Neuro Review

3/27/2016
Physic
DANILHAMMOUDI.MD
sinoemedicalassociation
USMLE1REVIEW
Physic
A35yearoldmaleisgiven0.03molesofthiocyanateintravenouslytomeasuretotalextracellularwaterand0.03molesofI131albumintomeasure
plasmavolume.Aftercorrectingforlosesfromthebody,itisdeterminedthattheinitialmixedconcentrationsofthesesubstancesinplasmawere
0.008mol/LI131albuminand0.0015mol/Lthiocyanate.
Whatisthevolumeofhisextracellularcompartment?20L
Whatisthepatient'sbloodvolume(assumehematocrit=0.40)?6.3
Whatisthevolumeofhisinterstitialcompartment?16.2l
Thiocyanatedistributesthroughouttheextracellularspace.Thevolumeoftheextracellularcompartmentcanthereforebedeterminedusingthisdyebyperformingthe
followingcalculation:
V=quantityofdyeadded
Mixedconcentration
V=0.03/0.0015=20l
Thequestionindicatesthatthecalculationshouldbedetermined"aftercorrectingforlosesfromthebody."Alternatively,ifthequestionindicatesthequantityofdyelost,
thisvaluemustbesubtractedfromtheinitialquantityofmarkeradded.
Thisquestionrequirestwosteps,thefirstofwhichistodetermineplasmavolume.I131albuminisalargemoleculeandremainsintheplasmacompartment.Itis
thereforeausefulmarkerindeterminingplasmavolume.Fromthevaluesgiveninquestion1,plasmavolumecanbecalculatedasfollows:
v=0.03/0.008=3.75
Thesecondstepistodeterminewhatthecorrespondingbloodvolumewillbegivenahematocritof0.40:
Bloodvolume=plasmavolume/[1hct]
Bv=3.8/10.4=6.3
Nomarkerispresentthatcanspecificallytargettheinterstitialspace.Rather,twomarkersareusedonetomeasurethevolumeoftheextracellularcompartment,andthe
othertomeasurethevolumeoftheplasmacompartment.Thesetwovolumesweredeterminedinthefirsttwoquestionsofthesequence.Theinterstitialspaceisthen
determinedasfollows:
Imterstitialvolume=extracellularplasmavolume
203.8=16.2
HOMEOSTASIS: The life of every organism depends upon the preservation of a constant internal environment (volume and composition).
Objectives
To identify the volumes and ionic composition of the major fluid compartments in the human body.
To explore how the body maintains a constant volume and composition of body fluids.
To define the role of epithelial cells in fluid and electrolyte balance.
To understand how epithelial cells function.
To define the overall functions of the kidney.
BODY FLUID WATER AND ELECTROLYTE COMPOSITION
The body can be divided into several major fluid compartments: Intracellular fluid (ICF) is within cells and accounts for about 2/3 of the body fluid. Interstitial fluid, (ISF)
is located between the cells and outside of the blood stream. Intravascular fluids (IVF) include plasma and red blood cells. Finally, transcellular fluids (TCF) are specialized
glandular secretions. The term extracellular fluid (ECF) is used to mean the sum of ISF + IVF + TCF. ECF accounts for about 1/3 of total body fluids.
Water Compartments: Total body water is between 50 to 80% of total body weight, depending on the quantity of adipose tissue. Water is freely exchangeable between all
body compartments. (There are about 42 liters of water in a 70-kg person.)
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The amount of water in each body compartment is dependent upon the number of solute particles in each compartment. This is a colligative property of a solution because it
depends solely on the number of solute particles and not on any specific property of a solute such as charge or size. For example, in this diagram a semi-permeable membrane
that is permeable to water but not to solutes separates two solutions. In Figure I. there is no pressure difference between the two chambers and the solute content is also
the same. If solute particles are added to compartment A without a change in volume, the osmotic pressure in compartment A will increase as water will try to move in.
(Remember water will flow from an area of lower to one of higher solute content). If however, as shown in Figure III, the volume can change then water will flow from
compartment B to A. To a large extent Figure III does depict what happens in the human body. If we eat salt, we increase the number of particles in our extracellular fluid,
water moves from within our cells into the extracellular space.
The second factor that determines how much volume is contained within a particular body compartment is the hydrostatic pressure. As shown in the accompanying Figures IIII. If the hydrostatic pressure in compartment A is increased water will flow into compartment B. Fluid is constantly leaving the blood stream and entering the interstitial
fluid space because of the hydrostatic pressure produced by the heart. Most of the fluid that enters the interstitial space ultimately returns back to the blood. However, in
some cases when hydrostatic pressure increases in some disease states, edema can occur.
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IONIC COMPOSITION OF THE BODY WATER COMPARTMENTS
mEqui per liter
Cations
Plasma
ISF
Cell
Na+
142.0
145.1
12
K+
4.3
4.4
150
Ca2+
2.4
4*
Mg2+
1.5
34
Total
154
153.0
200
Anions
Plasma
ISF
Cell
Cl-
104
117.4
HCO3-
24
27.1
12
Phosphates
2.3
40
Proteins
14
0.0
54
Other
5.9
6.2
90
Total
149.9
153.0
200
The distribution of ions is different between the major compartments of the body. The ionic composition of plasma and interstitial fluid is quite similar with differences
reflecting the inability of large solutes to cross the capillary walls. In contrast, large differences are evident between the ionic composition of intracellular fluid (ICF) and
ECF. The predominant cation in ECF is sodium whereas in ICF potassium is most abundant. The differences in anion concentration between ICF and ECF are also striking.
Whereas, in ECF, chloride is a major anion, in ICF its concentration is relatively minor. Major anions in ICF are inorganic and organic phosphates, and proteins.
It is important to understand that, although differences exist in the total electrolyte concentrations between ICF and ECF, the osmolality in the two compartments is equal.
The apparent contradiction arises because values in the Table are total concentrations (bound + free). Only solutes in free solution are osmotically active.
(*Note that intracellular free Ca2+ concentration is approximately 100 nM.)

CHECK YOUR KNOWLEDGE
Serum values measured in two people (electrolytes in mM, pCO2 in mm Hg). Without looking at the proceeding table determine which person is normal and which one is not. Also
what is your diagnosis?
#1
#2
Na+
156
140
HCO3-
10
25
Cl-
113
102
pCO2
23
40
pH
7.26
7.42
Often the body is divided into two compartments, intracellular and extracellular fluids. There are large differences in the concentration of solutes between ICF and ECF. For
example, ECF is rich in Na+ and Cl-, whereas, ICF is rich in K+ and organic anions. The organic solutes which are found inside of cells include polyphosphates such as ATP, amino
acids, proteins and sugars.
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Cell water volume is dependent critically upon intracellular content of particles such as K+, and organic anions. In contrast, the extracellular volume is determined by the
content of particles such as Na+ and Cl-.
There are many reasons why a cell has to control its composition. For example, nerve and muscle conduction depends upon a proper balance of Na+, K+ and Cl- within the cell.
Plasma cell membranes that separate all cells from the extracellular fluid are permeable to water. However, they are also permeable to solutes such as Na+, K+ and Cl-. Because
all cells are permeable to Na+ and to K+, Na/K pumps are important in maintaining the composition and the volume of the ICF. The Na/K pump is also important in controlling cell
volume.
If there is an interruption of cellular metabolism causing a fall in intracellular ATP, the Na/K pumps will begin to work less effectively. Na+ begins to enter and K+ leaves. The
problem is that the organic anions are impermeable and cannot leave. Because extracellular Cl- is higher than intracellular Cl- and cell membranes are permeable to Cl-, Cl- will
try to enter bring with it a negative charge and dragging in Na+ along with it. The increased number of Na+ and Cl- particles within the cell cause water to enter and swelling
occurs. This process is particularly lethal in parts of the body such as the brain where cells swelling in a restricted space can be particularly damaging.
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Fluidcompartment
Totalbodywater(TBW)=ICF+ECF[antipyrin,tritium]
ECF(1/3TBW)=Plasma+Interstitialfluid[inulin,mannitol]
Plasma[EvansBlue,I131albumin]
Interstitialfluid=ECFPlasma
ICF(2/3TBW)=TBWECF
REGULATION OF CELL VOLUME

Healthy cells in the body can also regulate their volume when the number of particles in ECF changes. For example, in this illustration, salt is added to the ECF in Figure II,
causing water to shift from cells into ECF, causing cell shrinkage. Cells will then take up solutes and recover the lost water (Figure III). Once back to their original volume
(compare Figure I and IV), they stop taking up additional solues. In summary, each individual cell in the body controls its own intracellular solute composition and cell volume.
All cells are permeable to water and to small solutes such as Na+, K+ and Cl-. The Na/K pump plays a critical role in controlling intracellular solute content. During changes in
ECF osmolality, cells can alter their input or output of solutes to maintain a constant volume.
Control of ECF Volume

Na/K pumps are important in maintaining the composition of ICF, whereas epithelia determine the composition of ECF. Epithelia maintain ECF by matching the intake and
outflow of body fluids. The only normal route of fluid intake is via the epithelia of the gastrointestinal tract. Several routes of outflow include epithelia of the kidney, and the
GI tract, and those that generate specialized secretions such as airways fluid, sweat, and tears. The major route of outflow is normally through the kidneys. Thus, for our
studies, we will focus specifically on the kidney. However, you should keep in mind that in some circumstances other routes could be significant. For example, during exercise
the amount of fluid loss can be significant. Also in some diseases which cause massive diarrhea fecal loss can be very large reaching from 5 to 10 liters per day. Within 1-5
days severely affected patients could die from loss of fluid.
Intake
At Rest
Exercise
Ingested Fluids
2100
6400
From Metabolism
200
200
2300
6600
Total
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Output
At Rest
Exercise
Skin
350
350
Lungs
350
650
Sweat
100
5000
Feces
100
100
Urine
1400
500
2300
6600
Total
GENERAL PRINCIPLES:
Steady State: An organism is in a steady state when total body water and electrolyte content are constant, and Input = Output.
Normal input of solutes and water occurs primarily as dietary intake. Normal losses of fluids and solutes occur either via renal and extrarenal routes. Although renal excretion
is the major pathway, extrarenal losses can be considerable in some circumstances.
Major routes of extrarenal output include:
Evaporation: Pure water (about 1 L/day) is lost via the respiratory passages, and by evaporation through the skin.
Sweat: Sweat has appreciable quantities of electrolytes and urea. Losses at rest are usually small. However, during strenuous exercise, sweat losses can be as much as
5 L/day, (3-5 times the normal urine output/day).
Hole in the Bucket Model of Fluid Balance:
The model shows a bucket with a hole in the side. Over a limited range, when inflow is increased the level of the bucket will adjust until a new steady state is achieved with
input equal to outflow. Although the bucket model illustrates steady state conditions that vary with flow rate, the human body does not regulate the volume and composition of
body fluids by simply achieving a steady state. This simple mode is missing several important components.
Set Point: Optimum conditions exist within the body which allow the organism to perform normally body functions. These optima are regulated quite rigorously. Thus, input and
output are regulated not only to maintain constant internal composition, but also to retain an optimal composition. For example, extracellular fluid volume (ECF) is regulated at
a set point which maintains an optimal degree of "fullness of the circulatory system" relative to its capacity.
Sensors, Mediators, Effectors: To maintain a set point the body must have sensory mechanisms to evaluate the magnitude of the components in the internal environment.
Many sensory mechanisms are located throughout the body that monitor blood pressure, temperature, volume, ionic composition, O2, CO2, pH. When some change in either
input or output changes a body component away from the set point, mediators (hormones, nerve signal etc.) report the change to an effector that then changes either input or
output.
Homeostatic Bucket Model
The homeostatic bucket model is more realistic of how the body controls a physiological parameter. The model attempts to control the bucket volume at a setpoint. To do this,
a sensor must be able to evaluate the level of water in the bucket, and determine the magnitude of the setpoint. When the inflow is increased the water level rises. The
sensor evaluates the change in water level and sends a signal via a mediator to an effector which transiently increases water outflow. At this point efflux is greater than
inflow until the bucket volume reaches back to the original set point. When the bucket volume returns to the set point, the outflow decreases and inflow equals outflow at a
new steady state.
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Physiological Setpoints. It is important to note that setpoints are not single values but vary over a normal range. This table lists some physiological values and their normal
range. Also given are some approximate non-lethal limits that can be tolerated for short periods without death. Values outside of the normal range are caused by illness.
Knowledge of normal physiological values and concerning how to recognize the severity of the disease state is an important component of your training. Ions in meq/l, glucose in
mg/dl, temp in FC.
Normal Range
Approximate Non-lethal Limits
Na+
138-146
115-176
K+
3.8-5.0
1.5-9.0
Ca2+
2.0-2.8
1.0-4.0
Cl-
103-112
70-130
HCO3-
24-32
8-45
Glucose
75-95
20-1500
Temperature
98.0-98.6
65-110
pH
7.3-7.5
6.9-8.0
FUNCTION OF EPITHELIA
Structural Polarity
Shown below is an example of a non-polar muscle cell which can only transport ions in and out. Epithelial tissues are composed of polar cells which have different structural
components on their lumen and blood facing membranes. These epithelial cells adhere tightly together to form sheets that separate compartments such as inner and outer
surfaces of the eye. A fluid that is secreted by the cornea moistens the surface of the eye. These sheets are also organized into various structures such as tubules (kidney),
sacs (gallbladder), and canaliculi (liver). The zone of adhesion between epithelial cells is a highly specialized region which act not only to hold the epithelial cells together but
also as a barrier to the migration of plasma membrane proteins from one side of the cell to the other.
Major Components of epithelial cells. Because epithelial cells move solutes and water across a sheet of cells, they must be polarized such that substances more in one
membrane, cross the cells and move out across the other membrane (see A). Therefore, the transport proteins must be different on each membrane (see B). Once these
transport proteins are made within a cell, they must be sorted into the proper membrane (see C) and once in the membrane, they must be keep in place (see D).
The occluding zone or "tight junction" is a barrier that restricts the free diffusion of protein molecules within the plasma membrane. This is very important because it divides
epithelial cell membranes into two portions, a lumenal or apical portion, and a blood facing or basolateral portion, each with different membrane proteins.
Structural Features of Transporting Epithelia.

