What is the total amount of drug metabolized?
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Liver and tissue metabolism + renal clearance
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How much of the cardiac output goes to the kidneys via the renal arteries?
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~1/4 of CO (1,100-1,200 mL/min)
--660-720mL of that is plasma (hematocrit 40) |
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How much plasma is filtered?
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20% (125 mL/min or 180 L/day)
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How is the plasma filtered?
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--glomeruli (capillaries)
--Bowman’s capsule --filtered into nephrons (tubules) --solutes and water are reabsorbed and returned to circ via renal vein --rest is excreted |
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How much plasma is excreted in urine?
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~1% of plasma is excreted in urine
(1mL/min or 1.5 L/day) |
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Why would the volume and composition of urine change?
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To maintain plasma volume and composition within a normal range
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How many nephrons are in each kidney?
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About 1 million
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What are the 3 elements of renal function?
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-Glomerular filtration
-Tubular reabsorption -Tubular secretion |
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Are drugs that are bound to plasma proteins filtered by the kidneys?
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NO!
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What is usually reabsorbed?
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99% of Na+, Cl-, and water
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What is usually excreted?
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K+, organic ions (uric acid), drugs
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How much of plasma is filtered by the kidneys?
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--20% is filtered
--80% passes to peritubular capillaries |
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What is the GFR of plasma?
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125mL/min = 180L/day
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What is the final urine output per day?
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~1.5L / day
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What is inulin?
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-Inert poly saccharide
-MW=5.5 Kd -freely filtered by kidney, not reabsorbed or secreted |
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What is inulin clearance?
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Amount inulin filtered = amount excreted --used to calculate GFR
P(inulin) = 1mg/mL U(inulin) = 125 mg/mL V=1mL/min |
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What is creatine?
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-naturally occurring metabolite in the plasma
--filtered and only moderately reabsorbed or secreted |
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What is creatine clearance used for?
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Estimate GFR
--24hr urinary creatine output is used to evaluate renal function (same equation as inulin clearance) |
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What will indicate a decline in glomerular filtration?
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Accumulation of creatine in plasma
-- dx for reduced GFR in renal disease |
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If there is reduced GFR, what will also be reduced?
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Rate of drug elimination will also be reduced
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What is the clearance of glucose?
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0 !!! (completely reabsorbed)
--any present in urine = problem |
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What is the clearance of solutes?
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Most are mostly reabsorbed so clearance is > 0
Some solutes (creatine) are secreted so their clearance > GFR (125mL/min) |
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What gives an approximation of renal plasma flow?
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Para-aminohippuric acid (PAH)
--almost completely secreted from blood + that filtered --U(PAH) = 5.85 mg/mL |
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What does the ratio of inulin clearance to PAH clearance give?
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GFR/renal plasma flow = Filtration Fraction
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T/F—A drug that is only filtered wil be eliminated more rapidly than a drug that is secreted.
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FALSE!
A drug that is secreted (and filtered) will be eliminated more rapidly. |
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What does the proximal tubule reabsorb?
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-67% Na+ and water
-100% glucose and amino acids |
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What does the proximal tubule secrete?
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-organic waste (uric acid)
-Toxins or DRUGS |
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What does the Loop on Henle do?
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-Reabsorb 25% NaCl
-Reabsorb 15% water -sets up osmotic gradient for peritubular fluid |
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What does the distal tubule do?
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-Reabsorb 7% NaCl
-Reabsorb 8-17% water -Secrete K+ -works based on Na+/K+ balance |
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What does the collecting duct do?
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-final reabsorption of NaCl and water
--Site of final urine concentration |
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What regulates NaCl and water reabsorption in the collecting duct?
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Antidiuretic Hormone (ADH)
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What is a common mechanism of drug secretion?
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Organic cation (OC) secretion
--actively draws charged molecules from plasma in peritubular capillaries--pumps them into tubular lumen (drugs and organic cations, also similar mech for organic anions from liver) |
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What is the simplest model for drug elimination?
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Liver and tissue metab + renal clearance = Vd (effective volume in whuch drug is distributed in body)
Where the body is considered as one SINGLE compartment |
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What are some methods of delivering drugs continuously?
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IV drip, transcutaneous patches, time release capsules, slowly diffusing IM injections
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What does continuous drug delivery do?
|
-Maintains constant plasma concentration
--”Zero order” kinetics |
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What are “first order” kinetics?
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Drugs given in single dose are eliminated at a constant rate
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How is the elimination of some drugs “capacity limited”?
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Liver enzymes are saturated and unable to lower plasma concentration (zero order)
Until the concentration declines below saturating levels (first order) |
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What are 2 example of “capacity limited” drugs?
|
-Aspirin (T(1/2)=3 to 20hrs)
-Alcohol (T(1/2)=1.4 to 20hrs) ..very variable!! |
|
|
What is the half life?
|
-Time req to eliminate half of drug.
-2 half lives eliminate half of what’s left-- ¼ -4 half lives leave 6% |
|
|
How is half life calculated?
|
T(1/2) = Vd / Clearance rate or…
|
|
|
What is the half life of inullin?
|
-Make GFR=110mL/min to simplify
-Vd of inulin =11L |
|
|
What is the half life of Evans blue?
|
-Make GFR 150mL/min to simplify
-Vd of Evans Blue = 3L |
|
|
What can INC half life?
|
-Drugs taken up by tissues (larger Vd)
-Plasma protein binding -Liver metabolism |
|
|
Which has a longer half life Amoxicillin or tetracycline?
|
Tetracycline! (t(1/2)=10hrs)
(amoxicillin t(1/2)=1.7hrs) |
|
|
After a single oral dose, what can cause an increase in the amount of drug remaining after 4 half lives?
|
-Higher dose
-Less absorption -Less elimination |
|
|
For repeated doses, how long does it take to reach a steady state equilibrium?
|
4 half lives!
