W systemie Windows 10 użytkownik konta standardowego (konta należące do lokalnej grupy Użytkownicy) posiada:

1. Uprawnienia do modyfikowania własnego konta.
2. Nieograniczony dostęp do własnych plików i folderów.
3. Ograniczony dostęp do pozostałych zasobów komputera.
4. Standardowi użytkownicy mogą m.in.
   a) Instalować aktualizacje za pomocą usługi Windows Update.
   b) Instalować sterowniki pobrane z usługi Windows Update lub lokalnego magazynu sterowników komputera.
   c) Przeglądać ustawienia systemowe.
   d) Podłączać urządzenia Bluetooth do komputera.
   e) Resetować połączenia sieciowe i przeprowadzać ich typowe operacje diagnostyczne.
   f) Konfigurować połącz enia sieci Wi-Fi.
   g) Zmienić strefę czasową.

   Natomiast konta administratorów (konta należące do lokalnej grupy Administratorzy) posiadają nieograniczone uprawnienia (przy czym przed skorzystaniem z nich administrator musi potwierdzić swoją decyzję), obejmujące: 1. Wszystkie uprawnienia konta standardowego użytkownika. 2. Możliwość zarządzania kontami innych użytkowników. 3. Uprawnienia do zmian konfiguracji komputera. 4. Dostęp do wszystkich plików. 5. Możliwość instalowania sprzętu i oprogramowania. Jeżeli użytkownik należy do wielu grup, jego wynikowe uprawnienia są sumą uprawnień nadanych poszczególnym grupom. Jeżeli jednak którejś z grup jawnie odmówiono uprawnienia, użytkownik nie będzie mógł wykonać danej operacji.

Drug molecules obey the law of mass action.

When the plas ma concentration exceeds the tissue concentration, the drug moves from the plasma into tissue.

Most drugs that readily cross the blood-brain barrier (eg, lipophilic drugs li ke hypnotics and opioids) are avidly taken up in body fat.

Biotransformation is the chemical process by which the drug molecule is altered in the body.

The liver is the primary organ of metabolism for drugs.

Small unbound molecules freely pass from plasma into the glomerular filtrate.

The nonionized (uncharged) fraction of drug is reabsorbed in the renal tubules, whereas the ionized (charged) portion is excreted in urine.

Elimination half -life is the time required for the drug concentration to fall by 50%.

For drugs described by multicompartment pharmacokinetics (eg, all drugs used in anesthesia), there are multiple elimination half-lives.

The context - sensitive half-time is a clinically useful concept to describe the rate of decrease in drug concentration

The context - sensitive half-time should be used instead of half -lives to compare the pharmacokinetic properties of intravenous drugs used in anesthesia.

Pharmacokinetics consists of 4 linked absorption, distribution, biotransformation, and excretion

nitroglycerin is well absorbed by the gastrointestinal tract but has low bioavailability when administered orally NTG does this because it undergoes
extensive first-pass hepatic metabolism as it transits the liver before reaching the systemic circulation.

The reason is that nitroglycerin undergoes extensive first-pass hepatic metabolism as it transits the liver before reaching the systemic ci rcu lation

Oral drug administration exposes the drug to first-pass hepatic metabolism, and permits gastric pH, enzymes, motility, food, and other drugs to potentially reduce the predictability of systemic drug delivery.

Non ionized (uncharged) drugs are mo re read il y absorbed than ionized (charged) forms.

an ac i dic environment (stomach) favors the absorp- tion of acidic drugs (A - + H+ =>AH), whereas a more alkaline environment (i11testine) favors basic drugs (BH+ => W + B).

Most drugs are largely absorbed from the intestine rather than the stomach because of the greater surface area of the small intestine and longer transit duration.

AJl venous drainage from the stomach and small intestine flows to the liver. As a result, the bioavailabil- i ty of highly metabolized drugs may be significantly reduced by first-pass hepatic metabolism.

Because the venous drainage from the mouth and esophagus flows into the superior vena cava rather than into the por tal system, sublingual or buccal drug absorption bypasses the liver and first-pass metabolism.