Plasma membranes of epithelial cells are highly specialized. These specializations function to maximize the cell surface available for transport and to act as extracellular
compartments where solutes are concentrated
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Functional Polarity
Epithelia can transport solutes and water in two directions: Reabsorption is the transport from some lumenal compartment back into blood. The fluid transported is either
isotonic, or hypertonic to plasma. Secretion is transport from blood into some lumenal compartment. The fluid can be either isotonic or hypotonic.
Two-membrane Model For Transepithelial Solute Transport: The directional nature of transporting epithelia requires that substances enter the cells across one cell
membrane and exit across the other. Ions enter epithelial cells by two pathways, via ion channels and/or by means of carrier-mediated transport systems. The energy for the
entry of ions usually comes from sodium concentration differences across the plasma membrane generated by the Na+-K+ ATPase pump. This pump is the major pathway for
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sodium to exit and for potassium to enter the cell. The Na+-K+ pump is most often located on the blood facing membrane. The pump lowers intracellular sodium to 10-20 mM
and raises intracellular potassium to 90-120 mM. The energy derived from electric and ionic concentration differences for Na+ across the plasma membrane are available for
use by other transport systems. Thus the Na+-K+ pump plays two important roles, one as the exit step for Na+ and a second as the generator of the ion gradients essential to
the solute entry mechanisms. Two models of transport are shown in these Figures. Note that although the Na/K pump is located on the blood facing membrane, the upper
model depicts reabsorption and the lower secretion. The difference is the positioning of the individual transporters.
WATER TRANSPORT
Water movement across epithelia tissues is coupled to solute transport. Water flow can be described by the following equation:
where Lp = the hydraulic water permeability, P = hydrostatic pressure difference and is the osmotic pressure difference. P is close to zero across most epithelial tissues.
Movement: The mechanism by which epithelia transport fluids without a large concentration gradient is as follows
Solute Coupled Water Movement:
1. It is thought that apical solute entry mechanisms raise the osmolality of the cytoplasm by 2 m0sm when compared to the apical solution.
2. Similarly, basolateral Na-K+ ATPase pumps move solutes into the restricted intercellular space raising the osmolality of the solution by about 3.5 m0smol with respect to
cytoplasm
3. This small gradient ( 5.5 m0smol) which is too small to measure experimentally between apical and basolateral solutions, is thought to be enough to support large movements
of water across highly water permeable cell membranes provided that the Lp of the epithelium is very high.
Highly Water Permeable Epithelia: Epithelia that transport large amounts of solute and water have long and highly enfolded lateral intercellular spaces. The apical surface
area is usually enlarged by long and numerous microvilli called the brush border. All surfaces of these cells are highly permeable to water (large Lp).
Water Impermeable Epithelia. Other epithelia have low water permeability (small Lp) of their apical surfaces. These cells are more flattened, and have fewer and shorter
microvilli. They transport a solution which is strongly hypertonic. In some epithelia water permeability is regulated. For example, in the absence of antidiuretic hormone (ADH),
the collecting duct has very low water permeability. ADH increases the water permeability of the collecting duct allowing water to be reabsorbed.
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FUNCTIONS OF THE HUMAN KIDNEY

1.One of the most important roles of the kidney is to maintain the volume of the extracellular fluids. Extracellular fluids bath every organ of the body. The body
monitors the degree of fullness of the circulatory system and directs the kidney to alter the volume of excreted fluid.
2.The concentration of solutes in the extracellular fluids is maintained within narrow limits. Some of these solutes include glucose, Na+, K+, and HCO3- and H+. The kidney
regulates the excretion solutes in response to variations in dietary intake or metabolic production to preserve the concentration of solutes in extracellular fluid.
3.The kidney eliminates a variety of metabolic wastes and foreign substances from the body. Urea is normally the most abundant metabolic by-product in urine. Other
waste products include creatinine and bilirubin. Foreign chemicals may include food additives and many drugs.
4.The kidney synthesizes glucose and generates NH3. The renal cortex produces more glucose per gram of tissue than the liver. The kidney in the renal medulla also
consumes most of this glucose.
5.The kidney produces or modifies important regulatory hormones such as erythropoietin and 1, 25-dihydroxyvitamin D3.
UNDERSTANDING RENAL PHYSIOLOGY

1.kidney structure and function
2.fluid and electrolyte physiology
3.hormonal control
KEY TOPICS
homeostasis
ionic composition of ICF, ECF, and ISF (learn normal values for Na+, Cl-, Mg2+, Ca2+, proteins, etc..)
body fluid compartments
steady state, set point, mediators, effectors
physiological setpoints (for reference only)
absoption and secretion (general concepts - do not memorize individual transport models)
overall function of transporting epithelia
solute coupled water transport
overall concepts of structrual and functional polarity
overall functions of the kidney
MUSCLECELLPHYSIOLOGY
Myofibril
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Sarcomere
Thick filament ( myosin ) : 2 head ( bind to ATP & actin )
Thin filament :
contain actin, tropomyosin, 3 isoform of troponin ( I, T, C )
anchored at Z lines ( border of sarcomere )
T tubule : transit action potentials
Sarcoplasmic reticulum : calcium storage & release
In cross section:
6 actins can interact with each myosin. Actins are in a hexagonal array.
3 Myosins can interact, in triangular fashion, with each actin.
SKELETAL MUSCLE CONTRACTION: Myosin plays the role of an ATPase Actin-Binding Motor Protein.
Start with myosin bound to actin. When Myosin is bound to Actin, ATP is bound to the myosin head.
With ATP bound, Myosin can then detach from the actin thin filament.
Once detached, the myosin is free to hydrolyze the bound ATP to ADP + Pi. It hydrolyzes the ATP, and the ADP + Pi remain attached to the myosin head.
The myosin then reattaches to the thin filament.
Reattachment leads to the release of the Pi group, which in turn strengthens the interaction between the actin and myosin.
Rowing Stroke: With the ATP gone, the myosin head undergoes a conformational change, causing the actin and myosin to move relative to each other.
Then the myosin head releases the ADP.
Then Another ATP must bind to the myosin, in order for the myosin to release from the Actin to start another cross-bridge.
If there is no more ATP, Rigor Mortis results, in which the muscle is stuck in the contractile state, with myosin bound to actin.
REGULATION OF THE CROSS-BRIDGE CYCLE: Regulation is according to intracellular levels of Calcium and is mediated by Troponin Complex and Tropomyosin.
RELAXED STATE:
Tropomyosin is bound to the thin filament around its major groove, in the absence of calcium.
The Troponin Complex is periodically bound to the thin filament such that it blocks the interaction between Actin and Myosin.
CONTRACTED STATE
Calcium binds to the Troponin Complex, causing a conformational change in Troponin-C.
Troponin Complex (Troponin plus tropomyosin) removes itself from the thin filament as a result, such that Myosin can bind.
SMOOTH MUSCLE CONTRACTION

more slow contraction, requires less energy, greater forces over greater periods of time.
contraction can be maintained in low intracellular Ca++
Single unit vs. Multi-unit subtypes
Organs
Single unit
Multiunit
Small intestine, colon, uterus (myometrium), Ciliary muscle, iris muscles, bronchial muscle,
urinary bladder, ureters, lymph vessels, and tracheal muscle, vas deferens, and GI sphincters,
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smaller arterioles.
Gap junction & Many gap junctions, innervation :relatively

innervation
sparse.
and larger blood vessels.

Less gap junctions,higher innervation ratios
Depolarization
Slow Wave Potentials,rhythmical, graded

depolarizations, associated contraction
Stable,no spontaneous depolarization
Effect
Plasticity : stress relaxation
Tone : example in blood vessels and GI sphincters
Stimulation
Stretch induced contraction:Fast stretch
Intrinsic property: modified by nerves as well as

hormones and drugs
CHARACTERISTICS OF SMOOTH MUSCLE.

A. Spindle shaped cells, smaller than skeletal muscle
B. Gross : No sarcomeres (hence the name smooth). Actin/myosin ratio is greater than 10:1 in smooth muscle ( in skeletal muscle it is 2:1). No neat hexagonal
arrangement of actin and myosin like in striated muscle.
1.Intermediate filaments : cytoskeletal elements a structural backbone against which contraction occurs. Desmin and vimentin are 2 protein components of this
cytoskeleton.
2.Dense bodies contain the protein actinin (functionally analogous to z-lines in striated muscle). They serve as anchors for the thin-filament protein actin.
3.Gap Junctions : direct electrical communications between adjacent cells. Their density varies from tissue to tissue. Mechanical junctions also attach adjacent
smooth muscle cells.
4.No T-tubules and no terminal cistern system. (so, small size & lack of dependence on a muscle action potential for inducing contraction.)
5.Sarcoplasmic reticulum : poorly developed. Therefore, more dependent on an extracellular Ca++ for contraction than cardiac (partial-dependence) or skeletal
muscle (negligible-dependence).
C. Myosin plays a special role in smooth muscle.
1.Tropomyosin is associated with smooth muscle actin. No troponin is associated with smooth muscle actin (remember troponin-Iinhibits cross-bridge cycling in
striated muscle).
2.Myosin has six subunits: 2 paired heavy chains (a head & a tail region) & 4 light-chains (ass. with the head of the heavy chain. serve a regulatory function).
D. Hormonal Modification of Smooth Muscle. Hormones can change the basic character of smooth muscle.
high progesterone (pregnancy) :reduce the number of gap junctions in myometrial smooth muscle --> behave more like multiunit smooth muscle (relatively
quiescent). At , rising
high estrogen (term): smooth muscle hypertrophy and increase the number of gap junctions.--> behave more as a single unit smooth muscle (in parturition).
DIFFERENT PROCESS OF CONTRACTION IN SMOOTH MUSCLE THAN IN STRIATED MUSCLE.
1.Intracellular Ca++ rise -->trigger contraction (as in striated muscle)

1.Regulation occurs on the thick filament (myosin) not the thin filament (actin-troponin-tropomyosin) as used in striated muscle.
2.Ca++ binds calmodulin (4:1). The Ca-calmodulin complex binds to myosin light chain kinase (MLCK) to form an active enzyme Ca-calmodulin-MLCK complex. (This is a
different role for Ca++ than in striated muscle where it binds to troponin.)
3.The active Ca-calmodulin-MLCK enzyme complex phosphorylates a serine residue on 2 of the myosin light chains (P-chains or LC2 chains) associated with each myosin
head (thick filament head). This phosphorylation requires 1ATP.--high ATPase activity.
4.Myosin light chain phosphatase (phosphatase C) is continually removing the phosphates put on myosin light chains by active MLCK.
5.Fast cross-bridge cycling. same as in striated muscle. This cycling requires an ATP (second one) to bind the myosin head, hydrolyze to myosin-ADP-P, release the
myosin from actin, and reset the myosin head to a high potential energy 90o angle. Multiple cross bridge cycles, each with an ATP hydrolysis, can occur following a single
myosin light chain phosphorylation. Since myosin ATPase activity is high when the light chains are phosphorylated, this will occur rapidly and the smooth muscle will
shorten and develop force. Fast cycling and shortening occurs when MLCK/Phosphatase C activity ratio is high.
6.Model of the Latch State. maintain tone (force) with minimal expenditure of ATP. No shortening
1.If myosin light chains are dephosphorylated myosin ATPase activity decreases. This means that it is more difficult to release myosin heads from actin which
requires ATP hydrolysis.
2.The myosin heads that stay attached can hold force at the muscle ends. (Think of this latch state as analogous to rigor in striated muscle.)
3.A low myosin ATPase activity probably still exits even after dephosphorylation of the light chainson some myosin molecules. Those (actin-myosin head) bonds that
are broken by the low ATPase activity can proceed through cross-bridge reattachment in the usual manner if there is sufficient Ca++-calmodulin-MLCK present.
7.Efficiency is low, Economy is high because the ATP use is low to maintain force in the absence of external work (shortening). -->latch state.
8.Relaxation of smooth muscle is associated with low intracellular calcium concentrations. Low intracellular calcium concentrations are brought about by calcium
extrusion from the cell using the 3Na+/Ca++ exchanger and sarcolemmal Ca++ ATPase, and by reuptake by the sarcoplasmic reticulum using the Sarcolemmal ATPase.
These are similar to striated muscle cells.
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Gastrointestinalsystem
Endotrachealtubedeliverabledrugs
NAVEL:
Narcan
Atropine
Valium
Epinephrine
Lidocaine
Hepaticnecrosis:drugscausingfocaltomassivenecrosis
"VeryAngryHepatocytes":
Valproicacid
Acetaminophen
Halothane
Misoprostol
"YouneedthisinBED":
gastricmucousBarrier
PGE1
Diarrhea
1.Functionsofthegastrointestinaltractareregulatedbychemicalmediatorsincludinghormones,
paracrinesubstances,andneurocrinesubstances.
2.Neuralregulationofgastrointestinalfunctionsisintrinsicandextrinsic.
3.Establishedgastrointestinalhormonesincludegastrin,cholecystokinin,secretin,GIP,and
motilin.
4.Paracrinesubstancesincludesomatostatinandhistamine.
5.NeurocrinesubstancesincludeVIP,bombesin,andenkephalins.
Phases of Gastric-Acid Secretion:

Cephalic Phase: Anticipation of food ---> vagal stimulation.
Gastric Phase: Stomach distension. Gastric-acid secretion also stimulated by:
Amino Acids: phenylalanine, tryptophan
Alcohol
Coffee: some product other than caffeine
Calcium
Intestinal Phase: Entry of chyme into small intestine. Stimulating factors:
Proteins, protein digestion-products
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Distension of small intestine
Gastric acid secretion still remains relatively low 1.0 - 1.5 hours after a meal, because the food neutralizes the secreted acid.
Formation of Gastric Acid
INSIDE CELL: Carbonic Anhydrase forms H+ and HCO3- from CO2 and H2O (products of metabolism)
H+/K+-ATPase: The H+ is then excreted into the lumen, exchanging it for K+
HCO3- is exchanged for a Cl-, via a basolateral exchanger.
The Cl- is then also excreted into the lumen

Result: net excretion of HCl
Gastric Receptors:
Stimulatory:
Histamine H2 receptors
Muscarinic receptors
Gastrin receptors
Inhibitory:
Somatostatin receptors
Suggested, but not confirmed:
PGE2, PGI2 receptors
EGF Receptors: They are thought to interact with PGE2 to form new vessels (angiogenesis), which helps speed up the healing
PEPTIC ULCER DISEASE (PUD):
process.
TGF-alpha
DISTRIBUTION: 30% of ulcers occur in stomach, 70% in the duodenum.