(time to plateau is independent of dosage!) |
|
|
What are fluctuations in steady state proportional to?
|
Dosage interval / half life
--blunted by slow absorption |
|
|
What are steady-state concentrations proportional to?
|
- Dosage/dosage interval
Half life |
|
|
How do you calculate equilibrium concentration?
|
1.44 times the peak concentration at a single dose times the # of doses per half life
So, if there are 2 doses given every half life -- 1.44 x Peak x 2 = 2.88 x Peak …equilibrium concentration= 2.88(Peak concentration for single dose) |
|
|
If a drug is administered with first order kinetics, what will happen to the steady state?
|
There will be fluctuationa
|
|
|
If a drug is administered with zero order kinetics, what will happen to the steady state?
|
It will stay steady
(constant administration maintains constant levels) |
|
|
What are the 2 phases of elimination in drugs that accumulate in tissue reservoirs?
|
a-phase = fast, initial elimination from plasma
b-phase = slower, transfer from tissues to plasma |
|
|
What happens to more lipophilic drugs?
|
Retained longer in the tissues
--The longer the administration of the drug -- the more the drug accumulates -- the longer the half time for elimination …”context sensitive halve lives” |
|
|
What are some highly lipophilic drugs?
|
Opiods!
Ex) fentanyl |
|
|
What happens when some drugs require time to pass from the plasma to the site of action?
|
Plasma concentration initially rises but as plasma levels initially rise, little effect is seen
--BUT there is a continued effect seen after plasma levels fall because the drug remains in the tissue Ex) Lorazepam (in the brain) |
|
|
What may lead to diminished effect even with sustained plasma levels?
|
DEC in effect may be due to receptor de-sensitization or receptor reuptake via endocytosis
Ex) Inhaled cocaine reaches brain rapidly, but effect diminishes even w/sustained plasma concentration |
|
|
What are some patient related variables?
|
-Pt weight
-Pharmacogenetic factors: Individual effective dose Hyporeactivity Hyperreactivity Idiosyncrasy |
|
|
What should be taken into account when considering dose and patient weight?
|
(amount of drug / kg body weight)
-Manufacturer’s recommendation -Clinician’s experience |
|
|
What is the “Individual Effective Dose”?
|
Dose of drug required to produce a specific response in an individual
|
|
|
What may cause hyporeactivity?
|
-Tolerance
-Tachephylaxis—rapid decrease in response to drug after repeated doses over short period of time |
|
|
What is idiosyncrasy?
|
An unusual reaction of any intensity, irrespective of drug dosage
|
|
|
What are the pharmacokinetic factors of oharmacotherapeutics?
|
Route, amount, and freq of drug administration influence onset and duration of drug action
Loading dose Maintenance dose --Time course of accum --Max amount accum --Fluctualtions associated w/dose interval Variation in response (patient and disease related) |
|
|
Who is the founder of the Scientific Method?
|
Francis Bacon
(Books—The Proficience and Advancement of Learning, Novum Organum, De Augmentis Scientiarum) |
|
|
What are the medical equivalents of the scientific method?
|
-Observation = Symptoms (inductive logic)
-Hypothesis = Dx (deductive logic) -Experiment = Tx -Support Hypothesis = Positive Outcome -Refutes hypothesis= Neutral or Neg outcome -Theory = Medical Application |
|
|
In the lab what does feedback allow?
|
Feedback allows theories to be tested and revised
|
|
|
In the clinic what does feedback allow?
|
Feedback allows detection of side effects and new drug development
|
|
|
What does preclinical testing consist of?
|
IN LAB! (1-5yrs, av= 2.6yrs)
-studies in vitro -animal testing (short term) -animal testing long term starts at end and extends into clinical testing …after this there is an FDA 30 day safety review! |
|
|
What does long term animal testing evaluate?
|
-Chronic toxicity
-reproduction -teratagenicity -carcinogenicity |
|
|
What does clinical testing consist of?
|
IN CLINIC! (2-10yrs, av= 5.6yrs)
-Phase 1 -Phase 2 -Phase 3 …after this there is a 12 month NDA review! |
|
|
What is Phase 1 clinical testing?
|
Who—Normal volunteers, special pops (hepatic and renal impairment)
Why—Safety, bio effects, metab, kinetics, drug interactions Done by Clinical pharmacologists |
|
|
What is Phase 2 clinical testing?
|
Who—Selected patients
Why—Therapeutic efficacy, dose range, kinetics, metab Done by clinical pharmacologists and clinical investigators |
|
|
What is phase 3 clinical testing?
|
Who—large sample of selected pts
Why—safety and efficacy Done by clinical investigators |
|
|
When does treatment use begin?
|
At the end of Phase 3 clinical testing
(BEFORE NDA approval) |
|
|
What is Postmarketing Surveillance?
|
Phase 4: IN GENERAL PRACTICE
(after NDA approval) -Who—Pts given drug for therapy -Why—adverse rxns, patterns of drug use, additional indications -Done by all physicians |
|
|
T/F—ED50 is variable among pts.
|
True! (some may be sensitive, others less sensitive--hypothetical bell curve)
10mg (sens)—100mg (norm)—10g (less sens) |
|
|
How does individual variation in plasma concentration from a given dose affect the steady state plateau in multiple doses?
|
Can produce equal or greater variation!!
|
|
|
What is the therapeutic range for Phnytoin?
|
(anticonvulsant)
Plasma concentration=10-20ug/mL Dose=1-15mg/kg …plasma concentration can vary a lot for a given dosage and produce a variety of side effets (nystagmus, ataxia, somnolence) |
|
|
What are Extension Effects?
|
(included in side effects)
What happens when therapeutic benefit becomes toxic Ex) Insulin is used to reduce blood glucose BUT toxic extension--hypoglycemia |
|
|
How are some general side effects not related to therapeutic application but are still predictable?
|
Predictable general side effects based on physio/biochem properties!