Rectal administration part ly bypasses the por ta l system, and represents an alternative route in small ch ildren or patients who are unable to tolerate oral ingestion

many drugs irritate the rectal mucosa.

Transdermal drug administration can provide pro longed continuous administrati on for some drugs. However, the stratum corneum is an effec- tive barrier to all but small, lipid-so lub le drugs (eg, clonidine, nitroglycerin, scopolamine, fentanyl, and free-base local anesthetics

Su bcutaneous and intramuscular absorption depend on drug diffusion from the site of injecti on to the bloodstream.

Pharynx is the Posterior aspect of nasal cavity down to cricoid cartilage

Nasopharynx -posterior aspect of nasal cavity

Oropharynx-posterior aspect of oral cavity

Hypopharynx- tip of epiglottis to cricoid cartilage

NOSE (NASAL CAVITY) is the primary pathway of air exchange, resistance is 2-3 times greater through the nose than the mouth lined with highly vascular mucous membranes, cilia and hair

The nasal cavity functions by providing warmth, humidification and filtration

OROPHARYNX Includes the uvula, the soft and hard palates, the palatine tonsils and the tongue and extends to the tip of the epiglottis

Pharyngeal tonsils (adenoids) located in nasopharynx.
Pharyngeal tonsils can be damaged by nasal intubation

Palatine tonsils located in oropharynx and can be damaged by nasal intubation

Lingual tonsils paired at base of the tongue

Waldeyer’s ring located btw palantine tonsils and tubal tonsils
Waldeyer’s ring is a continuous ring of lymphoid tissue that surrounds entrance to pharynx

TONGUE is the largest structure in the oropharynx.
The tongue is the main source of resistance and obstruction

The Root of the tongue is connected to hyoid bone and the genoiglossi muscles

Genioglossi muscles relax and the tongue obstructs the pharynx (during swallowing??)

LARYNX

Larynx is the organ of phonation
Larynx is the Inlet to lower airways and defense for lower airways

Larynx is located Level of C3-4 in the child and C3-6 in the adult

VALLECULA is the Groove located between the base of the tongue and the epiglottis

Epiglottis is the covering for the laryngeal opening Thyroid cartilage – Adam’s apple.
The Epiglottis is located at the anterior wall of larynx

Cricoid is the only continuous cartilage of the larynx.
The Cricoid measures about 15 cm in adults

Although the mechanism of action of the general anesthetics remains unknown, the primary site of anesthetic action is now considered to be membrane receptors

Spinal cord receptors are being dif- ferentiated from receptors in the brain and targeted with specific drugs.

Receptor super families with definable amino acid subunits are the targets of new classes of anesthetic drugs such as α 2 -agonists and analgesics

The poten- tiation of the inhibitory γ-aminobutyric acid (GABA) receptors is considered a primary mechanism of action of inhalation and intra- venous anesthetics

The recovery from intravenous anesthesia is described in terms of context-sensitive half-time, which in addi- tion to the usual concept of drug half-life takes into consideration the duration of anesthetic administration rather than just drug redistribution and elimination profiles

Clinical experience has shown that the response to anesthetic drugs in elderly patients differs from that in younger patients.

Studies to date in elderly patients, although limited, demonstrate an age-related decline in most receptor populations and an overall decrease in pharmacodynamic responses

The choice of anesthetic agents will be based on age-related receptor profiles and the patient’s genetic ability to rapidly clear and recover from anes- thetic drugs once their administration has been terminated

anesthetists will continue to administer anesthesia based on age-indexed population drug profiles adjusted for individ- ual pathologies (i.e., general principles of pharmacology)

The current medical economic climate necessitates the optimum selection and use of anesthetic drugs based on their pharmacologic profiles.

pharmacology refers to the study of processes by which a drug produces one or more measured physiologic responses.

Recent attention has focused on the biosphere, or the protein receptor site, as not only the locus of drug binding but also a primary regulator of the measured pharmacologic response.

A re ceptor is a protein or other substance that binds to an endog- enous chemical or a drug

Receptors have three common proper- ties: sensitivity, selectivity, and specificity.

These receptors properties are characterized by the fact that a drug response occurs from a low concentration (sensitivity) produced by structurally similar chemicals (selectivity), and the response from a given set of receptors is always the same because the cells themselves determine the response (specificity).