PATHOGENESIS: Excess gastric acid production, Helicobacter Pylori.
SYMPTOMS:
Pain is aggravated by food.
Pain does not occur at stomach pH above 2.0
DIET: The following irritate PUD
Alcohol, tobacco, caffeine all stimulate gastric acid secretion.
Pepper is corrosive to gastric mucosa.
TREATMENT of PUD:
1. ANTACIDS:
EFFECTS: Should take them about 1 hour after eating for maximum effect.
At a pH of 3.3, 90% of gastric acid is neutralized.
Pepsin is reversibly inactivated at pH 6.0-7.0, and irreversibly inactivated at pH 7.0-8.0
ADVERSE EFFECTS:
Renal Dysfunction: Could form urinary stones or could accumulate metal ions in blood.
Excess Metals:
Excess NaHCO3: Can cause metabolic alkalosis, leading to alkalinization of the urine and hence renal stones.
Hypercalcemia and hyperphosphatemia also contribute to formation of renal stones.
Excess Mg+2: Neurologic, CV, neuromuscular dysfunction.
2. H2-BLOCKERS:
Excess Ca+2: Hypercalcemia

Weakness, nausea vomiting
Mental confusion, change in mental status
Anorexia
Milk-Alkali Syndrome: NaHCO3 and CaCO3 can lead to hypercalcemia, alkalosis, renal failure.
PHARMACOKINETICS:
Food slows absorption, so don't give with food.
Pregnancy:
All the drugs cross placenta, so don't give during pregnancy.
Cimetidine and Ranitidine get into breast milk.
Metabolism decreases with age. Give about half the dose to old folks.
ACTION: Block histamine ---> block acid secretion
H+ blockade is cyclical, according to the secretion of histamine.

ADVERSE EFFECTS:
Cimetidine:
Allergic reactions: leukopenia, skin rash.
Mental confusion
Gynecomastia and impotence: 50% occurrence with chronic usage of 1 year or longer.
Interfere with Phase-I oxidation (Cyt-P450) ---> prolong duration of theophylline, anticoagulants, propanolol.
Ranitidine: Interfere with Phase-I oxidation (Cyt-P450)
Famotidine: Muscle cramps, headaches, constipation
Nizatidine: No appreciable effects found yet.
3. PUMP INHIBITORS: Omeprazole has the highest initial healing rates for ulcers of all drugs.
ACTION: Binds irreversibly (covalently) to the H+/K+-ATPase acid-pump, completely blocking acid secretion, until more pumps are made.
Increases gastric levels continuously, rather than cyclically, as in the H2-blockers.
Hypergastrinemia: Gastrin levels are tonically higher due to disinhibition of Gastrin secretion.
PHARMACOKINETICS: Acid environment is required for the drug to work.
Drug is administered in enteric-coated granules, which dissolve in the intestine. This protects it from premature activation in
stomach.
Acid is required for the drug to work, so it has maximal activity when taken before meals.
Metabolized to active metabolites. Elimination is affected by renal and hepatic dysfunction.
ADVERSE EFFECTS: No significant effects found so far.
Stomach Cancer: Carcinoid tumors were found in one study in rats, probably due to the effects of hypergastrinemia.
A few reported incidents of gynecomastia and impotence.
DRUG INTERACTIONS:
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Due to its action, it inactivates drugs that require an acidic pH in order to work. Ketoconazole is inactivated because it requires acidic
pH.
Affects Cyt-P450 metabolism ---> delayed excretion of warfarin, phenytoin.
4. CYTOPROTECTIVE AGENTS:
ACTIONS: Generally they increase production of mucus, HCO3-, and prostaglandins.

SUCRALFATE:
STRUCTURE: Glucose + Sulfate + Al(OH)3
MECHANISM: In the stomach, the free SO4-2 group binds to proteins in stomach ---> increased production of mucus, HCO3-,
prostaglandins.
Sucralfate should not be administered with antacids: antacids prevent sucralfate from forming its protective gel in
gastric mucosa ---> neutralize its effects.
PHARMACOKINETICS: Sucralfate is not appreciably absorbed.
ADVERSE EFFECTS:
Constipation, 3%. Constipation often occurs with drugs that are not absorbed.
Aluminum Toxicity can occur in people with renal insufficiently.
Decreases absorption of Cyt-P450 drugs.
MISOPROSTOL:
MECHANISM: PGE1 analog
PHARMACOKINETICS: Misoprostol is well-absorbed in GI tract.

ADVERSE EFFECTS:
Diarrhea, because the drug is well-absorbed. This decreases if the drug is administered with food.
Vaginal bleeding in post-menopausal women.
Spontaneous abortion in pregnancies thus it's absolutely contraindicated.
5. ANTIBIOTICS: Recommended therapy for eradication of H. Pylori, and treatment of all ulcers found to be H. Pylori-positive (~60% of ulcers).
Regimen 1:
Amoxicillin 500 mg 3X daily14 days
Metronidazole 250 mg 3x daily14 days
Bismuth subsalicylate 300 mg 4x daily30 days
Regimen 2:
Omeprazole 20 mg 2 x daily14 days
Amoxicillin 500 mg 3x daily14 days
6.
ANTI-EMETICS:
LOCALLY-ACTING: Temporarily numb receptors in the GI tract, preventing vomiting

Viscous Lidocaine: Topical anesthetic increases the threshold of receptor-activity to vomiting.
Adsorbents and Demulcents: Act on stomach mucosa and/or GI receptors to make them less sensitive.
Kaolin and Pectin
Activated charcoal
Bismuth subsalicylate
Attapulgite
Cholestyramine
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Cola Syrup, Phosphorylated Carbohydrate Solution: They decrease GI muscle spasm-fewer inputs into vomiting centers.
DOPAMINE-ANTAGONISTS: Centrally-acting compounds that suppress dopamine also suppress the chemoreceptor trigger zone in the medulla.
PHENOTHIAZINES: Anti-psychotic agents are also anti-emetic.
Very low dose required. But still only administered for this purpose when other agents have failed.
INDICATIONS: Post-operative nausea, radiation sickness, ingestion of toxins.
METOCLOPRAMIDE:
STRUCTURE: Derivative of procainamide
MECHANISM: Is anti-emetic and pro-kinetic. It blocks dopamine receptors.
Anti-Emetic: Block dopamine-receptors in the brain.
Pro-Kinetic: Promote gastric motility, via blocking dopamine receptors in the GI tract.
ACTIONS:
Stimulates motility in upper GI tract
Increases rate of gastric emptying, without speeding up secretions.
Increased serum prolactin levels
INDICATIONS:
Gastroparesis: Relieves delayed gastric emptying. Particularly used with Diabetic Gastroparesis.
GERD
Prevents nausea and vomiting associated with cancer chemotherapy
Treats anorexia nervosa
Enhances absorption of ergotamines, used in migraine headaches
ANTICHOLINERGICS (SCOPOLAMINE): Centrally-acting effective for treating motion sickness
ADVERSE EFFECTS: Causes blurred vision and xerostomia at therapeutic doses.
CONTRAINDICATIONS: Use with caution in glaucoma, pyloric obstruction, urinary obstruction.
LAXATIVES:
CONTACT-STIMULANT LAXATIVES: Castor Oil, Cascara Sagrada
MECHANISM: They stimulate the intestinal wall, producing an increase in peristalsis.

Increase cAMP, which increases secretion of electrolytes
Release prostaglandins
CONTRAINDICATION: Pregnancy. Castor oil gets into breast milk too.
BULK-FORMING AGENTS: Dried fruits have the same effect
MECHANISM: They absorb water into the fecal contents and expand, giving more bulk to the stool.
Several days may be required before achieving maximal effect.
Evacuate only the colon and not the small bowel, thus they are less likely to be habit-forming.
Always administer with a full glass of liquid, to avoid impaction.
INDICATIONS:
Constipation in the elderly.
Diverticulosis, Irritable Bowel Syndrome
Hemorrhoids, to relieve painful defecation.
OSMOTIC LAXATIVES:
MECHANISM: They pull solutes and water into the bowel, increasing intestinal contents and bulk.
INDICATIONS: Powerful, fast-acting cathartics. Active 2-6 hrs after administration.
Cleansing the entire GI-tract for diagnostic tests.
Flushing poisons or removing parasites from the GI tract.
FECAL SOFTENERS: Stool softeners
MECHANISM: They soften the intestinal contents and retard water absorption.
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INDICATION: Only to prevent constipation. No catharsis occurs.
LUBRICANTS: Mineral Oil
INDICATIONS: Onset 6-8 hours after administration
Treat tearing of hemorrhoids or fissures.
Temporary relief of constipation
LACTULOSE SYRUP:
INDICATION: Acidifies the colon, pulling NH3 into the bowel, thus it is used for hepatic encephalopathy.
CONTRAINDICATIONS:
Absolute Contraindication: anybody who can't tolerate galactose
Pregnant women
Patients concurrently receiving neomycin, because neomycin evacuates colonic bacteria, nullifying the effects of lactose.
Diabetic patients, because of its high sugar content
ADVERSE EFFECTS:
Flatulence, intestinal cramps, gas, belching
Excessive dose: Diarrhea, hypokalemia, nausea
ADVERSE EFFECTS:
Excessive GI Activity: Nausea, diarrhea, vomiting
Perianal irritation, due to frequent stools
Abdominal cramps, bloating, flatulence
CONTRAINDICATIONS: Cathartics are contraindicated in:
Undiagnosed abdominal pain (which may be appendicitis)
Pregnancy
Hemorrhoids
Intestinal obstruction
After abdominal surgery
INFLAMMATORY BOWEL DISEASE: Crohn's disease usually cannot be managed pharmacologically. Ulcerative Colitis is managed with Sulfasalazine, Mesalamine, Olsalazine
Sodium.
Augmentstheinsulinsecretoryresponsetoameal:Gastricinhibitorypeptide(GIP)
Hyperglycemiaproducedbytheingestionofglucoseproducesagreaterincreaseininsulinsecretionthanasimilarlevelofhyperglycemiaproducedbyintravenous
infusionofglucose.Gastricinhibitorypeptide(GIP)ismostlikelyresponsiblefortheaugmentedinsulinsecretionobservedfollowingameal.Ingestionofa
carbohydratemealincreasesplasmalevelsofGIPandinjectionofGIPhasbeenshowntoincreaseinsulinsecretion.BecauseofGIP'seffectoninsulin,some
investigatorshaveproposedchangingitsnametoglucosedependentinsulinotropicpeptide.
Gastrinstimulatesacidsecretionbyparietalcells,butthiseffectisselflimitingthatis,asthepHofgastricjuicedecreases,additionalgastrinsecretionisinhibited.
DeltacellsinthegastricmucosarespondtothedecreaseinpHbyreleasingsomatostatin,whichactsonGcellsthroughaparacrinemechanismtoinhibitgastrin
secretion.
Biliaryductandductulecellssecreteabicarbonaterichaqueoussolutionthatcontributestobileacidindependenthepaticbileflow.Secretinactsonthesecellsto
increasebicarbonatesecretion.Duringtheintestinalphaseofthedigestiveperiod,whensecretinlevelsareelevated,thepHofhepaticbileincreasesduetothe
increaseinbicarbonatesecretion.
Experimentsshowthatthemigratingmotorcomplex(MMC)canbeinitiatedfollowingvagotomy,suggestingthatagastrointestinalhormonemayinitiateMMC
activity.Theleadingcandidateinthisregardisthehormonemotilin.Duringafast,motilinisreleasedbycellsinthesmallintestineinacyclicpatternthatmimics
thepatternoftheMMC.Furthermore,injectionofmotilincaninduceMMClikemotoractivity.
MediatestheinhibitionofGcellsecretioninresponsetoacidicgastricjuice:Somatostatin
IncreasesthepHofhepaticbile:Secretin
Initiatesthemigratingmotorcomplex(MMC):motilin
Feedbackinhibitionofneurotransmitterrelease
2Adrenergicdecreasedcyclicadenosinemonophosphate(cAMP)
2Adrenergicreceptorsareprimarilypresynapticautoreceptorsthatmediatefeedbackinhibitionofneurotransmitterreleasebyinhibitingadenylylcyclaseand
decreasingcyclicadenosinemonophosphate(cAMP)formation.
1Adrenergicreceptorsmediatevasoconstrictionthroughtheformationofinositoltriphosphate(IP3)andthesubsequentreleaseofcalciumfromthesacroplasmic
reticulum.
BronchoconstrictionismediatedbymuscarinicreceptorsviaformationofIP3andthesubsequentreleaseofcalcium.
1and2AdrenergicreceptorsactivateadenylylcyclaseandincreasecAMPlevelsinsmoothmuscleandcardiacmuscle,leadingtosmoothmusclerelaxation
(vasodilation)andcardiacstimulation,respectively.
Vasoconstriction:1Adrenergicformationofinositoltriphosphate(IP3)
Bronchoconstriction:CholinergicmuscarinicformationofIP3
Cardiacstimulation:1AdrenergicincreasedcAMP
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Vasodilation:2AdrenergicincreasedcAMP
AUTONOMIC NERVOUS SYSTEM

CATECHOLAMINE SYNTHESIS:
Tyrosine ---> DOPA (Tyrosine Hydroxylase)
This is the rate-limiting step in synthesis.
alpha-Methyltyrosine is a false substrate for this step and inhibits the enzyme.
DOPA ---> Dopamine (DOPA Decarboxylase)
Dopamine ---> Norepinephrine (Dopamine beta-Hydroxylase)
Norepinephrine ---> Epinephrine (Phenylethanolamine N-Methyltransferase, PNMT)
The methyl group is obtained from S-Adenosyl-Methionine (SAM)
SYNTHESIS OF ACETYLCHOLINE: Choline + Acetyl-CoA --> Acetylcholine (Choline Acetyltransferase)

ACETYLCHOLINE RELEASE: Other neurotransmitters are released along with ACh.
ATP
VIP
Prostaglandins
CATECHOLAMINE RELEASE: Other neurotransmitters are released along with NE.