Ex) Phenytoin is an anticonvulsant that can also cause GINGIVAL HYPERPLASIA |
|
|
What is one theory on why Phenytoin can cause gingival hyperplasia?
|
INC expression of PDGF (6x’s)
Stimulates cell growth and division (this is also seen in Cyclosporine A) |
|
|
What is an “Idiosyncratic (individual) effect”?
|
Related to genetic variations that are “silent”
So, genetic issue-- drug taken -- idiosyncratic response Ex) G6P dehydrogenase deficiency, when you take aspirin--hemolytic anemia |
|
|
Although not always preventable, how can drug allergy occurrence be minimized?
|
Good med hx
Avoid offending drug and likely cross reactors Avoid inappropriate drug admin Promote oral use and limit topical exposure Request allergy testing when appropriate |
|
|
T/F—Some drugs have useful side effects.
|
True!
Ex) Quinidine—antimalaria drug, also useful as an anti-arrhythmic! |
|
|
What is the therapeutic index of a drug?
|
Therapeutic Index (TI) = LD50 / ED50
--Provides margin of safety (determined w/animals) --measures toxicity ED99 can lay from lower range for toxic side effects to a near lethal dose |
|
|
What does it mean if drug A has a TI of 5/I and a ED99 in the low range of LD?
|
It will have a smaller therapeutic range for dose, but the higher end of the dose range will be less likely to experience negative side effects
|
|
|
What does it mean if drug B has a TI of 25/1 but and ED99 very close to LD50?
|
It will have a large therapeutic range for dose, but there is a greater risk of side effects in patients needing larger dose
|
|
|
What is the Certain Safety Factor?
|
CSF= LD01 / ED99
The minimal toxic effect over the max therapeutic effect --another method to evaluate toxicity! CSF ~ 1 = fairly safe (drug A above) CSF << 1= smaller safety factor (drug B above) |
|
|
What is the Standard Safety Margin?
|
SSM = (LD01-ED99) / ED99
--Evaluate toxicity! When ED99>LD01 -- negative value (less safe) |
|
|
What can be used to show Relative Safety of local anesthetics?
|
First, find TIC / TAC for 2 local anesthetics
TIC—Threshold Irritant Concentration TAC—Threshold Anesthetic concentration Then, compare. Ex) Procaine—176/8.8 = 20 Cocaine—79/1.16 = 68 -- 68/20-- cocaine is 3.4 times more safe relative to procaine |
|
|
T/F—Drug interactions are more common in patients taking more drugs.
|
True.
|
|
|
What happens when you take Penicillin G with acidic fruit juices?
|
Less antibiotic is absorbed --blood concentrations are reduced
|
|
|
What happens when you combine local anesthetics with epinephrine or levonordefrin?
|
Decreased absorption of anesthetics w/ prolongation of anesthetic
|
|
|
What are some mechanism of drug interaction?
|
Inhibition of absorption
Enhancement of absorption Alteration of binding Alteration of distribution Induction of drug-metabolizing enzymes Inhibition of biotransformation Alteration of excretion Competition for same receptor Opposing pharm effects on diff systems Antagonism involving enzyme inactivation Summation of effects on same receptor Summation of pharm effects on diff systems Potentiation involving enzyme inactivation |
|
|
What happens when Pilocarpine is given with Atropine (Scopolamine)?
|
Competition for muscarinic parasympathetic nerve receptor
--Responses to muscarinic drugs and stim are blocked! |
|
|
What is terfenadine?
|
-Antihistamine (no longer used)
-Seldane, Triludan, Teldane -prodrug--active form = fexofenadine by CYP3A4 (gut) BUT, Terfenadine itself is cardiotoxic if it reaches myocytes--risk=cardiac arrhythmias (elong QT interval) **reaches myocytes if pt is also taking a CYP3A4 inhibitor (erythromycin or GRAPEFRUIT JUICE) |
|
|
What is in grapefruit juice that can cause interactions in addition to those caused by other acidic juices?
|
è Grapefruit juice has flavinoids!
Inhibits CYP3A4 in the gut |
|
|
How common are fetal abnormalities in the US?
|
3-6% of pregnancies
--drugs are responsible for 1-5% of these abnorms (each drug has a threshold above which fetal abnorms can occur and below which they are not discernable) |
|
|
What factors affect the ability of the drug to reach threshold concentration in the fetus?
|
-Drug’s biochem properties:
MW Lipid solubility pKa plasma protein binding -Genes of mom and fetus: Pharmacokinetic and pharmacodynamic factors |
|
|
How can drugs cross the placenta?
|
Free drug diffuses! Or Active transport of metabolites.
|
|
|
What happens to the apparent Vd (volume of distribution) of many drugs during pregnancy?
|
Vd--INCREASES!
Plasma Volume INC (20% midterm, 50% endterm) Total plasma protein concentration DEC Total body fat INC |
|
|
Why might INC dosage of a drug have to be given to a mother during critical periods of pregnancy?
|
Cardiac Output INC
-- Renal Blood flow INC-- GFR INC |
|
|
When is the placental membrane LESS permeable to drugs?
|
Early pregnancy
(placental membrane is thick)\ |
|
|
When is placental membrane MORE permeable to drugs?
|
Later pregnancy
(thickness DEC, surface area INC) |
|
|
T/F—Human teratogenesis is NOT predictable.
|
True.
|
|
|
When due major malformations (usually caused by drugs) generally occur?
|
Critical period of Organogenesis (1st trimester)
|
|
|
What does exposure to drugs in the 2nd and 3rd trimesters usually cause?
|
Affect organ function
|
|
|
What are the effects of drugs given to mothers who are near term?
|
May have prolonged effects on newborn
(especially if drug has long half life) --b/c infant’s metab and excretory capabilities are limited |
|
|
What effect does Lysergic acid diethylamide (LSD) have on a fetus?
|
-Chromosomal damage
-Stunted growth (most susceptible in 1st trimester!) |
|
|
What effect do opioid analgesics have on a fetus?