The bonds that form between drugs and receptors typically fall into these categories from weak- est to strongest: van der Waals, hydrophobic, hydrogen, ionic, and covalent

We now have identified multiple mechanisms by which an endogenous substance or drug may complex with a receptor and transmit a signal

There are seven classes of drug receptor proteins based on genetic characterization and similarity of structure and functions.

Drug receptor proteins may be located within the luminal membrane and at the surface of the ionic channel.

Studies of acetylcholine and its receptor at the neuromuscular junction indicate that less than 1% of the cell surface binds drug to receptor protein to achieve the tissue response

Complete saturation of available receptors with drug molecules is not necessary for a desired tissue response to be elicited.

Receptor Classification
7-Transmembrane receptors are
• Ligand-gated ion channels
• Ion channels
• Catalytic receptors
• Nuclear receptors
• Transporters
• Enzymes

For intravenously administered drugs, sufficient drug for a max- imal tissue response is delivered to the receptor site within the time required for a single complete circulation (approximately 1 minute), provided an adequate drug dose was administered initially.

Current understanding of molecular pharmacology suggests that the delay recorded from initial drug administration to the onset of the tissue response reflects the time required for molecu- lar orientation and attachment to the receptor—that is, the time course of the receptor protein conformational change and the tis- sue response time

As long as both the drug and the receptor are hydrophobic, bonding occurs

Intravenous anesthetics act by binding to membrane receptor channel proteins

The GABA A (ionotropic receptor family A) inhibitory receptor has been impli- cated and suggested as a primary site of intravenous anesthetic action, except in the case of ketamine.

inhalation anesthetics, like intravenous anesthetics, bind to GABA A recep- tor proteins and cause inhibition of signal transduction by increas- ing the influx of chloride ions through membrane channels

ndividual agonist drugs have at least three configuration points for attachment to their receptors

With more points of attachment, a more perfect drug-receptor fit occurs. Agonist drugs can induce receptor proteins to alter their topography to achieve a more exacting fit with the drug.

The alignment of a drug with its receptor is aided by various bonding forces, of which van der Waals forces and ionic bonding are prominent

Volatile anesthet- ics (e.g., desflurane, sevoflurane, isoflurane, and nitrous oxide) bond to cell receptors by means of a nonspecific hydrophobic bonding mechanism

Some endogenous proteins provide alternative drug-binding sites. These sites are more correctly termed acceptors; the acceptor reduces the amount of unbound drug available for receptor com- plexing.

Albumin contains numerous acceptor sites and generally binds to acidic drugs.

Alpha 1 acid glycoprotein and β-globulin favor basic drugs.

The acetylcholine receptor protein is a pen- tamer of five peptide subunits conceptually forming a five-sided ring, with the central portion serving as the transduction ion channel. Only two of the five subunits are involved in acetylcho- line binding. The remaining three peptide subunits participate in the signal transduction process that involves a protein conforma- tional shift, allowing inward movement of sodium ions through the opened ion channel.

It is interesting to note that the GABA A receptor also has been shown to be composed of five peptide sub- units arranged to form a pentameric ring

signal transduction refers to processes by which a cell converts one kind of signal or stimulus into another. Most often, these involve ordered sequences or cascades of biochemi- cal reactions inside the cell. They are commonly referred to as second messenger pathways.

Many of the actions of the common anesthetic drugs are transduced through cell-surface receptors that are linked to GPCRs.

Receptor signaling translates changes to G proteins that are then linked to a second messenger such as cyclic AMP (adenosine monophosphate) or cyclic GMP (guanosine mono- phosphate). These second messengers regulate enzymes such as protein kinases and phosphatases, which drive their ultimate intracellular actions

ignal transduction for the GABA A receptor, for example, involves inward chloride ion movement through the opened central channel.

he protein compositions of acetylcholine and GABA receptors are remarkably similar, despite their functional differences—specifically, acetylcholine and sodium ion transduce an excitatory signal, and GABA and chloride ion transduce an inhibitory signal

The specific peptide subunits are ultimately responsible for the phar- macologic properties of specificity, affinity, and potency

Drugs such as dexmedetomi- dine, ropivacaine, and cisatracurium are selective in their receptor binding and thus achieve a better clinical side effect profile

The drug response equation is fundamental to pharmacologic principles. 35 It is derived from the law of mass action and is shown in the following equation, where drug (D) combines with receptor (R) to form a drug receptor complex (DRC) that elicits a tissue response (TR)

This is the occupancy theory. Simply stated, the magnitude of a drug’s effect is proportional to the number of receptors occu- pied.