Neuropeptide-Y (NPY)
Dopamine
Metenkephalin
CGRP
CATECHOLAMINE BREAKDOWN: The primary way to get rid of NE is reuptake back into the pre-synaptic neuron.
UPTAKE I: Reuptake of NE back into the presynaptic neuron.

Monoamine Oxidase (MAO): Breaks down Norepinephrine in the pre-synaptic neuron. Before it can work, NE must be reuptaken into the presynaptic neuron.
UPTAKE II: Reuptake of NE back into non-neuronal cells -- glial and smooth muscle cells.
Catechol-O-Methyltransferase (COMT): Breaks down NE in glial cells and other non-neuronal cells.
The methylated products of COMT then diffuse out of the glial cells and make their way back to neurons, where they are further broken down MAO. So, MAO is
required in either case.
Catecholamine Metabolites: Two metabolites are found in urine and can be measured to estimate Catecholamine turnover.
NE ---> Vanillyl Mandelic Acid (VMA)
Epi ---> Vanillyl Mandelic Acid (VMA)
Dopamine ---> Homovanillic Acid (HVA)
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AUTONOMIC RECEPTORS: Brief summary

Receptor
Location
Effect
Nicotinic Ganglionic (NG)
ANS Ganglions
Activation of parasympathetic and sympathetic post-synaptic neurons.
Nicotinic Neuromuscular Junction (NMJ)
Neuromuscular Junction
Activation of skeletal muscle
Muscarinic (M1)
Sympathetic post-ganglionics
Inhibit sympathetic NE release. This is the way in which ACh causes relaxation of
vascular smooth muscle: ACh ---> inhibit NE ---> vasodilation.
Muscarinic (M2)
Heart
Lower rate (on SA node) and force (on myocardium)
Inhibitory: cAMP, K+ influx
Eye
Pupillary constriction (contract iris muscle) accommodation
GI / UG
Contraction of GI smooth muscle and relaxation of sphincters.
Respiratory
Bronchoconstriction and increased secretions
Penis
Erection (via NO), vasodilation
Vascular
Vasodilation: Strong indirect vasodilatory effect due to inhibition of sympathetics. At low

doses, this leads to a reflex tachycardia.
IP3 / DAG
Muscarinic (M3)
IP3 / DAG
Adrenergic (alpha1)
IP3 / DAG ---> Ca+2
Adrenergic (alpha2)
Some direct vasodilatory effect (especially when exogenous ACh is given)

Exocrine glands
Increased sweating in non-adrenergic sweating areas (regular eccrine sweat glands).

Under sympathetic control, but they are M3 muscarinic receptors.
Vascular smooth muscle
Vasoconstriction (via IP3 / DAG, increased Ca+2)
GI / UG
Smooth muscle relaxation and contraction of sphincters
Eye
Pupillary dilation (contract radial muscle)
Post-ganglionics
Inhibitory on sympathetic and parasympathetic post-ganglionic neurons. For sympathetics,

this is auto-regulatory feedback.
Gi ---> cAMP
Adrenergic (beta1)
Adenyl Cyclase / cAMP
Adrenergic (beta2)
Adenyl Cyclase / cAMP
Dopamine (D1)
Gi ---> inhibit cAMP

Pancreatic beta-Cells
NE Inhibits the release of insulin ---> hyperglycemia
Heart
Increase rate (SA node) and inotropic state (myocardium)
Lipocytes
Increase lipolysis
Brain
NE stimulatory CNS effects.
Kidney
Increased Renin release --> higher b.p. ultimately
Vascular
Relaxation of vascular smooth muscle in skeletal muscle and brain.
Pancreatic beta-Cells
Stimulate release of insulin in Pancreatic beta-Cells. Thus beta-Blockers can lead to

hyperglycemia as side-effect.
Vasculature
Vasodilation, especially in Kidney --> higher Renal Blood Flow.
Anterior Pituitary
Inhibit Prolactin Release
CNS
Various stimulatory effects.
G-Protein, cAMP
Dopamine (D2)
G-Protein, cAMP
VASCULATURE: There are little or no parasympathetics innervating the vasculature.

alpha1-Receptors: Vasoconstrictive. They predominate in the splanchnic beds and kidneys, which do not need a lot of blood flow during sympathetic stimulation.
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The vasculature is primarily under sympathetic control, via alpha1 receptors.
Muscarinic Receptors: There are, however, muscarinic receptors on vascular smooth muscle, and they do cause vasodilation. Thus, if there is ever a muscarinic agonist
(such as ACh) in the blood, then you will see a pharmacologiceffect of direct vasodilation on vascular smooth muscle.
Coronary Arteries: An exception to the rule. Dilation of coronary arteries occurs by parasympathetic stimulation ---> vasodilation.
beta2-Receptors: Vasodilatory. They predominate in skeletal muscle and brain, which get all the blood flow during sympathetic stimulation.
SWEAT GLANDS:
Cholinergic Sweat Glands: Thermoregulatory sweat glands throughout the body are under sympathetic control, but they release
ACh and synapse with muscarinic
receptors.
Adrenergic Sweat Glands: Nervous sweating on palms, soles, and armpits is also under sympathetic control, but it releases
NE and synapses with adrenergic receptors.
MUSCARINIC AGONISTS:
LOW DOSES: Primary effect is vasodilation due to inhibition of sympathetics. In response you see a reflex tachycardia.
HIGH DOSES: You see a direct bradycardia.
You can see
Atrial Fibrillation as a side effect, as the Ventricular refractory period is prolonged and the atrial refractory period is shortened.
EFFECTS: Cholinergic outflow shows the following symptoms:
SLUD: Sweating, Lacrimation, Urination, Defecation

Profuse diarrhea, vomiting, nausea.
Flushed skin.
Direct Muscarinic Agonists:
Choline Esters
Alkaloids
Indirect Muscarinic Agonists
Carbamates: Reversible inhibitors of cholinesterase.
Organophosphates: Irreversible inhibitors of cholinesterase.

ORGANOPHOSPHATE POISONING:
DEATH by
Respiratory Suppression in the CNS is the most common cause. This is notan effect on the diaphragm, but rather is a suppression of the
respiratory drive (muscarinic receptors) in the CNS.
2-PAM (Pralidoxime): Only effective within the first five minutes of exposure.
Acetylcholinesterase is a Serine-Protease. It binds to Acetylcholine by latching onto the NH3 group with a His residue, and hydrolyzing the ester group
with a Ser residue.
Organophosphates phosphorylate the cholinesterase, rendering it inactive. Within the first few minutes, this phosphorylation is reversible.
2-PAM is a strong nucleophile, and binds with the organophosphates to reverse the phosphorylation.
After the first 5 or 10 minutes, aging occurs and the phosphorylation becomes irreversible. After that, 2-PAM no longer works.
ATROPINE is the treatment of choice after that.
ANTI-MUSCARINIC AGENTS:
SIDE-EFFECTS
: Inhibit all muscarinic activities
Peripheral:
Dry mouth (no salivation)
Constipation (no anal sphincter relaxation, lost GI motility)
Blurred Vision (no accommodation)
Urinary retention (lost UG motility, no sphincter relaxation)
Increased intraocular pressure (sympathetics increase intraocular pressure and parasympathetics decrease it).
Central: Impairment of all things that ACh mediates in the CNS
Confusion
Memory impairment
Hallucinations, delusions
GANGLIONIC BLOCKERS: Trimethaphan and Hexamethonium.
They block all autonomic responses.
RESULTS:
Orthostatic Hypotension: block sympathetic reflex control of vasculature.
Tachycardia: Block parasympathetic reflex control of the heart.
GI / UG: Decreased motility, urinary retention, constipation (lost parasympathetic reflexes)
Mouth: Xerostomia
ADRENERGIC AGONISTS: Catecholamine, catecholamine-like compounds.
PHARMACOKINETICS: Never administered orally, due to high first-pass effect.
ADVERSE EFFECTS:
Increased cardiac excitability and arrhythmias ---> ventricular fibrillation.
CONTRAINDICATIONS: MAO Inhibitors, Cocaine, Tri-cyclics. These all potentiate NE, thus don't give catecholamines!
SHORT-LIVED: Endogenous catecholamines, or catechol-like compounds, have very short half-lives, due to abundance of MAO and COMT.
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beta-AGONISTS:
beta2-AGONISTS: They are primarily used as bronchodilators, but in severe heart failure, there is down-regulation of beta1-receptors. Thus in CHF, beta2 may
have a significant effect on the inotropic state of the heart.
MAO-INHIBITORS: Mono-Amine Oxidase Inhibitors. MAO has two isozymes.
MAO-A: More effective in degrading NE and serotonin.

MAO-B: Less selective for individual amines.
Older MAO-Inhibitors are non-selective. Newer ones are isozyme-selective.
alpha-ANTAGONISTS:
PRINCIPAL EFFECTS:
Decreased TPR, decreased blood pressure (primary effect)
Tachycardia (reflex)
Increased release of renin (reflex)
SIDE EFFECTS:
Miosis
Decreased adrenergic sweating
Stuffy nose
Increased insulin release
Impaired ejaculation
beta-ANTAGONISTS:
PRINCIPLE EFFECTS:
They decrease the inotropic state of the heart ---> decrease oxygen demand of the myocardium. Useful in treating angina pectoris.
They decrease blood pressure:
They increase TPR and decrease cardiac output, but the net effect is to decrease blood pressure.
They decrease renin secretion in the kidney, which also helps to decrease blood pressure.
They decrease AV conduction in the heart, and are useful in treating arrhythmias.
SIDE-EFFECTS:
Rebound Tachycardia can result if the drug is withdrawn quickly, due to denervation supersensitivity (i.e. up-regulation of beta1-receptors after using
the drug for a while).
Insulin release is blocked in pancreas ---> possible hyperglycemia, which can be a problem with Diabetics.
Can also lead to hypercholesterolemia.
Local Anesthesia: Membrane-stabilizing effect occurs as the drugs block Na+-channels in heart muscle & in neurons. This is not of clinical consequence,
except when using as eye drops.
CONTRAINDICATIONS:
ASTHMA is an absolute contraindication, for non-selective beta-blockers. You don't want to block the bronchodilatory effects of
beta2-receptors!
You can possibly use beta1-selective (cardioselective) antagonists with asthmatics, but even these drugs still have some beta2-activity (even if minimal).
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CHEMICALNEUROTRANSMISSION
A. Types of connections between neurons
1.Axodendritic - axon terminals of transmitting cell connect with dendrites of receiving cell - most common type of connection
2.Axosomatic - axon terminals of transmitting cell connect with soma of receiving cell - very common
3.Axosynaptic - axon terminals of transmitting cell connect with axon terminals of receiving cell
4.Axoaxonic - axon terminals of transmitting cell connect with axon of receiving cell
5.Axosecretory - axon terminals of transmitting cell connect with capillaries type of connection used by neuroendocrine cells
B. Structure of synapse
1. Presynaptic site - terminal - contains presynaptic membrane

