Gluconeogenesis

TRANSDUCTION MECHANISMS

Type 1: ligand-gated ion channels:- (also known as ionotropic receptors). These are membrane proteins with a similar structure to other ion channels, and incorporate a ligand-binding (receptor) site, usually in the extracellular domain. Typically, these are the receptors on which fast neurotransmitters act. Examples include the nicotinic acetylcholine receptor (nAChR); GABA_A receptor  and glutamate receptors of the NMDA, AMPA and kainate types

The nicotinic acetylcholine receptor, the first to be cloned, It is assembled from

four different types of subunit, termed α, β, γ and δ.The pentameric structure

(α₂, β, γ, δ) possesses two acetylcholine binding sites, each lying at the interface

between one of the two α subunits and its neighbour. Both must bind

acetylcholine molecules in order for the receptor to be activated.

THE GATING MECHANISM

Receptors of this type control the fastest synaptic events in the nervous system, in which a neurotransmitter acts on the postsynaptic membrane of a nerve or muscle cell and transiently increases its permeability to particular ions. Most excitatory neurotransmitters, such as acetylcholine at the neuromuscular  Junction or glutamate in the central nervous system, cause an increase in Na+ and K+s permeability. This results in a net inward current carried mainly by Na+, which depolarises the cell and increases the probability that it will generate an action potential. The action of the transmitter reaches a peak in a fraction of a millisecond,and usually decays within a few milliseconds. The sheer speed of this response implies that the coupling between the receptor and the ionic channel is a direct one, and the molecular structure of the receptor-channel complex agrees with this.In contrast to other receptor families, no intermediate  biochemical steps are involved in the transduction process. Type 2: G-protein-coupled receptors (GPCRs):- These are also known as metabotropic receptors or 7-transmembrane-spanning (heptahelical) receptors. They are membrane receptors that are coupled to intracellular effector systems via a G-protein (see below). They constitute the largest family,5 and include receptors for many hormones and slow transmitters, for example the muscarinic acetylcholine receptor (mAChR), adrenergic receptors and chemokine receptors G-proteins and their role G-proteins comprise a family of membrane-resident proteins whose function is to recognise activated GPCRs and pass on the message to the effector systems that generate a cellular response They are the go-between proteins, but were actually called G-proteins because of their interaction with the guanine nucleotides, GTP and GDP. G-proteins consist of three subunits: α, β and γ. Guanine nucleotides bind to the α subunit, which has enzymic activity, catalysing the conversion of GTP to GDP. The β and γ subunits remain together as a βγ complex. G-proteins appear to be freely diffusible in the plane of the membrane, so a single pool of G-protein in a cell can interact with several different receptors and effectors.In the 'resting' state, the G-protein exists as an unattached αβγ trimer, with GDP occupying the site on the α subunit. When a GPCR is activated by an agonist molecule, a conformational change occurs, involving the cytoplasmic domain of the receptor, causing it to acquire high affinity for αβγ. Association of αβγ with the receptor causes the bound GDP to dissociate and to be replaced with GTP (GDP-GTP exchange), which in turn causes dissociation of the G-protein trimer, releasing α-GTP and βγ subunits; these are the 'active' forms of the G-protein, which diffuse in the membrane and can associate with various enzymes and ion channels, causing activation of the target. Signalling is terminated when the hydrolysis of GTP to GDP occurs through the GTPase activity of the α subunit. The resulting α-GDP then dissociates from the effector, and reunites with βγ, completing the cycle. TARGETS FOR G-PROTEINS The main targets for G-proteins, through which GPCRs control different aspects of cell function cAMP is a nucleotide synthesised within the cell from ATP by the action of a membrane-bound enzyme, adenylyl cyclase. It is produced continuously and inactivated by hydrolysis to 5´-AMP, by the action of a family of enzymes known as phosphodiesterases (PDEs). Many different drugs, hormones and neurotransmitters act on GPCRs and produce their effects by increasing or decreasing the catalytic activity of adenylyl cyclase, thus raising or lowering the concentration of cAMP within the cell. Cyclic AMP regulates many aspects of cellular function including, for example, enzymes involved in energy metabolism, cell division and cell differentiation, ion transport, ion channels, and the contractile proteins in smooth muscle. These varied effects are, however, all brought about by a common mechanism, namely the activation of protein kinases by cAMP. Protein kinases regulate the function of many different cellular proteins by controlling protein phosphorylation. Examples 1.       