Therapeutic drug doses reflect average doses of a “nor- mal” population of individuals.

Steady-state plasma concen- trations of hypnotic drugs such as midazolam and propofol and minimum alveolar concentrations (MAC) for inhaled anesthet- ics (e.g., desflurane, isoflurane, or sevoflurane) required to achieve desired anesthetic end-points decrease as age increases, indepen- dent of any age effect on drug pharmacokinetics

the effective plasma concentration 50 (median effective concentration [EC 50 ]) needed to achieve sedation with midazolam infusion is reported to be decreased by 50% in elderly volun- teers

A graphic description of the dose-response relationship is dis- played in Figure 5-2. The theoretic normal distribution of quan- tal (desired) responses to increasing drug dose takes the shape of a Gaussian curve.

In a Gaussian distribution curve, the mean, median, and mode are equidistant from the two extremes

The SEM describes the variance of the mean. It is equivalent to the SD of the mean

A Few Words About Mice And Focus While the shell is all about the keyboard, you can also use a mouse with your ter- minal emulator.
There is a mechanism built into the X Window System (the un- derlying engine that makes the GUI go) that supports a quick copy and paste tech- nique. If you highlight some text by holding down the left mouse button and drag- ging the mouse over it (or double clicking on a word), it is copied into a buffer maintained by X.
Pressing the middle mouse button will cause the text to be pasted at the cursor location. Try it.

Note: Don't be tempted to use Ctrl-c and Ctrl-v to perform copy and paste inside a terminal window. They don't work. These control codes have different meanings to the shell and were assigned many years before Microsoft Windows.

to display the amount of free memory, enter the free command.

The graded dose-response curve, which is plotted in linear fashion, characterizes the change in measured response as an administered dose is increased (Figure 5-5). The response curve has a hyperbolic shape, with the greatest change in response occurring to the left on a small portion of the x-axis.

It should be noted that “antagonist” drugs that do not bind to the ago- nist receptor are actually not antagonists.

Neostigmine is not an antagonist of rocuronium because it does not compete with rocuronium for the muscle end-plate receptor site. Neostigmine inhibits acetylcholinesterase, which allows acetylcholine to compete effectively with rocuronium and other nondepolarizing muscle relaxants for the receptor, leading to a recovery of muscle tone. Therefore, its effect is at least a partial form of indirect antagonism.

Sugammadex is the first and so far only drug in a new class of muscle relaxant reversal drugs. Known as a selective relaxant bind- ing agent (SRBA), sugammadex offers a unique mechanism in that it encapsulates the muscle-relaxant molecule, rendering it inac- tive. The complex formed is eliminated. This is a form of chemical antagonism, because no direct receptor action is evident.

Clinically, a quantal dose-response curve provides information on the frequency with which a given drug dose produces a desired ther- apeutic response in a patient population.

When the therapeutic safety margin is great, the risk of drug- induced death is small, and the margin of therapeutic safety is wide. The opposite is true when the therapeutic safety margin is small.

Drugs that produce surgical depths of anesthesia, such as sevoflurane and other halogenated anesthetics, also have a relatively narrow margin of safety

Sevoflurane is administered clinically in an amount that is 1.3- to 1.4-fold the MAC (mini- mum alveolar concentration), or the dose at which 50% of the patients do not move on surgical stimulation. The MAC can be lethal if the volume percentage delivered is increased to 1.7- to 2.0-fold and maintained for a prolonged period of time.

(ED 50 )—the dose at which 50% of a population responds as desired. The ED 50 is often used for comparing the potency of drugs within a class. Because the ED 50 is derived from the linear portion of the quantal dose-response curve (20% to 80% of the responders), relatively accurate com- parisons of drugs that cause similar responses can be made

Typically, the pro- portion of subjects responding to an ED 50 dose ranges from 45% to 55%.