contains many organelles, especially enriched in mitochondria - energy generator - some manufacturing (synthesis) must take place locally
synaptic vesicles - filled with neurotransmitter - store them and release them
neurotransmitter (NT) - chemical messenger that transmits information (signal) from transmitting neuron to receiving neuron
- more precisely - neurotransmitter triggers an effect on the receiving neuron, which the neuron interprets (understands) as an
information byte
Ca2+ channels - in membrane of axon terminal - specifically permeable to calcium when channel is open - remember, they are voltage-dependent will open when action potential arrives at terminal
2. Intersynaptic site
synaptic cleft - kind of a thin web between presynaptic cell and postsynaptic cell - probably serves as a guide for neurotransmitter to get to
postsynaptic site
degradation enzymes - proteins that can degrade (destroy) unbound neurotransmitter after it has delivered signal to receiving neuron
3. Postsynaptic site - contains postsynaptic membrane - can be dendritic, somatic, axonic, etc.
receptors - protein molecules with very specific shape - where neurotransmitters exert effect - site where NT binds (attaches) to postsynaptic
(receiving) neuron - binding of NT to receptor differs depending on type of receptor
- two main types of receptors
A. ionotropic receptors - receptor molecules that include an ion channel ( sometimes called fast receptors )
- binding of NT to receptor causes influx of ions - just like the Na+ channels we talked about last class
cholinergic neuromuscular junction & CNS ( GABA, glutamate, glycine )
B. metabotropic receptors - also protein molecules - no ion channel ( sometimes called slow receptors )
- have another molecule attached to them inside the cell - called G protein ( guanine nucleotide binding protein)
- G protein can be directly linked to other ion channels or be linked through a series of additional steps called second messenger
systems - called metabolic steps - inside the cell - modulate ion channels - sometimes called chemically sensitive or chemically
gated channels
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C. Steps involved in neurotransmission (synaptic transmission)
1.Opening of Ca2+ channels - action potential travels down axon - remember after Na+ channels open, Ca2+ channels will open : Ca2+ enters the presynaptic
terminal
2.Fusion of synaptic vesicles with presynaptic membrane : Ca2+ triggers fusion of vesicles with membrane - remove Ca2+, no fusion
3.Release of vesicular content into cleft - vesicle walls rupture on side fused with membrane neurotransmitter released into synaptic cleft
4.Neurotransmitter binds to postsynaptic receptor
- if there is a fit between the NT and receptor, NT will bind to receptor
- think of as a lock (receptor) and key (NT) - if the key fits, a change will occur in the postsynaptic neuron
- if the receptor is ionotropic, the NT will cause the opening of the ion channel within the receptor
- if the receptor is metabotropic, the NT will cause G protein to modulate an adjacent channel(s) or set off a second messenger system signaling cascade inside the cell - that can result in the modulation of an ion channel(s)
5.Increase in ion permeability of postsynaptic membrane
a. ionotropic receptors - binding of NT can cause passage of cations (for example, Na+ ions) OR passage of anions (for example, Cl- ions)
- depends on both the type of NT and the type of receptor
if ionotropic receptor has channel for Na+, the NT binding causes Na+ gate inside receptor to open and Na+ ions to enter cell - inside of
postsynaptic cell becomes positive or "excited"
if ionotropic receptor has a channel for Cl-, the NT binding causes Cl- gate inside receptor to open and Cl- ions to enter cell - inside of
postsynaptic cell becomes negative or "inhibited"
b. metabotropic receptors - do not contain ion channel - instead G protein is attached
- G protein can be directly attached to a Na+ channel or a Cl- channel, or a K+ channel
- G protein can also be linked to signaling cascade inside postsynaptic cell that can result in modulation of ion channels far away - they don't
have to right beside the receptor
- whether the postsynaptic neuron gets excited or inhibited depends on the type of ion channel effected
example - signaling cascade results in opening of K+ channels, what happens? - positively charged K+ ions flow out of postsynaptic neuron neuron inhibited
- remember, metabotropic receptors will take longer to effect ion channels
6. Neurotransmitter removal
- NT does not stay bound to the receptor forever
- unbound NT either gets degraded by a degradation enzyme in synaptic cleft OR
- reuptaken into presynaptic neuron via transporters (like pumps) in presynaptic membrane - think of as recycling
D. Postsynaptic potentials
1. influx of Na+ ions - inside of postsynaptic cell more positive - excitatory postsynaptic potential (EPSP)
2. influx of Cl- ions - inside of cell more negative - inhibitory postsynaptic potential (IPSP)
3. efflux of K+ ions - inside of cell more negative - IPSP
4. influx of Ca2+ ions - inside of cell more positive - EPSP
E. Properties of postsynaptic potentials
1. amplitude of EPSP/IPSP is relatively small (1 - 3 mV)
2. EPSP/IPSP degrade across distance
- for example - change in membrane potential is largest on dendrite where Na+ enters or K+ exits
- EPSPs on a distal dendrite may be lost before it ever gets to soma
BUT
3. EPSPs and IPSPs demonstrate summation
- across space (spatial summation) and time (temporal)
- therefore summed EPSPs or IPSPs can cause a large change in membrane potential - as large as 30 mV consequences??? - enough of a change in
membrane potential in the positive direction will result in an action potential
F. Summary of properties of neurotransmission (synaptic transmission)
1.chemical in nature
2.receptor binding requirement - NT and receptor have to match exactly like key into lock
NOTE: NT is only key - NT IS NOT the signal that goes into the postsynaptic neuron
3.spatial specificity - message carried by NT is like one to one communication
- release site of transmitting neuron to very nearby receptor of receiving neuron
4.temporal specificity - effects of NT are very rapid in onset and duration onset - 5-100 msec duration - 10-100 msec
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G. Neurotransmitters - additional information
1.NT is synthesized from precursor molecules - enzymes catalyze this synthesis

2.NT is then packaged into vesicles
3.Any NT that leaks from vesicles is degraded by other enzymes
H. Other types of receptors
1.Autoreceptors - receptors on neurons that are activated by the NT that are released - usually outside of synapses
- usually activated when there are high concentrations of NT
- "feedback inhibition" - when activated usually decrease synthesis or release of NT
2.Presynaptic receptors - usually located on axon terminals - activated by NT released by another neuron (axoaxonic connection)
- similar to autoreceptors - usually decrease synthesis or release of NT
I. Drugs and Receptors
1.Agonist - compound with an affinity for and a capability of activating a receptor

a. ligand - an endogenous or naturally occuring agonist (like a NT)
b. exogenous agonist - called drug something produced outside the body
2.Indirect agonist - drug that does not combine directly with receptor, but enhances the amount of endogenous ligand
3.Antagonist - block action of agonists - usually a drug - exogenous antagonist
a. competitive antagonist - binds to agonist binding site to block agonist - reversible - addition of enough agonist can overcome effects of
competitive antagonists
b. noncompetitive antagonist - binds to different site from agonist binding site - irreversible
4.Mixed agonist-antagonist - drug acts as agonist, but blocks activity endogenous agonist
AUTONOMICNERVOUS
SYSTEM
I.Other names : visceral, vegetative, involuntary

II. Function - regulates activity of structures not under voluntary control
A. smooth muscle
B. cardiac muscle
C. secretory glands
III. Structural arrangements
A. connections - 2 neurons
1.neuronal fiber leaving brainstem and spinal cord synapses outside the CNS at a ganglion -- preganglionic neuron
2.second neuron impacts on effector organ -- postganglionic neuron
B. two divisions in ANS
1.based on differences in anatomy, function
2.sympathetic (thoracolumbar) division
a.fibers originate in the thoracic and lumbar regions (T1-L3) of the spinal cord
b.ganglia are located near the spinal cord (distant from effector organ)
c.other than a second neuron, preganglionic neurons innervate the adrenal medulla which is embryologically and anatomically analogous to other
sympathetic ganglia
d.one preganglionic neuron may act on many postganglionic neurons (up to 1:20)
e.diffuse distribution pattern leads to widespread massive responses
1.desirable if organism is confronted with a sudden emergency (e.g., pain, asphyxia, strong emotions)
2.fight or flight response
3.parasympathetic (craniosacral) division
a.fibers originate in tectal region of the brain stem (oculomotor [III], facial [VII], glossopharyngeal [IX] and vagus [X]) and sacral segments (S2-S4)
of the spinal cord
b.ganglia are located near the end effector organs (distant from spinal cord)
c.generally 1 preganglionic:1 postganglionic neuron
d.discrete distribution leads to fine and limited responses
e.functionally important in protection, conservation and restoration of bodily resources
IV. Innervation
A. tissues receive only parasympathetic innervation : parotid gland, lacrimal gland, nasopharyngeal glands
B. tissues receive only sympathetic innervation : sweat glands, adrenal medulla, piloerectors, most blood vessels
C.
tissues are innervated by both : salivary glands, heart, lungs (bronchial muscle), abdominal & pelvic viscera
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Characteristic
Sympathetic
Parasympathetic
Spinal Cord Origin
Thoraco-Lumbar
Cranio-Sacral
Length of Postganglioinc Fiber
Long
Short
Innervation
Diffuse (1:20)
Discrete (1:1)
Function
Fight or Flight
Minute-to-Minute
Control
Preganglioinc Neurotransmitter
ACh
ACh
Postganglionic Neurotransmitter
NE, ACh
ACh
I.Neurotransmission
A. Communication between cells in the nervous system is accomplished by chemical mediators (transmitter, neurotransmitter, NT) which are released by the nerve
terminals or varicosities. The NT interacts with a specific receptor on a second neuron (synapse or synaptic junction) or on a target tissue (neuroeffector
junction)
B. Neurotransmitters in the ANS are acetylcholine (ACh) & norepinephrine (NE) : since epinephrine (Epi) is released into the circulation it is referred to as a
neurohormone rather than a neurotransmitter
C. neurons which release ACh are called cholinergic
D. neurons which release NE are called adrenergic
I.Neurotransmitters associated with the autonomic nervous system
A. sympathetic division
1.preganglionic neurons release ACh
2.postganglionic neurons release
a.NE (ACh --> NE)
b.ACh - at sweat glands (ACh --> ACh)
3.adrenal medulla releases Epi, NE (ACh --> Epi, NE)
B. parasympathetic division
1.preganglionic neurons release ACh
2.postganglionic neurons release ACh (ACh --> ACh)
C. Caution:
1.cholinergic parasympathetic
2.adrenergic sympathetic
II. Receptors in the autonomic nervous system
A. cholinoceptors
1.muscarinic
i.actions of ACh on effector organs is similar to the plant alkaloid muscarine
ii.action of both ACh and muscarine are similar to parasympathetic nerve stimulation
iii.all the actions of muscarine and parasympathetic nerve stimulation can be blocked by atropine (a muscarinic antagonist)
iv.subtypes
1.via pharmacologic techniques

2.via molecular biologic techniques
1.nicotinic
i.
of ACh on autonomic ganglia and adrenal medulla is similar to that of nicotine
ii.action of ACh on skeletal muscle is also similar to nicotine, although antagonist selectivity is different indicating that these nicotinic receptors
action
are not alike
B. adrenoceptors
1.activation of adrenergic receptors results in contraction of some smooth muscles and relaxation of others
2.certain antagonists demonstrate selectivity in blocking the various effects of NE
3.adrenergic receptors are classified as being either a or b
i.in general, stimulation of a receptors results in contraction whereas stimulation of breceptors results in relaxation (exception: heart breceptors produce contraction)
ii.b1vs b2
iii.a1 vs a2
1.presynaptic receptors regulate the amount of NE released by action potentials

II. Summary of tissue responses to adrenergic and cholinergic nerve stimulation
Organ Or Tissue Function
Eye
Adrenergic
Response
a1
Contraction (mydriasis)
Radial muscle of the iris

Sphincter of the iris
Ciliary muscle
Heart
Adrenergic
Receptor
Cholinergic
Response
Dominant
Tone
C
Contraction (miosis)
b2
Relaxation for far vision
Contraction for near vision
Rate (SA node)
b1
Increase
Decrease
Contractile force (atrium)
b1
Increase
Decrease
Contractile force (ventricles)
b1
Increase
None
b2
Relaxation
Constriction
a1, b2
Decreased secretion, Increased

secretion
Increased secretion
Lungs
Bronchial smooth muscle

Bronchial glands
Blood vessels
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Arterioles (viscera, skin, brain)
a1
Constriction
Dilatation (via EDRF)
Coronary vessels
b2 (a1, a2)
Dilatation (constriction)
Constriction
Skeletal muscle
b2 (M?)
Dilatation
Dilatation
a1
Constriction
a2, b2
a1
Relaxation
Contraction
Contraction
Relaxation
Detruser muscle
b2
Relaxation
Contraction
Trigone-sphincter
a1
Contraction
Relaxation
A, C
a1
Contraction
Variable
b2
Relaxation (non-preg>preg)
Erection
Veins
GI tract
Walls (Tone and motility)

Sphincters
Urinary bladder
Uterus
Penis, seminal vesicles
a1
Ejaculation
Salivary glands
a1
b
Increased secretion of K+ and H20
Sweat glands
a1
Increased secretion
Increased secretion (sympathetic)
Liver
b2
Glycogenolysis
Glycogen synthesis
Increased secretion of amylase
Increased secretion of K+ and H20
Fat cells
b (b3)
Lipolysis
None
Renin secretion
b1
Increase
None
Insulin secretion
a2
Decrease
Increase
* C= Cholinergic, A=Adrenergic
CNS PHARMACOLOGY
Outline of Topics
BENZODIAZEPINES
BARBITURATES
GENERAL ANESTHETICS
PARKINSONISM
SEIZURES
SCHIZOPHRENIA
ENDOGENOUS DEPRESSION
ANTI-DEPRESSANTS
LOCAL ANESTHETICS
OPIOID ANALGESICS
DRUGS of ABUSE
SKELETAL MUSCLE RELAXANTS
BENZODIAZEPINES:
INDICATIONS:
Anxiolytic: Long-acting drugs
Hypnotic: Promote sleep short-acting drugs
Anticonvulsant
Muscle relaxant
Control of alcohol withdrawal (give tapering dose)
Pre-Anesthesia
PHARMACODYNAMICS: It enhances the affinity of the GABA Receptor, but only some GABA receptors. Thus it is an incomplete CNS depressant.
GABA Receptor: Pentameric structure, with different possible subunits: alpha, beta, gamma,
alpha-subunit: Binds to Benzodiazepines (alpha1, alpha2, alpha3, alpha5)
beta-subunit: Binds to GABA
Most common GABA Receptor (benzodiazepine-sensitive): alpha1, beta2, gamma2
Benzodiazepine-Insensitive Receptor: alpha4, betax, gamma2
PHARMACOKINETICS:
Active Metabolites: Diazepam and Chlordiazepoxide are converted to active metabolites in the liver, which prolongs their half-life.
TOLERANCE: Benzodiazepine tolerance is related to the half-life of the drug.
Physiologic tolerance and dependence is most pronounced in the short-acting (hypnotic) drugs: triazolam, oxazepam, lorazepam.
TOXICITY: It is not fatal when taken alone. Minimal adverse effects on other organ systems.
It can be fatal when given IV. The IV fatality may involve mechanisms other than the GABA receptor.
It can be fatal when taken with alcohol.
ADVERSE EFFECTS:
Sedation, ataxia, anterograde amnesia, light-headedness
Paradoxic excitement in children.
Menstrual irregularities
BARBITURATES: Complete CNS depressants.
PHARMACODYNAMICS: Binds indiscriminately to GABA channels to enhance Cl- transport and increase conductance at Cl- channels.
PHARMACOKINETICS: Highly lipophilic
They are weak organic acids, so they compete with salicylates and other acids for binding sites.
They increase Cyt-P450 metabolism.
Their duration of action (onset and termination) is dependent on their lipophilicity and how long it takes them to get into the brain and then redistribute to the body. It is n
TOLERANCE: Tolerance develops to all drugs, in several ways. Dose is usually tapered, and then replaced with a benzodiazepine, to remove treatment.
Metabolic Tolerance: Barbiturates increase P450 metabolism ------> increase the breakdown of itself.
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Pharmacodynamic Tolerance: Down-regulation of receptors probably occurs.