Increased cAMP production in response to β-adrenoceptor activation affects enzymes involved in glycogen and fat metabolism in liver, fat and muscle cells. The result is a coordinated response in which stored energy in the form of glycogen and fat is made available as glucose to fuel muscle contraction. 2.       Other examples of regulation by cAMP-dependent protein kinases include the increased activity of voltage-activated calcium channels in heart muscle cells. Phosphorylation of these channels increases the amount of Ca2+ entering the cell during the action potential, and thus increases the force of contraction of the heart. 3.       In smooth muscle, cAMP-dependent protein kinase phosphorylates (thereby inactivating) another enzyme, myosin-light-chain kinase, which is required for contraction. This accounts for the smooth muscle relaxation produced by many drugs that increase cAMP production in smooth muscle 4.       include certain types of mAChR (e.g. the M2 receptor of cardiac muscle; see, α2-adrenoceptors in smooth muscle, and opioid receptors The phospholipase C/inositol phosphate system The phosphoinositide system, an important intracellular second messenger system. PIP2 is the substrate for a membrane-bound enzyme, phospholipase Cβ (PLCβ), which splits it into DAG and inositol (1,4,5) trisphosphate (IP3), both of which function as second messengers. The activation of PLCβ by various agonists is mediated through a G-protein. After cleavage of PIP2, the status quo is restored. DAG being phosphorylated to form phosphatidic acid (PA), while the IP3 is dephosphorylated and then recoupled with PA to form PIP2 once again. Inositol phosphates and intracellular calcium Inositol (1,4,5) trisphosphate is a water-soluble mediator that is released into the cytosol and acts on a specific receptor-the IP3 receptor-which is a ligand-gated calcium channel present on the membrane of the endoplasmic reticulum. The main role of IP3, is to control the release of Ca2+ from intracellular stores. Because many drug and hormone effects involve intracellular Ca2+, this pathway is particularly important. IP3 is converted inside the cell to the (1,3,4,5) tetraphosphate, IP4, by a specific kinase. The exact role of IP4 remains unclear, but there is evidence that it too is involved in Ca2+ signalling. One possibility is that it facilitates Ca2+ entry through the plasma membrane, thus avoiding depletion of the intracellular stores as a result of the action of IP3. Diacylglycerol and protein kinase C Diacylglycerol is produced as well as IP3 whenever receptor-induced PI hydrolysis occurs. The main effect of DAG is to activate a membrane-bound protein kinase, protein kinase C (PKC), which catalyses the phosphorylation of a variety of intracellular proteins. DAG, unlike the inositol phosphates, is highly lipophilic and remains within the membrane. It binds to a specific site on the PKC molecule, which migrates from the cytosol to the cell membrane in the presence of DAG, thereby becoming activated. Ion channels as targets for G-proteins G-protein-coupled receptors can control ion channel function directly by mechanisms that do not involve second messengers such as cAMP or inositol phosphates. This was first shown for cardiac muscle, but it now appears that direct G-protein-channel interaction may be quite general . In cardiac muscle, for example, mAChRs are known to enhance K+ permeability (thus hyperpolarising the cells and inhibiting electrical activity. Similar mechanisms operate in neurons, where many inhibitory drugs such as opiate analgesics reduce excitability by opening potassium channels. Type 3: kinase-linked and related receptors:- This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators. They comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix. In many cases, the intracellular domain is enzymic in nature (with protein kinase or guanylyl cyclase activity). Type 3 receptors include those for insulin and for various cytokines and growth factors the receptor for atrial natriuretic factor (ANF), is the main example of the guanylyl cyclase type. The two kinds are very similar structurally, even though their transduction mechanisms differ. KINASE-LINKED AND RELATED RECEPTORS These membrane receptors are quite different in structure and function from either the ligand-gated channels or the GPCRs. They mediate the actions of a wide variety of protein mediators, including growth factors and cytokines, and hormones such as insulin and leptin, whose effects are exerted mainly at the level of gene transcription. They play a major role in controlling cell division, growth, differentiation, inflammation, tissue repair, apoptosis and immune responses, The main types are as follow Receptor tyrosine kinases (RTKs). These receptors have the basic structure, incorporating a tyrosine kinase moiety in the intracellular region. They include receptors for many growth factors, such as epidermal growth factor and nerve growth factor, and also the group of Toll-like receptors that recognise bacterial lipopolysaccarides and play an important role in the body's reaction to infection. The insulin receptor also belongs to the RTK class, although it has a more complex dimeric structure. Serine/threonine kinases. This smaller class is similar in