|
-Respiratory depression
-Neonatal death (most susceptible at term!) |
|
|
When is a fetus most prone to develop enamel hypoplasia and staining and cleft palate?
|
End of 6th week --9th week
|
|
|
What group of genes regulates body segmentation?
|
Homeobox genes (Hox genes)
--linearly arrayed along chromosomes --control segmentation of branchial arches --important for normal craniofacial development --mutation or teratogen can affect normal dev |
|
|
What are Dlx genes?
|
-Homeobox genes that are not in the HOX clusters, “distal less”
-important for dev of jaw! --control neural crest ectoderm migration and differential development of upper and lower jaws -mutation of Dlx--species diffs in jaw structure?? |
|
|
What types of drugs would most likely lead to craniofacial abnormalities in a fetus?
|
Drugs that interfere w/gene expression or cell signaling
|
|
|
What are some of the signaling molecules an pathways involved in tooth development?
|
Hedgehog, Bone Morphogenic Protein, Fibroblast GF
|
|
|
What is Treacher Collins Syndrome?
|
-Autosomal Dominant
-1 in 10,000 births -Varying severity: Craniofacial Disorder |
|
|
How does the FDA codify drugs for pregnant patients?
|
-According to their potential to cause fetal injury
-Categories A, B, C, D, X |
|
|
What is a category A drug?
|
Controlled studies in both animals and humans have FAILED to show risk to fetus
(ex--NaF) |
|
|
What is a category B drug?
|
-Animal studies show no risk, but no human tests
OR -Animal studies HAVE shown risk, but human studies have NOT (ex—Acetaminophen, Penicillin V) |
|
|
What is a category C drug?
|
-Animal studies HAVE shown risk, but there are no human studies
OR -There are no available animal or human studies (ex—hydrocortisone (oral)) |
|
|
What is a category D drug?
|
Evidence of risk exists, but benefits may outweigh risks in certain situations
(ex—aspirin, hydrocortisone (systemic)) |
|
|
What is a category X drug?
|
Risks exist and outweigh any potential benefit of use
(ex—estradiol, warfarin) |
|
|
In a breast feeding patient, what is an important determinant of the concentration of the drug in the milk?
|
Rate of passage of a drug from plasma to milk
MW Lipid solubility pKa plasma protein binding |
|
|
Is milk more or less acidic than plasma?
|
More (milk pH = 7.0, plasma pH = 7.4)
--milk acts as “ion trap” for weak bases --acidic drugs are limited in their ability to enter milk |
|
|
What are the common ratios of drug concentration in breast milk to drug concentration in maternal plasma?
|
--60% of drugs have ratio < 1
--25% of drugs have ratio > 1 --15% of drugs have ration > 2 --DANGER! |
|
|
About how much milk will infant ingest per day?
|
150mL / kg body weight PER day
|
|
|
What is the Exposure index in breast feeding patients?
|
Amount of drug in the breast milk that the infant ingests
--expressed as a percentage of therapeutic dose for infant --Arbitrary safe value is no more than 10% of therapeutic dose (for most drugs there is no known dose below which there are no clinical effects) |
|
|
What factors determine the advisability of using a particular drug while breast feeding?
|
-Dose and duration of therapy (acute/long term tox)
-Age of infant -Quantity of milk consumed by infant -Drug’s effect on lactation |
|
|
What are some strategies to minimize infant’s exposure to meds in milk?
|
-Withhold drug therapy
-Delay drug therapy temporarily -Choose alternative drug that passes into milk poorly -Use alternate routes of drug admin -Advise mom to avoid nursing at peak plasma concentration of drug |
|
|
What are some age related variables?
|
Total body water (DEC as age)
Fraction of lipophilic drug in fat (INC as age) Liver metabolism capability (lowest in babies, higher in young adults, decrease w/old age) Renal drug elimination capability (lowest in babies, higher in young adults, decrease w/old age) |
|
|
T/F—Responses to specific drug concentrations may be different in the adult and pediatric populations.
|
True! (poorly researched)
|
|
|
What is an example of a drug that can be tolerated by adult patients but may be inappropriate for children?
|
Acetylsalicylic acid (aspirin)
--Reyes syndrome! |
|
|
How is absorption different in pediatric patients?
|
-Gastric acid is low in 1st several months of life
-Absorption may be reduced by high freq of reflux and diarrhea |
|
|
At what age are adult values of absorption usually achieves?
|
2 years old
|
|
|
How is distribution mainly affected in pediatric patients?
|
Body composition (more water!)
|
|
|
How does the body composition of pediatric patients alter the volume of distribution for many drugs?
|
-Vd INC for hydrophilic drugs
-Vd DEC for lipophilic drugs -Binding affinity of albumen is low -BBB is more permeable |
|
|
At what age are adult levels of distribution usually achieved?
|
1st year of life
|
|
|
When do hepatic enzyme systems fully mature?
|
In the 1st months of life! (immature at birth)
--may greatly exceed that in an adult patient on a weight adjusted basis |
|
|
When does decrease in hepatic activity in children usually begin?
|
After child weighs 30kg (66 lbs.)
|
|
|
At what age do drug dosages approach adult values?
|
Adolescence
|
|
|
When do the kidneys systems mature?
|
-Immature at birth
--6 months old—glomerular filtration matures --1 year old—tubular secretion matures |
|
|
In old age, what are 3 things that can regulate drug receptors?
|
Down-reg or up-reg:
Age related changes Disease related changes Drug related changes Altered receptor sensitivity due to certain drugs |
|
|
How is absorption altered in old age?
|
-DEC gastric secretions
-DEC acidity -DEC emptying time -DEC peristalsis -DEC absorptive surface -DEC splanchnic blood flow --altered extent and rate of absortion (may counterbalance eachother) |
|
|
What affects distribution in old people?
|
Marked changes in Vd:
DEC total body water and lean mass INC total body fat Chronic disease--DEC cardiac output and blood flow DEC plasma protein binding (age, frailty, disease, immobility) |
|
|
How much does total body fat increase with age?
|
Young men=18%, old men=36%
Young women=33%, old women=45% |
|
|
How is metabolism altered in old age?
|
-DEC rate of drug elimination and Limited 1st pass metab of drugs w/high exctraction coeff
DEC liver size DEC hepatic blood flow Hepatic dysfunction |
|
|
How much does the liver shrink with old age?
|
--Old men = 28%
--Old Women = 44% |
|
|
How much does hepatic blood flow decrease with old age?
|
35%
|
|
|
How is excretion affected by old age?
|
Renal blood flow, GFR, Tubular secretion DEC with age!