TOXICITY: At anesthetic dose, depressed respiration and sometimes depressed CV tone. Death is due to depression of the respiratory centers of the brain.
ADVERSE EFFECTS:
Intermittent Porphyria: Barbiturates increase porphyrin synthesis and are absolutely contraindicated in patients with Intermittent Porphyria.
At toxic levels, the respiratory center becomes insensitive to the levels of CO2, and the only thing that allows breathing to persist is low blood O2 levels.
Thus it can be dangerous to give O2 to overdosing patient, as it may stop him from breathing.
DRUGS: Phenobarbitol, Pentobarbitol, Thiopental
OTHER ANXIOLYTICS:
beta-Blockers: They can inhibit some of the somatic effects of anxiety.
Antipsychotics, Antidepressants: They display side effects which are anti-cholinergic and anti-histaminic ------> sedation, which can be beneficial in anxiety.
GENERAL ANESTHETICS:
Partial Pressure: The concentration of the inhalational anesthetic that is not in solution. The depth of anesthesia is directly proportional to the partial pressure.
Lipophilicity:
The more lipophilic the agent, the more efficacious and potent is the anesthetic.
Explanation: More of the drug penetrates the CNS.
The more lipophilic the agent, the longer it will take to induce anesthesia, and the longer it will take to emerge from anesthesia.
Explanation: More drug sticks to the membranous components of the blood, hence the blood has a higher carrying capacity for the drug and requires more to be satur
Ostwald Coefficient: The blood:gas partition coefficient. It is the ratio of total amount of drug in the blood to the amount of drug in the gas-phase, in the lungs.
High Ostwald Coefficient ------> Highly lipophilic drug ------> highly potent drug ------> slow rates of induction and emergence.
STAGES of ANESTHESIA:
Analgesia Stage (I): No loss of consciousness. NO only induces anesthesia to this extent.
Delirium Stage (II): Complete loss of inhibitory and autonomic control, delirium, excitement. Pre-anesthetic medications generally prevent the occurrence of this stage, or
Surgical Stage (III): Loss of consciousness, return of regular respiration. Major surgery is performed here.
Medullary Paralysis Stage (IV): Death quickly results afterward. Anesthesia must be rapidly terminated.
Minimum Alveolar Concentration (MAC): A measure of the potency of an inhalational anesthetic. It is the concentration of inspired anesthetic, when measured at equilibrium, at w
patients.
Pre-Anesthetic Medication:
BENEFITS:
It decreases the dose of general anesthetic required to induce anesthesia. Thus it decreases the adverse effects of anesthetics.
It increases the rate of induction of anesthesia.
It virtually eliminates the delirium stage (Stage II).
It reduces pre-operative pain and anxiety.
DRUGS:
Midazolam
Thiopental
Propofol
Diazepam
Morphine
Scopolamine
Glycopyrrolate
Fixed Anesthetics: IV anesthetics given at fixed dose.
ADVANTAGE: Quick, easy, smooth induction.
DISADVANTAGE: Slow elimination. Cannot be removed if there is an emergency and hence can be dangerous.
DRUGS:
Innovar: Combination of two drugs -- Droperidol (anti-psychotic), and fentanyl (opiate). It causes neuroleptanalgesia, a state of indifference, but not sleep.
ADVERSE EFFECTS: Depressed respiration (due to opiate) and blood pressure (due to anti-psychotic). Vomiting.
PHARMACODYNAMICS: It is proposed that they permeabilize neuronal membranes in the CNS, thereby disrupting neurotransmission.
Higher CNS centers are most sensitive to their effects, and medullary centers are least sensitive. The medulla is the last part of the CNS to be affected (Stage IV,
ADVERSE EFFECTS:
Post-Op nausea and vomiting.
CV and respiratory depression, in dope-dependent fashion.
All but isoflurane decrease cardiac output.
DRUGS:
Nitrous Oxide: Least potent, incomplete anesthetic.
Methoxyflurane: Most potent.
Enflurane
Isoflurane: Usually preferred drug.
Halothane
PARKINSONISM:
DISEASE:
DOPAMINERGIC PATHWAYS:
Nigrostriatal Tract: Provides inhibitory regulation on extrapyramidal nuclei. Substantia Nigra ------> Globus Pallidus ------> Thalamus ------> Motor Cortex
Mesocortical / Mesolimbic Tracts: Their over-activation is hypothesized to result in psychosis. Cell bodies are in ventral tegmental area.
Tuberoinfundibular Tract: Projects from Arcuate Nucleus of Hypothalamus to Pituitary, where it inhibits Prolactin secretion.
MECHANISM: Deficiency of dopamine-containing Nigrostriatal Tract. Results:
Cholinergic interneurons become overactive as a result. Dopamine normally provides inhibitory input on these interneurons.
Hence central anti-cholinergics can be used as adjunct therapy to treat Parkinson's.
Ultimately, loss of regulatory control of the Extrapyramidal Nuclei (Basal Ganglia) results in resting tremor, bradykinesia.
CAUSES:
Idiopathic Parkinsonism: Most common, occurs with elderly.
Encephalitis Epidemic of 1917: As portrayed in Awakenings, led to Parkinsonian symptoms.
Adverse Effects of Anti-Psychotics.
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MPTP is a by-product of some street-drug opioids, which can cause Parkinsonian symptoms.
Creutzfeldt-Jacob Disease has Parkinsonian symptoms.
SYMPTOMS:
Lead Pipe Rigidity: Resistance to movement.
Resting Tremor: To be distinguished from an intention tremor (as in Cerebellar Syndrome). This is a tremor when there is no movement.
This tremor is of a lower frequency than corresponding Intention Tremor (tremor with voluntary cerebellar movements)
The tremor is better when in motion, so it is less debilitating than a moving tremor.
Akinesia / Bradykinesia: Inability to initiate movement, or slow initiation of movement.
This symptom responds well to treatment.
Postural Instability
Cognitive Problems
DOPAMINE RECEPTORS: D1 and D2 receptors have been identified. Both are present in equal density in the nigrostriatum.
DOPA METABOLISM:
Aromatic Amino-acid Dopamine Decarboxylase (AADC): L-DOPA ------> Dopamine.
Inhibited by Carbidopa.
Monoamine Oxidase B (MAO-B): Dopamine ------> DOPAC. Breaks down Dopamine in CNS.
Inhibited by Selegiline.
TREATMENT:
Levodopa (L-DOPA): Dopamine precursor is given because it can get into CNS. In the CNS, AADC then converts L-DOPA into Dopamine, where it can replace lost dopamine
PERIPHERAL ADVERSE EFFECTS: Can be minimized with carbidopa administration. Nausea and vomiting, postural hypotension, tachycardia, arrhythmias.
Blood pressure can be altered in either direction. Individual response depends on patient. IV Dopamine, because of its effect on kidneys, is normally given as tr
CENTRAL ADVERSE EFFECTS: Long-term effects
MOTOR:
On-Off Effects: Suddenly therapy is ineffective, periodically and paroxysmally.
Freezing Phenomenon: All of the sudden become rigid and stop, unable to initiate movement.
Tolerance: The drug becomes less effective with long-term use. To an extent, can be counteracted by increasing dose. Can also stop treatment and then
NEUROLOGICAL:
Dystonias: Alterations in muscle tone.
Dyskinesias: Choreiform (dancing with arms) movements.
PSYCHIC: Depression, hallucinations, paranoia, anxiety.
NEUROENDOCRINE: Renewed sexual interest, increased libido.
Carbidopa: In the periphery, carbidopa inhibits AADC, inhibiting the conversion of L-DOPA to dopamine. Hence it inhibits the peripheral effects of dopamine.
Anticholinergics: Used in L-DOPA resistant patients. Works by inhibiting the cholinergic interneurons -- the next neurons in the nigrostriatal circuits, distal to the degener
SPASTICITY Violent, painful, involuntary muscle contractions.
CAUSE: Associated with Multiple Sclerosis and Cerebral Palsy, among others.
TREATMENT:
Baclofen: GABAB agonist used in spinal cord lesions and multiple sclerosis.
Diazepam: Used in spinal injuries, and sometimes cerebral palsy.
Dantrolene: Decreases Ca+2 release from muscle sarcoplasmic reticulum. Used in wide variety of spastic disorders.
SEIZURES
ETIOLOGY: Spontaneous seizures elicited by various stimuli (emotional, light). Problem relates to a shortened inactivation state of Na+-channels. Na+-channels are more
CLASSIFICATION
PARTIAL SEIZURES: Localized to specific areas of brain, no loss of consciousness.
Jacksonian March: Seizure often starts in finger and works proximally, make the arms shake in characteristic way.
Psychomotor: Emotional outbursts with complex symptomatology, due to seizure of areas localized to mesolimbic system.
TREATMENT: Vigabatrin, GABApentin
GENERALIZED SEIZURES:
PETIT MAL (ABSENCE): Occurs in children, temporary loss of consciousness, "daze." No memory of the event.
TREATMENT: Valproic Acid, Succinimides
GRAND MAL (TONIC-CLONIC): In adults.
Definitions:
Tonic: Continual contraction of muscle, rigidity.
Clonic: Rapid successive contraction of muscle followed by relaxation, leading to convulsions.
TREATMENT: Phenytoin, Barbiturates, Carbamazepine
STATUS EPILEPTICUS: Severe, life-threatening, continual convulsions.
GRAND-MAL / PARTIAL TREATMENT: Traditionally, the same drugs are used to treat grand-mal and partial seizures. They prevent the spread of seizures, but they do
PHENYTOIN:
PHARMACODYNAMICS: Prolong inactivation of Na+-channels in CNS. It increases depolarization threshold and prevents the spread of seizures, but it does not pr
ADVERSE EFFECTS:
Diplopia, ataxia, sedation.
Hyperplasia of the gums
Hirsutism.
Rarely, agranulocytosis.
PHARMACOKINETICS:
Slow and incomplete absorption.
Highly bound to plasma proteins.
Metabolized by microsomes, so barbiturates decrease potency.
CARBAMAZEPINE: An iminostilbene. Popular choice. Same mechanism as phenytoin.
BARBITURATES:
Phenobarbitol: Do not withdraw drug abruptly, or you could elicit status epilepticus.
Primidone: Usually a second-line drug.
PHARMACODYNAMICS: Pro-drug, converted to phenobarbitol and phenylethylmalonamide (PEMA). Both parent drug and metabolites are active against seizure
Never give with phenobarbitol. Often given with phenytoin.
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BENZODIAZEPINES:
GABAPENTIN: Can be adjunct therapy.
PETIT-MAL TREATMENT:
VALPROIC ACID (VPA): A carboxylic acid
PHARMACODYNAMICS: Multiple proposed mechanisms of action.
Prolong Na+ inactivation. Explains its effectiveness against grand-mal seizures.
Inhibit T-Type Ca+2 channels.

Inhibit GABA transaminase, increasing GABA levels. This only occurs at a high dose, so people wonder how important this mechanism is.
ETHOSUXIMIDE: A succinimide.
May precipitate grand-mal seizures, so it is given with barbiturates or phenytoin to prevent that.
ADVERSE EFFECTS: Sedation
TRIMETHADIONE: An oxazolidinedione
ACETAZOLAMIDE: Carbonic Anhydrase Inhibitor
BENZODIAZEPINE:
PARTIAL SEIZURE TREATMENT:
CARBAMAZEPINE:
PHENYTOIN:
VIGABATRIN:
GABAPENTIN: Used in combination with any of the above.
STATUS EPILEPTICUS TREATMENT:
DIAZEPAM:
LORAZEPAM:
PHENOBARBITOL:
SCHIZOPHRENIA
POSITIVE SYMPTOMS: Hallucinations, delusions. Anti-psychotics only treat the positive symptoms.
First-rank Symptoms: Not pathognomonic, but occur most frequently in Schizophrenics: Delusional perceptions, feelings of being controlled, thought broadcasting.
NEGATIVE SYMPTOMS: Anti-psychotics do not treat the negative symptoms.
Flat Affect
No Conation, no goal-directed behavior.
Thought Disorder, word-salad.
Downward Drift: Patients tend toward poverty, as a consequence of the disorder, as they cannot function well enough to prosper.
DOPAMINE HYPOTHESIS: Schizophrenia results from hyperactivity and dis-regulation of the Mesolimbic pathway (ventral tegmentum--> limbic system) and possibly mesocortic
EVIDENCE:
Drugs used to treat Parkinson's have psychosis as a side-effect.
Amphetamines are dopamine-releasing and can induce psychosis.
The drugs used to treat Schizophrenia are known to be Dopamine-receptor antagonists.
The affinity of anti-psychotics for Dopamine receptors closely correlates with their potency as anti-psychotics.
ANTI-PSYCHOTICS
INDICATIONS: Primarily for Schizophrenia or Schizophreniform disorders, however they are also used for an assortment of other disorders:
Tourette's Syndrome
Intractable Hiccoughs
Acute Mania of Bipolar Disorder
Huntington's Disease
Alcoholic Hallucinosis
Urticaria: Phenothiazines can be used to treat Type-I hypersensitivities
Pruritus
Some depressed patients, esp. depression with psychotic features
Nausea: Anti-emetics, but only for chemically induced nauseas. They are not effective against motion sickness.
PHARMACODYNAMICS: D2 Dopamine Antagonists
DRUG-CLASSES:
PHENOTHIAZINES
ALIPHATIC: Pronounced sedative effects. Chlorpromazine
PIPERAZINE: Higher extra-pyramidal and anti-emetic effects. Fluphenazine, Perphenazine, Acetophenazine
PIPERIDINE: Lower extra-pyramidal and anti-emetic effects. Thioridazine, Piperacetazine
THIOXANTHENE: Low hypotensive effects. Thiothixene, Chlorprothixene
BUTYROPHENONE: Highest incidence of extra-pyramidal effects. Haloperidol, Droperidol
EFFECTS:
It takes 2 to 3 weeks for therapeutic effects to occur. During that time, dopamine levels often return to normal, before therapeutic effect is seen. This is a line of counte
INITIAL EFFECT: Sedation.
NORMAL EFFECTS: Dysphoria, disinterest, blunted affect.
IN SCHIZOPHRENICS: Relief of hallucinations and delusions. Negative symptoms usually are not affected.
No euphoria, so dependence is not a problem.
Neuroleptic Syndrome: Psychomotor slowing, and affective indifference. Characteristic behavior of patients taking these drugs.
Anti-Emetic: They have inhibitory effect on chemotactic trigger zone, thus the drugs are also effective as anti-emetics. This is only for a chemical nausea -- the drugs are
NEUROLEPTIC: Anti-Histaminergic, Anti-Cholinergic, Anti-alpha-Adrenergic, Anti-Serotoninergic, Anti-Dopaminergic. All of the drugs have differing affinities for these rec
ADVERSE EFFECTS:
SHORT-TERM:
Extrapyramidal Effects: Particularly early in treatment, then hopefully it goes away.
Parkinsonian resting tremor, bradykinesia, dystonia, perioral tremor.
Akathisia: Terrible motor restlessness. Patient has to walk around all the time.
These side-effect can be alleviated by concomitant use of centrally-acting anti-cholinergics (benztropine, trihexyphenidyl, diphenhydramine), just as it can wit
Endocrine: Increased prolactin release
Gynecomastia in males
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Amenorrhea, Galactorrhea (but not dysmenorrhea) in females.