The drug receptor interaction describes the formation of a single drug receptor com- plex, which leads to a fractional tissue response

The desired tissue response is observed when sufficient recep- tors have been occupied and activated by free drug. This process obeys the law of mass action: At steady state, equilibrium exists between bound and unbound drug receptors and the concentra- tion of free unbound drug at the site.

Specific characteristics of the drug and the receptor determine the association and dissociation of a drug with regard to its receptor and the kinetic, k, rates, which are constants

The terms affinity and efficacy (intrinsic activity) describe the degree of drug receptor interaction for a given drug and recep- tor protein population (e.g., GABA A and propofol).

The observed tissue response reflects the quantity of drug receptor complexes intact at any given moment

The phrase pharmacokinetic analysis of drug absorption and distribution describes onset time and magnitude of drug response. Drug elimination kinetic analysis describes the dura- tion of the tissue response.

With drug- receptor-response triad, when a drug combines with its receptor, a conformational change occurs in the receptor protein itself. No tissue response can occur without the structural shift. Evidence does suggest that events within the biosphere after drug associa- tion with the receptor are the principal regulatory variables of the response onset-offset time course

In the two-state model, the recep- tor is thought to exist in equilibrium between either an activated or inactivated state.

Until recently, the primary time constant thought to influence the onset of tissue response was the duration of the delay in the delivery of drug to the receptor sites.

Constitutively active receptors can exist and are shifted toward the activated state, even though no agonist or ligand is present. Receptors for benzodiazepines, cannabinoids, and serotonin are examples. Agonists shift the equilibrium toward activation. Antagonists freeze the equilibrium, and inverse ago- nists shift the equilibrium toward inactivation. The two-state model

It is now known that drug delivery sufficient to occupy 1% of the receptors is in many instances all that is required for a maximum tissue response to occur.

the syn- thesis and destruction of receptor proteins occur at a much more rapid rate than was previously believed—within minutes rather than days.

Receptor up-regulation and down-regulation can occur during drug infusion, with new receptor protein being synthesized in response to availability of free unbound drug

Pure pharmacologic antagonist drugs are similar in molecular structure to their corresponding agonist drugs.

However, owing to the addition or subtraction of one or more chemical moieties, Pure Antagonists are unable to initiate the receptor protein conformational shift necessary for eliciting a tissue response. Such antagonist drugs have receptor affinity but lack intrinsic activity or efficacy.

Antagonists that possess the property of weak affinity for the same receptor protein (e.g., atropine, esmolol) are competitive and may be displaced by an agonist. Noncompetitive antagonists, such as phenoxybenzamine and aspirin, have a strong affinity for the receptor protein, usually via covalent bonds, and cannot be displaced by the agonist

New receptor protein must be synthe- sized if agonist receptor complexing is to occur. As with ago- nist drugs, not all receptors are bound by antagonists. Antagonists cause a rightward shift in the drug dose-response curve. The extent of rightward shift reflects the number of available receptors occu- pied by the antagonist drug (Figure 5-9). Comparison of the ED 50 in Figure 5-9 shows a reduced affinity of the agonist for its receptor when the antagonist is present.

agonist-antagonist drugs have recep- tor protein affinity and intrinsic activity, but often only a fraction of the potency of the pure agonist

The mechanism by which agonist-antagonist drugs elicit less of a tissue response is not fully understood.

Addition The combined effect of two drugs acting via the same mechanism is equal to that expected by simple addition of their individual actions. 1 + 1 = 2
Synergism The combined effect of two drugs is greater than the algebraic sum of their individual effects. 1 + 1 = 3
Potentiation The enhancement of the action of one drug by a second drug that has no detectable action of its own. 1 + 0 = 3
Antagonism The action of one drug opposes the action of another. 1 + 1 = 0

Physiologic antagonism, another form of antagonism, involves two agonist drugs that bind to different receptors.
At the physiological antagonism, drugs bind to specific unrelated receptor proteins, initiate a protein conformational shift, and elicit individual tissue responses. The responses, however, generate opposing forces such as are observed with isoproterenol-induced vasodilation and norepinephrine- induced vasoconstriction.