Volume depletion CHF Renal dysfunction |
|
|
How does Creatine Clearance decrease as we age?
|
Creatine Clearance DEC 1% per year after age 40yrs
|
|
|
What is one of the most common causes of morbidity in patients receiving pharmacotherapy?
|
Hepatic dysfunction
|
|
|
What are some things that can lead to hepatitis and cirrhosis?
|
-Autoimmune disease
-Viral infections -Toxic insults |
|
|
What is the difference between acute and chronic hepatitis?
|
Acute—transient reduction in liver function
Chronic hepatitis and hepatic cirrhosis—permanent loss of liver function! |
|
|
In hepatic dysfunction patients, what are most adverse drug effects related to?
|
--Altered pharmacokinetics
(metab, distribution, excretion) |
|
|
How is metabolism altered in Liver disease?
|
-DEC hepatic blood flow
-Portal vein HTN -Shunt of blood around liver |
|
|
How is distribution altered in liver disease?
|
-DEC protein binding
-DEC albumin, DEC alpha-acid glycoprotein, INC bumping by endogenous substances)\ |
|
|
How is excretion altered in liver disease?
|
DEC hepatobiliary and/or renal clearance
|
|
|
T/F—Only one simple lab test is necessary to assess liver function.
|
False!
Most common way to estimate ability of liver to metab drugs is to determine Child-Pugh score. |
|
|
What is the Child-Pugh score?
|
- Most common way to estimate ability of liver to metab drugs. Based on severity of symptoms.
Serum Albumin Total bilirubin Prothrombin time Acites Hepatic encephalopathy |
|
|
What are the score ranges for Albumin?
|
Score: 1— > 3.5 mg/dL
Score: 2— 2.8-3.5 mg/dL Score: 3— < 2.8 mg/dL |
|
|
What are the score ranges for Total bilirubin?
|
Score: 1— < 2 mg/dL
Score: 2— 2-3 mg/dL Score: 3— > 3mg/dL |
|
|
What are the score ranges for Prothromibin time?
|
Score: 1— < 4seconds over control
Score: 2— 4-6 seconds over control Score: 3— > 6 second over control |
|
|
What are the score ranges for Ascites?
|
Score: 1— Absent
Score: 2— Slight Score: 3— Moderate |
|
|
What are the score ranges for Hepatic encephalophathy?
|
Score: 1— None
Score: 2— Moderate Score: 3— Severe |
|
|
How do you interpret the results of the Child-Pugh score in relation to med dosage?
|
--C-P = 5 --Normal liver function
--C-P= 5-8 -- no dosage modification indicated --C-P =8-9-- 25% DEC in daily dose for drugs metab primarily (60+%) in liver --C-P= 10+-- 50% DEC in daily dose for drugs metab primarily in liver |
|
|
What happens in a pt with renal dysfunction?
|
Kidneys no longer able to carry out normal excretory functions
|
|
|
What are some types of acute kidney failure?
|
-Infection
-Trauma -Severe burns -Blood transfusion -drug induced acute renal failure |
|
|
What are some types of chronic renal failure?
|
-Glomerulonephritis
-Pyelonephritis -Nephretic syndrome -Drug induced chronic renal failure |
|
|
What are most adverse drug effects in renal disease related to?
|
Altered pharmacokinetics
|
|
|
How is absorption altered in a patient with kidney disease?
|
-Nausea, vomiting, diarrhea
-INC gastric pH secondary to INC salivary urea levels -Antacids for Ca/P abnorms |
|
|
How is distribution altered in a patient with kidney disease?
|
Vd may be INC, DEC, or unchanged secondary to altered plasma protein binding and/or accum of acidic by-prods of uremia
|
|
|
When is adjustment to the drug dosage necessary in kidney disease?
|
Normal Creatine clearance (Cl(cr)) is 140 mL/min
Adjustment of dosage isn’t necessary until Cl(cr) = below 30-40mL / min |
|
|
In general, what is the correlation between Vd and half life?
|
Drugs that are taken up by tissues (larger Vd) generally have a longer half life.
|
|
|
How is metabolism altered in patients with kidney disease?
|
DEC in mixed-function oxidation, reduction, hydrolysis, and conjugation rxn (in pt w/uremia)
|
|
|
How is excretion altered in patients with kidney disease?
|
Degree to which renal dysfunction impairs drug elimination depends largely on the % of drug excreted by the kidney
|
|
|
How is the degree of renal failure defined?
|
By creatine clearance!