Sedation: Due to CNS anti-histaminergic effect.
Orthostatic Hypotension: Due to alpha-adrenergic blockade. Tolerance can develop to this effect.
Anticholinergic Effects: Dry mouth, constipation, urinary retention.
Ocular: Blurred vision, retinitis pigmentosa.
Decreased seizure threshold: Can promote seizures.
Poikilothermia, which can lead to hypothermia
Neuroleptic Malignant Syndrome: Extreme Parkinsonian side-effects and lack of sweating (no cholinergics) ------> dangerously high fever.
LONG-TERM:
Tardive Dyskinesia: Irreversible Parkinsonian tremor. Stereotypes abnormal movements and facial disfigurement. Perioral tremor.
Blood dyscrasias, especially agranulocytosis with Clozapine.
DRUG-INTERACTIONS:
Amplifies the depressive effects of sedative hypnotics, including alcohol.
Amplifies the respiratory-depressant effect of opiates.
PHARMACOKINETICS: Can be given IM, IV, or PO. Extreme hepatic metabolism.
LITHIUM: Used in the long-termtreatment and prophylaxis of mood swings with Bipolar Disorder.
CLINICAL USE: Lithium is not useful to treat acute episodes of mania use anti-psychotics for that.
Effects noted 7-10 days after instituting treatment. It has a slow-acting effect (must build up blood levels)
Lithium is more useful at alleviating mania than it is at alleviating depression, but it has effects at both ends of the spectrum.
MECHANISM: Unknown. May affect membrane transport, second-messenger systems (phosphoinositol hydrolysis), synaptic neurotransmission.
ADVERSE EFFECTS: Contraindicated in patients with renal or CV disease.
Thyroid: Benign Goiter noticed in many people, which can lead to hypothyroidism.
Kidneys: Polydipsia, Polyuria. Nephrogenic Diabetes Insipidus makes distal tubules insensitive to ADH.
Can counteract this side-effect by treating with thiazide diuretic, paradoxically, as it presents a greater load of sodium to the distal tubule, increasing the
CV: EKG Abnormalities.
Leukocytosis
Edema
Acne
Tremor
PHARMACOKINETICS:
Lithium excretion depends on the presence of sodium, therefore decreased Na+ causes a decrease in lithium excretion ------> potentiate the effects of lithium.
The Therapeutic Index of Lithium is very narrow:
Symptomatic effects at therapeutic concentrations (0.4 - 1.0 mEq/L): excessive thirst
Symptomatic effects at high concentration (1.0 - 1.6 mEq/L): diarrhea, nausea, incoordination, poor attention.
Symptomatic effects at toxic levels: Ataxia, confusion, stupor, coma, death.
ENDOGENOUS DEPRESSION
SYMPTOMS
Sleep Disturbances: Terminal Insomnia, middle insomnia, reduced REM Latency. Sleep is usually insomnia but maybe hypersomnia.
Appetite disturbance, usually appetite loss.
Neuroendocrine Disturbances
Elevated Cortisol
Dexamethasone Suppression Test: Synthetic cortisol should supress endogenous cortisol secretion, but it fails to in depressed people, yielding a positive test.
Test is very specific for depression but unfortunately it is not sensitive.
Reduced pituitary response to exogenous TRF (analogous to above) is also seen.
Emotional / Cognitive Symptoms:
Subjective complaints of poor memory, from poor concentration. Patient will actually complain of the memory loss, as compared to dementia, where patient has no clue
Dysphoria, anhedonia
Suicidal Ideation.
Somatic Complaints: General complaints of fatigue, malaise, weight change, decreased libido, decreased hygiene.
RISK-FACTORS:
Stroke: 25-55% of patients with stroke become endogenously depressed.
Diabetes: 35% prevalence of depression.
Malignancies: 25% prevalence of depression.
Chronic Fatigue Syndrome: 46-75% incidence.
Coronary Disease: 18-25% incidence post-MI.
GENETIC PREDISPOSITION: 54-65% concordance in MZ twins. 14-24% concordance in DZ twins.
TREATMENT:
Anti-Depressants: 15-25% of patients will remain symptomatic even with treatment.
Cognitive Therapy
Supportive Therapy
Electroconvulsive Therapy (ECT): Safe and reliable in eliciting a remission of symptoms. It is the treatment of choice for those who cannot tolerate or do not respond to a
Treatment of choice if suicide is imminent, because the anti-depressant effect is immediate.
EPIDEMIOLOGY:
5.8-12% incidence
8th leading cause of death, via suicide.
About 15% of depressed people ultimately die by suicide.
COMORBIDITY:
Substance Abuse: 32% for endogenous depression 60% for bipolar disorder.
SUICIDE:
Risk in depression is about 15%, regardless of treatment with anti-depressants, although anti-depressants may prolong the occurrence to a later age.
Women 10X more likely to attempt it, men 4X more likely to succeed.
Cancer and other terminal illnesses have no correlation to suicide, except AIDS does correlate.
Risk Factors for DEATH by suicide:
Male
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Age > 40 years
Being single, divorced, widowed, not married.
Depression
Alcoholism
ANTI-DEPRESSANTS
TRI-CYCLIC ANTIDEPRESSANTS (TCA'S):

STRUCTURE: They are structurally related to the phenothiazine anti-psychotics.
PHARMACODYNAMICS: The therapeutic effect is to block reuptake of Norepinephrine and Serotonin in the CNS ------> prolonged and heightened effects of those two ne
EFFECTS: Very efficacious, but effect are delayed -- 1-2 week of therapy required before therapeutic effect.
ADVERSE EFFECTS: Anti-Histaminic, Anti-Cholinergic, Anti-alpha-Adrenergic
Anti-Histaminic: Sedation, weight gain, possible hypotension.
Anti-Cholinergic: urinary retention, constipation, dry mouth, blurred vision, anti-cholinergic psychosis.
Use caution in patients with glaucoma or BPH, because of anti-cholinergic effects.
CV: Can be seriously cardiotoxic.
Orthostatic Hypotension, myocardial depression.
Arrhythmias: Can make worse or precipitate AV heart-block. Prolonged QRS or QT intervals, and ST-T wave changes.
Tachycardia can progress to CHF, death.
Can precipitate seizures, although incidence is low.
Sexual dysfunction: Impaired erection, impotence, priapism, lost libido.
Hypersensitivity: Rash, leukopenia, cholestatic jaundice.
PHARMACOKINETICS: High volume of distribution, significant first-pass metabolism. Significant differences in individual drugs.
TOXICITY: Overdose results in death. Tricyclics are the leading cause of drug-overdose death in the United States.
MAO-INHIBITORS: Phenylzine, Isocarboxazid, Tranylcypromine
EFFECTS:
Delayed Therapeutic Effect: several weeks of therapy required for anti-depressants to take effect. Significant inhibition of MAO is required before effects are see
SIDE-EFFECTS:
Concomitant use of tyramine can lead to hypertensive crisis.
Treat the crisis with IV phentolamine (alpha-antagonist) until pressure stabilizes.
Myoclonus.
Hypertension.
Hepatotoxicity due to idiosyncratic reaction. Hepatocellular necrosis and jaundice result.
INDICATIONS: Atypical depression
SELECTIVE-SEROTONIN REUPTAKE INHIBITOR'S (SSRI'S):
EFFECTS: Delayed onset of effect, like the tri-cyclics. You may have to hospitalize the patient (if suicide is a risk), while the drug is taking effect.
The SSRI's are less toxic than the TCA's, but they are not more efficacious. Efficacy is the same.
ADVERSE EFFECTS: Nausea, nervousness, headache, insomnia, anxiety. Morning dosing is recommended.
Sexual Dysfunction: Lost libido. Common complaint.
Weight Loss: Some companies are trying to pursue this effect as the primary therapeutic use.
Insomnia can be a particular problem, esp. in patients already plagued by insomnia. In this case consider switching to a TCA.
Urticaria, rashes: Discontinue drugs if these effects occur.
DRUG INTERACTIONS: Do not use in combination with, or within 2 weeks of, use of MAO Inhibitors. Fatal reactions may result.
PHENOTHIAZINES: Used for depression with psychotic features, or depression where hostility is a prominent symptoms.
OTHER USES FOR ANTI-DEPRESSANTS:
Post-Traumatic Stress Disorder (PTSD): Tri-cyclics are specifically good for PTSD. They relieve the effects of hyper-reactivity, nightmares, and flashbacks. Can use propanolol
Obsessive-Compulsive Disorder (OCD): The SSRI's are very effective, a revolution in treatment.
LOCAL ANESTHETICS
IDEAL ANESTHETIC: One that acts quickly, predictably, and reversibly.
Procaine, lidocaine, tetracaine come closest to ideal.
DRUGS:
ESTERS: Shorter acting and more easily hydrolyzed (metabolized in both blood and liver).
Cocaine, procaine, tetracaine, benzocaine
Destroyed by esterases in blood and liver.
SIDE-EFFECTS: See more central effects than with amides. Convulsions are possible.
AMIDES: Longer acting
Lidocaine, mepivacaine, bupivacaine
Destroyed by amidases in liver.
EFFECTS: They block local nerve conduction.
MECHANISM: Depress Na+ and K+ conductance, stabilizing nerve membranes ------> slowing propagation of action potential.
Vasoconstrictors (epinephrine) can be given to prolong the effects of the local anesthetic.
SIDE-EFFECTS: They all depress heart conduction and blood pressure.
OPIOID ANALGESICS
OPIOID RECEPTORS: Endorphins are the endogenous agonists of opioid receptors.