For competitive antagonism, the agonist and antagonist have affinity for the same receptor protein;

Chemical antagonism occurs when a drug’s action is blocked and no receptor activity is involved. For example, protamine is a positively charged protein that forms an ionic bond with heparin, thus rendering it inactive. Sugammadex, mentioned previously, is another example

Continued stimulation of cells with agonists generally results in a state of desensitization, also referred to as refractoriness or down-regulation, such that the effect that follows continued or sub- sequent exposure to the same concentration of drug is diminished.

A drug interaction is an alteration in the therapeutic action of a drug by concurrent administration of other drugs or exogenous substances.

Chronic administration of an antagonist results in up- regulation as the number and sensitivity of the receptors increase as a response to chronic blockade.

refractoriness or down-regulation is very important in therapeutic situations; an example is attenuated response to the repeated use of β-adrenergic agonists as bronchodilators for the treatment of asthma

With up-regulation, the patient develops tol- erance, requiring higher doses of the antagonist to counteract the increasing receptor number

The "." notation refers to the working directory and the ".." notation refers to the working directory's parent directory.

The drug receptor sub- unit site is the primary regulator of onset-offset drug response

cd Changes the working directory to your home directory. cd - Changes the working directory to the previous working directory.

The anesthetist uses pharmacologic intervention to elicit a desired patient response. The site of the intervention is the bio- sphere, or the protein drug receptor, which is the primary regulator of the therapeutic response. Observed variation in patient drug response reflects the functionality of the biosphere and genetics, as well as physiologic variability

More and more evidence suggests that individual genetic variation in receptor proteins accounts for drug-response variation within seem- ingly normal populations. In clinical anesthesia, the range of patient responses to a given drug dose reflects this variation

The age-related decline in anesthetic drug dose needed to achieve a desired anesthetic end-point is related to a change in both pharmacodynamics and pharmacokinetics

The mean, median, and mode typically describe the dose- response relationship of a “normally distributed” population.

The SD, SEM, and median effective dose provide a description of a population’s response to a drug. Such descriptors provide only an approximate dosage; the anesthetist must adjust this dosage for each patient to achieve the desired physiologic response

Viewed at the molecular level, the observed response to a drug represents countless individual drug responses at the biosphere. Each drug-receptor interaction at the protein receptor elicits a fractional tissue response, and the sum of the fractional responses provides the observed response.

In accor- dance with the law of mass action, when free drug binds to a recep- tor, a conformational shift occurs in the receptor protein. This shift causes a central space or channel to open, allowing specific ions to enter or leave the cell or a G protein to be activated, resulting in a biochemical cascade yielding pharmacologic effects. The resultant tissue response continues until the drug dissociates from the recep- tor.

ls
-a --all List all files, even those with names that begin with a period, which are normally not listed (i.e., hidden).
-A --almost-all Like the -a option above except it does not list . (current directory) and .. (parent directory).
-d --directory Ordinarily, if a directory is specified, ls will list the contents of the directory, not the directory itself. Use this option in conjunction with the -l option to see details about the directory rather than its contents.
-F --classify This option will append an indicator character to the end of each listed name. For example, a “/” if the name is a directory.
-h --human-readable In long format listings, display file sizes in human readable format rather than in bytes. -l Display results in long format. -r --reverse Display the results in reverse order. Normally, ls displays its results in ascending alphabetical order. -S Sort results by file size. -t Sort by modification time.

Antagonist drugs also bind to the receptor but lack the ability to initiate the required protein conformational shift. The sum of fractional tissue responses elicited when an antagonist is present is inadequate for maintaining the desired tissue response.

Molecular pharmacology is identifying site-specific and age- related causes for the observed variation in patient drug response.

Linux system tick.

This will give us a chance to practice our navigation skills. One of the things we will discover is that many of the interesting files are in plain human-readable text. As we go about our tour, try the following:

1. cd into a given directory
2. List the directory contents with ls -l
3. If you see an interesting file, determine its contents with file
4. If it looks like it might be text, try viewing it with less