-Normal to minimal impairment: >50 mL/min -Moderate impairment: 10-50 mL/min -Severe impairment: <10 mL/min |
|
|
What may happen to therapeutic levels of some drugs when patients are on hemodialysis?
|
-Therapeutic levels may be lost when pts are put on dialysis
|
|
|
What chemical characteristics of drugs may affect the rate of drug removal in a hemodialysis patient?
|
MW
Vd Lipid solubility Water solubility Plasma Protein binding |
|
|
How can the type of dialyzer affect rate of drug removal in a dialysis patient?
|
Conventional Dialyzer:
--cuprophane membrane--removes small MW drugs High Flux Dialyzer: --polysulfone memb--removes large MW drugs |
|
|
What is the sensible approach to dealing with increased rate of drug removal in a dialysis pt?
|
Administer maintenance dose at the end of each dialysis tx
|
|
|
When evaluating a treatment failure, what should be considered?
|
Possibility of patient non-compliance
|
|
|
What are the determinants of patient compliance?
|
-Clinician
-Disease -Tx regimen -Patient (pediatric pt, elderly pt, guardian factor) |
|
|
What are the 5 conclusions we can draw from the general principles of pharmacology?
|
Drugs seldom exert beneficial effects w/out also causing adverse side effects
There are no “absolutely” safe bio active agents Clinician must identify the pharmacologically compromised patient Avoid misprescribing, over/under prescribing, or inappropriate prescribing Be aware of gimmicks and techniques used by drug seekers to get controlled substances |
|
|
What is pharmacogenetics?
|
Receptors and metabolizing enzymes are variable traits
(a phenotype that expresses genotype) --produce individual or familial differences in drug efficacy |
|
|
What are beta 2 receptors specific for? What happens if they are slightly changed?
|
Epinephrine!
--single amino acid substitution can make a large difference in binding affinity and specificity --Alpha 1 receptors are less specific --even further individual differences exist just as in hair color, eye color, blood group, etc. |
|
|
In pharmacogenetics, what are 3 things that can greatly affect the response to a drug?
|
--Variability in receptor affinity
--intrinsic activity --Tissue metabolism |
|
|
Is response phenotypic or genotypic?
|
Response is phenotypic.
|
|
|
What is the bottom line for a patient who has homozygous mutant receptors that reduce metabolic function and/or lower drug affinity?
|
Should not take drugs that act on these receptors!!
--less response, inability to metabolize--INC toxicity |
|
|
What can be used to determine safe dosage in warfarin patients?
|
Genetic fingerprinting!
(otherwise it’s trial and error that leads to hospitillizations and deaths) Dose: -Too little—stroke -Too much—life threatening bleeding (20-30% are either very fast or very slow to metabolize it…pharmacogenetics can determine and help!) |
|
|
What are the tools of pharmacogenetics?
|
mRNAs—reverse transcriptase--cDNAs (virus/plasmid)
--cDNA library -- Sequence polymorphisms (PCR) --determine +/- responses with dosage! |
|
|
What can cDNA sequences identify?
|
Specific genes and polymorphisms
|
|
|
What can be done after genes are identified?
|
You can use genomic DNA to identify polymorphisms and provide individual assessment of drug sensitivity.
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Where do the fibers of the sympathetic nervous system run?
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--T1-L2 (or L3) nerve fibers run to ganglia
--Ganglia in paravertebral chain ganglia OR prevertebral ganglia in abdomen near the celiac and superior and inferior mesenteric arteries --postganglionic cell travel to target tissues |
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What do postganglionic sympathetic cells primarily release?
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Nor-epi!
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What sympathetic innervations stimulates the release of epinephrne?
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Preganglionic sympathetic cells synapse directly with adrenal medulla
--adrenal medulla secretes primarily epi! |
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Where do the fibers of the parasympathetic nervous system run?
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-Pregang cells Carried by cranial nerves III, VII, IX, X and by S2-S4
-synapse in ganglia closely associated w/ target tissue --postgang cells are relatively short |
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T/F—Postgang sympathetic fibers may pass through parasympathetic ganglia.
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True! (tissue receives both types of control)
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How can the ANS stimulate or inhibit a reflex reaction?
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-Afferent (sensory) inputs can stim/inhibit reflex activation of efferent (motor) output of presynaptic cells
--stimulate postsynaptic cells to mediate response in tissue -Reflex may be local or involve ANS nuclei in brain |
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What is the neurotransmitter of all pregang fibers (both symp and parasymp)?
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Ach
(fibers are cholinergic) |
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What type of receptors are on the cell bodies of the postganglionic cells that synapse with the pregang fibers?
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Nicotinic receptors (receive Ach)
--”ionotropic” (these receptors are also stim by Ach release by motor neurons) |
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What sites have muscarinic receptors?
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--Postgang cells of the parasympathetic NS
--Postgang cells of som sympathetic NS (sweat glands, bv’s) |
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What is a muscarinic receptor?
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G-protein coupled receptor, “metabotropic” receptor
(receives Ach) |
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How does the ANS work on the heart, smooth muscle, and glands?
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Sympathetic—Norepi
Parasympathetic—Ach |
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What are most postgang sympathetic cells?
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Adrenergic -- release norepi
(except cells of adrenal medulla--epi) |
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T/F—Depending on receptor type, epi, norepi, and Ach may exert different effects in different tissues.
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True.
(nicotinic and muscarinic receptors may also according to G-protein association) |
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How are multiunit smooth muscles controlled?
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Relatively finely
Ex) iris, arterioles |
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How are single unit smooth muscles controlled?
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Less finely-- forms syncitium
Ex) gut |
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How can sympathetic stimulation be mediated?
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Circulating Epi or locally released norepi
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What do Gs, Gq, Gi, and Go stand for?
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Gs=stimulates adenylyl cyclase
Gq=stimulates phospholipase C Gi=inhibits andenylyl cyclase Go=activates K+ conductance |
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What are the 3 subnits of G-proteins?
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a, B, y
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How is acetylcholine synthesized?
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Acetyl CoA + choline –cholineacetyl transferase-- Ach
Then it is packaged in vesicles and secreted by pregang and postgang cells. If pregang cells-- nicotinic receptors If postgang cells--muscarinic receptors |
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What are varicosities?
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Enlargements on branches of postganglionic celss that release neurotransmitters (NTs)
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What are the 5 types of muscarinic receptors that mediate parasymp control in diff tissues?
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M1—gastric/salivary secretion; Gq (Gi, Gs??)