MU: Responsible for euphoria and physical dependency. Also produces respiratory depression.
Responsible for supraspinal analgesia
KAPPA: Produces miosis (constricted pupils) and sedation.
Responsible for spinal analgesia
SIGMA: Produces dysphoria, cardiac stimulation, hallucinations.
EFFECTS: They alter the psychological perception of pain, rather than reducing the pain itself.
CNS:
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Analgesia: Due primarily to altered perception of pain, but a secondary effect is that they raise the threshold for pain.
Euphoria: Habit-forming. Can cause dysphoria at analgesic doses, particularly in patients who are not in pain.
Cough Suppression
Respiratory Suppression
GI: Constipation
GU: Urinary retention, increased bladder tone.
Uterine: Prolonged labor, due to muscle relaxation.
Neuroendocrine: Stimulate prolactin, growth hormone, ADH (urinary retention). Inhibit LH.
INDICATIONS:
Acute pulmonary edema, dyspnea: Decreased myocardial preload and afterload, decreased perception of shortness of breath and decreased anxiety relieve symptoms of
Renal and biliary colic: Severe pain is effectively treated with opioids, because it secondarily relaxes spasmodic smooth muscle around the stones.
Suppression of cough (anti-tussive).
Cancer pain: Should be given orally for cancer, without regard to tolerance.
SIDE-EFFECTS:
Histamine degranulation ------> impaired respiration and hypotension.
Respiratory Depression which can be deadly. Two mechanisms:
Direct suppression of medullary respiratory center.
Lessen sensitivity of the respiratory center to carbon dioxide.
Readily cross placental barrier ------> cause respiratory depression in newborn.
WITHDRAWAL: Effects often opposite to the effect of the drug.
Apprehension, tremor, headache, tachycardia, muscle spasm, ketosis, vomiting, anorexia.
Diarrhea, instead of constipation.
CNS hyperactivity, but rarely convulsions.
DRUG INTERACTIONS:
Sedative Hypnotics: Enhance the likelihood of respiratory depression.
Anti-Psychotics: Enhanced sedation, anti-cholinergics, and hypotension.
MAO-Inhibitors: Absolute contraindication, as it results in hyperpyretic coma and hypertension.
DRUGS of ABUSE
METHYLXANTHINES
NICOTINE
ALCOHOL
Tolerance: Pharmacologic tolerance -- not metabolic -- is the major form of tolerance to alcohol. It results from adaptation to the effects of ethanol in the CNS.
Alcohol OD (Alcohol Poisoning): Main objective - prevent death from respiratory suppression. Cardiorespiratory support.
WITHDRAWAL: Delirium Tremens. Treat with tapering doses of diazepam, an incomplete CNS depressant.
If the patient has confirmed liver disease, may use Oxazepam rather than Diazepam.
OPIOIDS: Heroin, morphine, oxycodone
RISKS: IV blood-born infections, including HIV, HBV, meningitis, osteomyelitis.
Withdrawal: Treat with methadone, and/or clonidine which reduced sympathetic outflow.
STIMULANTS: AMPHETAMINES, COCAINE
Cocaine is more addictive than the amphetamines.
Withdrawal: Mental depression, exhaustion, hunger, sleepiness.
Overdose: Death occurs by respiratory depression and convulsions.
HALLUCINOGENS: They may be acting through 5-HT receptors.
GENERAL EFFECTS: Mydriasis, increased sensitivity of sympathetic responses, hallucination, altered mood, impaired judgment.
MARIJUANA (TETRAHYDROCANNABINOL, THC) Laughter, red eyes, heightened pulse-rate.
PSILOCYBIN
LYSERGIC ACID (LSD)
PHENCYCLIDINE (PCP): Produces feelings of detachment and disorientation.
SKELETAL MUSCLE RELAXANTS
INDICATIONS: Used primarily as an adjunct to anesthetics, in surgery, to relax muscle and allow incisions. Aids intubation and incision.
DRUG-CLASSES:
COMPETITIVE BLOCKERS: Blocks nicotinic receptors, causing flaccid paralysis.
Small (distal) muscles are affected first, and respiratory muscles are affected last.
DEPOLARIZING BLOCKERS: Binds to nicotinic receptors with higher affinity than ACh ------> inactivate Na+ channels, depolarization blockade.
EFFECTS: Initially muscle fasciculations are seen, later relaxation.
PHARMACOKINETICS: Almost always administered IV.
DRUG-INTERACTIONS: Lots of interactions
GENERAL ANESTHETICS: Increase sensitivity to muscle relaxants, with additive effect (block of Na+ channels).
AMINOGLYCOSIDES, TETRACYCLINE: Decrease ACh release and thus inhibit muscular activity.
CALCIUM-CHANNEL BLOCKERS: Potentiate the effects of muscle-relaxants.
INDIVIDUAL RESPONSES: Responses vary greatly, according to individual levels of non-specific cholinesterase, and to individual renal function.
Dantroleneistheonlyskeletalmusclerelaxantthatactsdirectlyonskeletalmuscletoblockexcitationcontractioncouplingbyinhibitingtherele
reticulum.Besidesitsuseintreatingspasticity,dantroleneiseffectiveinmalignanthyperthermia,adisorderthatmaybetriggeredingenetically
andneuromuscularblockingagentsandischaracterizedbyaprofoundreleaseofcalciumfromthesarcoplasmicreticulum.
Dantrolenesodium
Dantrolenesodium(Dantrium)
Dantrolenesodium
(DANtrohleen)
PregnancyCategory:C(parenteraluse)DantriumDantriumIV(Rx)
Dantrolene(Dantrium)isadirectmusclerelaxantthatblockscalciumfromsignalingmusclestocontract.Itisoccasionallyusedinchildrenwithseverespasticity,usuallyincom
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somecases,dantrolenehasbeenreportedtobeusefulforhospitalizedchildrenwhoexperiencebriefepisodesofveryseveredystonicspasms.Dantroleneisalsousedtotreatmali
effectofanesthesia,andneurolepticmalignantsyndrome,ararebutdangerouscomplicationofneurolepticmedications.Overalongperiodoftime,dantrolenemaycauseachang
fibers.Itmayalsocausegastrointestinalorliverdisease,inadditiontomilddrowsinessandnausea.
Classification:Musclerelaxant,centrallyacting
SeeAlso:SeealsoSkeletalMuscleRelaxants,CentrallyActing.
Action/Kinetics:Notrelatedtootherskeletalmusclerelaxants.Actsdirectlyonskeletalmuscle,probablybydissociatingtheexcitationcontractioncouplingmechanismas
fromthesarcoplasmicreticulum.Thisresultsinadecreasedforceofreflexmusclecontractionandareductionofhyperreflexia,spasticity,involuntarymovements,and
isduetoaninhibitionofreleaseofcalciumfromthesarcoplasmicreticulum.Thisresultsinpreventionorreductionoftheincreasedmyoplasmiccalciumionconcentratio
associatedwithmalignanthyperthermia.Absorptionisslowandincomplete,butconsistent.Peakplasmalevels:46hr.t1/2:PO9hrafteradoseof100mg
Uses:PO:Musclespasticityassociatedwithseverechronicdisorders,suchasmultiplesclerosis,cerebralpalsy,spinalcordinjury,andstroke.Preoperativelytoprevento
hyperthermia.Topreventrecurrencefollowingamalignanthyperthermiacrisis.IV:Malignanthyperthermiaduetohypermetabolismofskeletalmuscle.Preoperativelyo
developmentofsignsofmalignanthyperthermiainsusceptibleclients.Investigational:Exerciseinducedmusclepain,heatstroke,andneurolepticmalignantsyndrome.
Contraindications:Orallyinactivehepatitisorcirrhosis,wherespasticityisusedtosustainuprightpostureandbalanceinlocomotionortoobtainormaintainincreasedfu
torheumaticdisease.Pregnancy,lactation,orchildrenunder5yearsofage.
SpecialConcerns:Usewithcautioninclientswithimpairedpulmonaryfunction,especiallythosewithobstructivepulmonarydiseaseseverelyimpairedcardiacfunctiond
previousliverdiseaseordysfunction.
SideEffects:FollowingPOuse:Sideeffectsaredoserelatedanddecreasewithusage.Fatalandnonfatalhepatotoxicity.CNS:Drowsiness,dizziness,weakness,mal
seizures,speechdisturbances,fatigue,confusion,depression,nervousness.GI:Diarrhea(common),anorexia,constipation,GIbleeding,dysphagia,gastricirritation,abd
myalgia.Dermatologic:Rash(acnelike),photosensitivity,pruritus,urticaria,hairgrowth,sweating,eczematoideruption.CV:BPchanges,phlebitis,tachycardia.
urinaryincontinence,hematuria,crystalluria,nocturia,impotence.Ophthalmic:Visualdisturbances,diplopia.Miscellaneous:Chills,fever,tearing,feelingofsuffocation,a
pericarditis.
FollowingIVuse:Pulmonaryedema,thrombophlebitisurticaria,erythema.
OverdoseManagement:Symptoms:Extensionofsideeffects.Treatment:Immediategastriclavage.Maintainairwayandhaveartificialresuscitationequipmentavailable.
crystalluria.MonitorECG.
DrugInteractions:Clofibrate/ PlasmaproteinbindingofdantroleneCNSdepressants/ CNSdepressionEstrogens/ RiskofhepatotoxicityWarfarin/ Plasmaproteinbin
SIDEEFFECTS
Therehavebeenoccasionalreportsofdeathfollowingmalignanthyperthermiacrisisevenwhentreatedwithintravenousdantrolene:incidencefiguresarenotavailable(thepredantrolenemortality
Mostofthesedeathscanbeaccountedforbylaterecognition,delayedtreatment,inadequatedosage,lackofsupportivetherapy,intercurrentdiseaseand/orthedevelopmentofdelayedcomplicati
coagulopathy.Insomecasesthereareinsufficientdatatocompletelyruleouttherapeuticfailureofdantrolene.
Therearerarereportsoffatalityinmalignanthyperthermiacrisis,despiteinitialsatisfactoryresponsetoI.V.dantrolene,whichinvolvepatientswhocouldnotbeweanedfromdantroleneafter
TheadministrationofintravenousDantriumtohumanvolunteersisassociatedwithlossofgripstrengthandweaknessinthelegs,aswellasdrowsinessanddizziness.
Thefollowingadversereactionsareinapproximateorderofseverity:
TherearerarereportsofpulmonaryedemadevelopingduringthetreatmentofmalignanthyperthermiacrisisinwhichthediluentvolumeandmannitolneededtodeliverI.V.dantrolenepossibly
Therehavebeenreportsofthrombophlebitisfollowingadministrationofintravenousdantrolene:actualincidencefiguresarenotavailable.
TherehavebeenrarereportsofurticariaanderythemapossiblyassociatedwiththeadministrationofI.V.Dantrium.Therehasbeenonecaseofanaphylaxis.
NoneoftheseriousreactionsoccasionallyreportedwithlongtermoralDantriumuse,suchashepatitis,seizures,andpleuraleffusionwithpericarditis,havebeenreasonablyassociatedwithsho
Thefollowingeventshavebeenreportedinpatientsreceivingoraldantrolene:aplasticanemia,leukopenia,lymphocyticlymphoma,andheartfailure.(SeepackageinsertforDantrium(
reactions.)
ThepublishedliteraturehasincludedsomereportsofDantriumuseinpatientswithNeurolepticMalignantSyndrome(NMS).DantriumIntravenousisnotindicatedforthetreatmentofNMSand
Intravenous.
DRUGINTERACTIONS
Dantriumismetabolizedbytheliver,anditistheoreticallypossiblethatitsmetabolismmaybeenhancedbydrugsknowntoinducehepaticmicrosomalenzymes.However,neitherphenobarbital
Bindingtoplasmaproteinisnotsignificantlyalteredbydiazepam,diphenylhydantoin,orphenylbutazone.Bindingtoplasmaproteinsisreducedbywarfarinandclotibrateandincreasedby
Cardiovascularcollapseinpatientstreatedsimultaneouslywithvarapamilanddantrolenesodiumisrare.Thecombinationoftherapeuticdosesofintravenousdantrolenesodiumandverapamil
inventricularfibrillationandcardiovascularcollapseinassociationwithmarkedhyperkalemia.Itisrecommendedthatthecombinationofintravenousdantrolenesodiumandcalciumchannel
managementofmalignanthyperthermiacrisisuntiltherelevanceofthesefindingstohumansisestablished.
Administrationofdantrolenemaypotentiatevecuroniuminducedneuromuscularblock.
BaclofenandbenzodiazepinesbothworkbyaugmentingGABAneurotransmission,butbaclofenproduceslesssedationthandiazepamatdose
Cyclobenzaprine,orphenadrine,chlorzoxazone,andcarisoprodolareallcentrallyactingmusclerelaxantswhoseeffectsmaybepartlyattributed
treatmentofmusclespasmresultingfromminortrauma.
Diazepamisanalternativetodantroleneandbaclofenforthetreatmentofmusclespasmandspasticityresultingfromspinalcordinjuriesando
conditions.
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Pancuroniumisanondepolarizingneuromuscularblockerthatmustbegivenparenterallyandisprimarilyusedasanadjuncttogeneralanesthe
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IONIC COMPOSITION OF THE BODY WATER COMPARTMENTS

mEqui per liter

(*Note that intracellular free Ca2+ concentration is approximately 100 nM.)

REGULATION OF CELL VOLUME

Control of ECF Volume

Approximate Non-lethal Limits

Structural Features of Transporting Epithelia.

FUNCTIONS OF THE HUMAN KIDNEY

UNDERSTANDING RENAL PHYSIOLOGY

body fluid compartments

steady state, set point, mediators, effectors

physiological setpoints (for reference only)

overall function of transporting epithelia

solute coupled water transport

overall concepts of structrual and functional polarity

overall functions of the kidney

SMOOTH MUSCLE CONTRACTION

Gap junction & Many gap junctions, innervation :relatively

and larger blood vessels.

Slow Wave Potentials,rhythmical, graded

Stable,no spontaneous depolarization

Plasticity : stress relaxation

Tone : example in blood vessels and GI sphincters

Stretch induced contraction:Fast stretch

Intrinsic property: modified by nerves as well as

CHARACTERISTICS OF SMOOTH MUSCLE.

1.Intracellular Ca++ rise -->trigger contraction (as in striated muscle)

Phases of Gastric-Acid Secretion:

The Cl- is then also excreted into the lumen

PEPTIC ULCER DISEASE (PUD):

DISTRIBUTION: 30% of ulcers occur in stomach, 70% in the duodenum.

Excess Mg+2: Neurologic, CV, neuromuscular dysfunction.

Excess Ca+2: Hypercalcemia

H+ blockade is cyclical, according to the secretion of histamine.

ACTIONS: Generally they increase production of mucus, HCO3-, and prostaglandins.

PHARMACOKINETICS: Misoprostol is well-absorbed in GI tract.

LOCALLY-ACTING: Temporarily numb receptors in the GI tract, preventing vomiting

MECHANISM: They stimulate the intestinal wall, producing an increase in peristalsis.

AUTONOMIC NERVOUS SYSTEM

SYNTHESIS OF ACETYLCHOLINE: Choline + Acetyl-CoA --> Acetylcholine (Choline Acetyltransferase)

CATECHOLAMINE RELEASE: Other neurotransmitters are released along with NE.

UPTAKE I: Reuptake of NE back into the presynaptic neuron.

AUTONOMIC RECEPTORS: Brief summary

Nicotinic Ganglionic (NG)

Activation of parasympathetic and sympathetic post-synaptic neurons.

Nicotinic Neuromuscular Junction (NMJ)

Activation of skeletal muscle

Lower rate (on SA node) and force (on myocardium)

Inhibitory: cAMP, K+ influx

Pupillary constriction (contract iris muscle) accommodation

Contraction of GI smooth muscle and relaxation of sphincters.

Bronchoconstriction and increased secretions

Erection (via NO), vasodilation

Vasodilation: Strong indirect vasodilatory effect due to inhibition of sympathetics. At low

Some direct vasodilatory effect (especially when exogenous ACh is given)

Increased sweating in non-adrenergic sweating areas (regular eccrine sweat glands).

Vascular smooth muscle

Vasoconstriction (via IP3 / DAG, increased Ca+2)

Smooth muscle relaxation and contraction of sphincters

Pupillary dilation (contract radial muscle)

Inhibitory on sympathetic and parasympathetic post-ganglionic neurons. For sympathetics,

Gi ---> inhibit cAMP