M2—slow heart rate; Gi M3—Gastric/salivary secretion, eye accomidation, VASODILATION; Gq M4—CNS; Gi M5—CNS; Gq |
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Does Ach mediating parasym stimulation excite or inhibit specific tissues?
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Can do either!
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What are the most common muscarinic receptors?
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M1 and M3 (Gq pathway)
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What is the Gq pathway?
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Gq activate phospholipase C (PLC)
--PLC catalyzes breakdown of phosphadidyl inositol to inositol triphosphate (IP3) --IP3 stimulates release of Ca2+ from ER --Ca2+ binds calmodulin --activate myosin light chain kinase --stimulates smooth muscle contraction |
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What are the 2 enzymes that can break down Norepi and Epi?
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Catecholamine O methyl transferase (COMT)
-- in target cell Monoamine oxidase (MAO) -- in secreting neuron |
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What happens when norepi binds a2 receptors?
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Feed back to inhibit synth and secretion of norepi
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What is the synthetic pathway of norepi?
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Tyr--dopa--dopamine--norepi
(in secreting neuron) |
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What happens when Norepi bind a-1 receptors?
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a-1 receptors activate the Gq pathway
--stim release of Ca into cytosol--ativate myosin light chain kinase--contraction of smooth muscle In arterioles! |
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What 3 receptors initiate the Gq pathway?
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M1, M3, a-1
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What does IP3 signal?
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Release of Ca2+ from ER
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How is myosin light chain kinase activated?
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INC Ca2+ in cytosol allows cross bridge formation and ATP cycling
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T/F—Both symp and parasymp innervations can cause contraction of smooth muscle.
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True! (M1, M3, a-1)
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What does stimulation of alpha adrenergic receptors cause?
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Periperal vasoconstriction of arteriolar smooth muscle
(usually stim by postgang symp NE) |
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What might OTC cold remedies use to dry up a runny nose?
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Alpha adrenergic agonists--constrict nasal blood vessels
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During sympathetic stimulation, what do local factors promote in metabolically active tissues?
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(symp--a-1--constriction)
Local factors promote relaxation--metabolically active tissues receive MORE blood during exercise. Ex) local factors = CO2, low pH, temp |
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What is vasomotor tone?
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Maintaining the diameter of blood vessels and therefore blood pressure
--acted upon by symp, parasymp, and local factors |
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What G protein is associated with B-2 receptors?
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Gs
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What happens when Epi bind B2 receptors?
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Relax airway smooth muscle
--used to treat asthma |
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What happens in the Gs pathway?
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The a-subunit of Gs binds GTP and dissociates
--a-subunit activates adenylate cyclase --adenylate cyclase turns ATP into cAMP --cAMP activates Protein Kinase A (PKA) --PKA phosphorylates MLCK to prevent calmodulin binding --muscle relaxation |
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What breaks down cAMP?
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Phosphodiesterase
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What is theophylline?
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Inhibits phosphodiesterase (cAMP is not broken down)
--can be used to treat asthma b/c will potentiate effect of endogenous epi by inhibiting cAMP breakdown |
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Is it possible for a1 and B2 receptors in the same tissue to oppose eachother to reach a common goal?
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Yes!
Ex) During filling of the bladder, B2 relax the detrusor muscle (allows for filling) and a-1 receptors stimulate contraction of sphincters |
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What happens during the emptying phase of the urinary bladder?
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-Symp stim is inhibited!
-Parasymp stim of muscarinic receptors (M1) --contraction of detrusor muscle |
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What is Hytrin?
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a-1 blocker that further relaxes bladder and urinary tract smooth muscle
--facilitate urination in men w/enlarged prostate |
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What type of receptors mediate salivary secretion?
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Muscarinic! (Ach—signal)
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What is pilocarpine?
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Muscarinic agonist used to stim salivary flow
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What type of receptor induces contraction of the pupil?
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Muscarinic! (Ach—signal, released by CNIII)
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What type of receptor dilates the pupil?
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a-1 (Norepi—signal)
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What is Atropine?
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Muscarinic inhibitor
--causes relax of pupil constrictor--pupil dilation (aka—belladonna) |
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What are some examples of muscarinic stimulation of smooth muscle or secretion?
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Gut—INC peristalsis, DEC sphincter tone
Eye—pupil constriction Digestive glands—saliva and secretions INC Urologic—constrict detrusor, relax sphincter |
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What are 3 chatecholamines and what are the derived from?
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Catecholamines are derived from Tyrosine:
Dopamine Norepi Epi (aka—adrenaline) |
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What are receptors for Norepi and Epi called?
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Adrenergic receptors
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What do a-1 receptors respond to?
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Epi and Norepi
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What do B-1 receptors respond to?
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Epi, Norepi, and Isoproterenol
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What do B-2 receptors respond to?
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Epi and Isoproterenol
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What is Isoproterenol?
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B-agonist -- similar to epi
(used to treat bradycardi, heart block, sometimes asthma) |
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What does epi do?
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-Constricts blood flow in capillaries (a-1 receptors)
Ex) injection, OTC cold meds -Dilates airway and large blood vessel smooth muscle (B-2 receptors) Ex) inhaler |
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What G protein is the a-2 receptor coupled to?
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Gai -- inhibits adenylate cyclas and cAMP synth
(counteracts B1 receptor that activates Gas and stime cAMP synth) |
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What do prejunctional a-2 receptors cause?
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--Inhibit release of norepi
--Cause vasodilation |
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What is Clonidine?
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a-2 agonist --inhibit NE, cause vasodilation
used to treat high BP |
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What is the primary mode of synaptic breakdown of catecholamines?
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-Mainly in PRE-synaptic cell
-- MAO (monoamine oxidase) |
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What is the systemic breakdown of catecholamines?
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-Mainly in LIVER
--MAO and COMT (catechol-o-methyl transferase) |
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How effective is the systemic breakdown of catecholamines?
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Very effective!
-High 1st pass effect of any ingested -Rapid inactivation of any circulating |
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In addition to catecholamines, what does MAO also degrade?
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-Serotonin
-Histamine |
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How many isoenzymes of MAO exist?
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2-- A and B
--occur in diff locations --do have selective inhibitors |
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What are the types of drugs that act on adrenergic synapses?
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Direct receptor agonist
Direct receptor antagonist Inhibitors of vesicular uptake Inhibitors of degredation (MAOi or COMTi) Inhibitors of cellular reuptake ‘False Transmitters’ (bind but don’t activate) |
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What are the primary actions of a-1, B-1, and B-2 receptors?
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a-1 =constricts blood vessels
B-1=stim heart rate and contractility B-2=relax smooth muscle |
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What is a good way to remember the difference between B-1 and B-2?
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1 heart, 2 lungs!
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What are ALL parasympathetic responses mediated by?
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Muscarinic receptors**
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What is the predominant adrenergic receptor in the heart?
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B-1
(norepi release from symp nerves to the heart activates only B-1) |
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What type of receptors are stimulated by release of Epi from the adrenal medulla?
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B-1 and B2
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In most smooth muscles including blood vessels, what do a-1, B-2, and a-2 receptors cause?
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a-1--contract smooth muscle (constrict)
B-2--relax smooth muscle (dilate) a-2--inhib NE release--relax/dilate |
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What are blood vessels in skeletal muscle innervated by?
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Symp nerves that release Ach--muscarinic receptors
--Vasodilation |
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T/F—The human parotid glands do NOT receive sympathetic innervations.
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True! Parasymp--muscarinic
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What is the innervations of the sweat glands?
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Sympathetic!
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What is odd about most sweat glands even though they have sympathetic innervations?
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Muscarinic receptors! (Ach=signal)
[during activity--sweat!] |
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What is an exception to this?
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Sweat glands in palms-- a-1 stim
(you get nervous--sweaty palms) |
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What is the prominent location of a-1 receptors?
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Vascular smooth muscle
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How do a-1 receptors work?
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Gq-- activate IP3-- INC Ca2+--activate MLCK
contraction! INC blood pressure! --restrict blood flow to areterioles and capillaries to restrict blood flow to slowly metabolizing tissues |
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What is the predominant location of a-2 receptors?
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Nerve cells! (pre* and post synaptic)
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How do a-2 receptors work?
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Gi--inhibit cAMP-- DEC Ca2+-- nerve cell excitation
Vasodilate DEC blood pressure! DEC pain perception |
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What is the predominant location of B-1 receptors?
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Heart
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How do B-1 receptors work?
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Gs--stim cAMP--INC Ca2+
INC heart rate INC heart contraction force INC cardiac output |
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How are B1 receptors in the heart stimulated?
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-Locally by Norepi
OR -By Epi in circulation |
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What is the predominant location of B-2 receptors?
|
Smooth muscle in skeletal muscle arteries, bronchi, uterus
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How do B-2 receptors work?
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Gs--stim cAMP--inactivate MLCK--relax!
DEC contraction DEC blood pressure DEC labor DEC bronchial constriction --Relax large bv’s and airways --provide more blood flow |
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What primarily activates B-2 receptors?
|
Epi!
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What do Beta-1 Blockers do?
|
Reduce workload of heart
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What do Beta-2 agonists do?
|
Relax airway smooth muscle
(albuterol, salmeterol) |
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What do M2 parasympathetic receptors do?
|
Activate Go in nodal tissue
--DEC heart rate --Balance symp stim |
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What G protein is coupled to muscarinic receptors found in the pacemaker cells of the heart?
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Go (activated by Ach)-- activates K+ channels
--K+ leaves the cell-- Membrane hyperpolarizes --SLOWS heart rate |
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T/F—Ach can activate ion channels by binding Muscarinic AND Nicotinic receptors.
|
True!
Direct--Nicotinic ligand gated ion channel Indirect--M2--Go |
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What do M3 parasympathetic receptors do?
|
Stimulate NO synth in vascular endothelium
--INC vasodilation |
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How do M3 receptors stimulate NO synthesis?
|
G protein activates PLC-- INC Ca2+-- Ca binds calmodulin
-- activates NO synthase in vascular endothelium |
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How does NO relax smooth muscle?
|
NO rapidly diffuses to smooth muscle layer of blood vessels
--activates guanylate cyclase--INC cGMP Relax vascular smooth muscle Dilates bv’s to INC blood flow |
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What is nitroglycerin?
|
A substrate for NO synthesis
--relax coronary arteries |
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What breaks down cGMP?
|
Phosphodiesterase-5 (PDE-5)
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How does Viagra (silendafil) work?
|
Inhibits PDE-5 -- prolong INC cGMP -- prolong relax of smooth muscle and INC blood flow
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What is tyramine?
|
Compound found in red wine and some fermented cheeses
--Stimulates catecholamine release (similar to amphetamine) |
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In addition to nicotinic receptors, what may synapses between pre and post ganglionic cells also have?
|
-Other receptors (Muscarinic, adrenergic)
-Interneurons |
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What is serotonin synthesized from?
|
Tryptophan (Serotonin = 5-hydroxytryptamine, 5HT)
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Where is serotonin active?
|
Gut, platelets, brain
|
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What are low levels of serotonin associated with?
|
Depression
|
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What do Selective Serotonin Reuptake Inhibitors (SSRIs) do?
|
Prevent reuptake of serotonin by pre-synaptic cells
--INC serotonin levels at receptor level |
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What degrades Serotonin upon reuptake?
|
MAO (also degrade catecholamines)
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How many receptors does serotonin have?
|
15
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T/F—Abused drugs rarely affect adrenergic and serotonergic synapses.
|
FALSE! Many do.
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What does cocaine do?
|
Prevents Norepi reuptake
--large sympathetic effect |
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What does methamphetamine do?
|
-Blocks vesicular uptake
-Stimulates release (mainly dopamine) --large high followed by prolonged low |