structure to RTKs but phosphorylate serine and/or threonine residues rather than tyrosine. The main example is the receptor for transforming growth factor (TGF). Cytokine receptors. These receptors lack intrinsic enzyme activity. When occupied, they associate with, and activate, a cytosolic tyrosine kinase, such as Jak (the Janus kinase) or other kinases. Ligands for these receptors include cytokines such as interferons and colony-stimulating factors involved in immunological responses. Guanylyl cyclase-linked receptors. These are similar in structure to RTKs, but the enzymic moiety is guanylyl cyclase and they exert their effects by stimulating cGMP formation. The main example is the receptor for ANF. In many cases, ligand binding to the receptor leads to dimerisation. The association of the two intracellular kinase domains allows a mutual autophosphorylation of intracellular tyrosine residues to occur. The phosphorylated tyrosine residues then serve as high-affinity docking sites for other intracellular proteins that form the next stage in the signal transduction cascade. One important group of such 'adapter' proteins is known as the SH2 domain proteins (standing for Src homology, because it was first identified in the Src oncogene product).       Two well-defined signal transduction pathways are summarised in The Ras/Raf pathway mediates the effect of many growth factors and mitogens. Ras, which is a proto-oncogene product, functions like a G-protein, and conveys the signal (by GDP/GTP exchange) from the SH2 domain protein, Grb, which is phosphorylated by the RTK. Activation of Ras in turn activates Raf, which is the first of a sequence of three serine/threonine kinases, each of which phosphorylates, and activates, the next in line. The last of these, mitogen-activated protein (MAP) kinase, phosphorylates one or more transcription factors that initiate gene expression, resulting in a variety of cellular responses, including cell division. Many SH2 domain proteins are enzymes, such as protein kinases or phospholipases. Some growth factors activate a specific subtype of phospholipase C (PLCγ), thereby causing phospholipid breakdown, IP3 formation and Ca2+ release. Other SH2-containing proteins couple phosphotyrosine-containing proteins with a variety of other functional proteins, including many that are involved in the control of cell division and differentiation. The end result is to activate or inhibit, by phosphorylation, a variety of transcription factors that migrate to the nucleus and suppress or induce the expression of particular genes.       A second pathway, the Jak/Stat pathway is involved in responses to many cytokines. Dimerisation of these receptors occurs when the cytokine binds, and this attracts a cytosolic tyrosine kinase unit (Jak) to associate with, and phosphorylate, the receptor dimer. Jaks belong to a family of proteins, different members having specificity for different cytokine receptors. Among the targets for phosphorylation by Jak are a family of transcription factors (Stats). These are SH2 domain proteins that bind to the phosphotyrosine groups on the receptor-Jak complex, and are themselves phosphorylated. Thus activated, Stat migrates to the nucleus and activates gene expression.       The membrane-bound form of guanylyl cyclase, the enzyme responsible for generating the second messenger cGMP in response to the binding of peptides such as atrial natriuretic peptide, resembles the tyrosine kinase family and is activated in a similar way by dimerisation when the agonist is bound. Type 4: nuclear receptors:- These are receptors that regulate gene transcription. The term nuclear receptors is something of a misnomer, because some are actually located in the cytosol and migrate to the nuclear compartment when a ligand is present. They include receptors for steroid hormones, thyroid hormone, and other agents such as retinoic acid and vitamin D. NUCLEAR RECEPTORS Receptors for steroid hormones such as oestrogen and the glucocorticoids were present in the cytoplasm of cells and translocated into the nucleus after binding with their steroid partner. Other hormones, such as the thyroid hormone T3 and the fat-soluble vitamins D and A (retinoic acid) and their derivatives that regulate growth and development, were found to act in a similar fashion.

Glycolysis

Permanent methods of family planning

The Vasectomy Procedure

Vasectomy is a safe, simple and effective birth control method.

One of the most common and popular means for contraception around the world is vasectomy – a brief, surgical procedure used for male sterilization. It is a popular means of birth control for couples that have decided that their family is complete. It is nearly 100% effective and is intended to be permanent.
The procedure starts with the administration of local anesthesia, to numb the genitals. This allows the patient to remain awake and alert during the procedure, but unable to feel the surgery. In some cases, a new technology, the needleless injection, is used to administer the anesthetic in this sensitive area. Your doctor may or may not have this new system available for use during surgery.
Once the genital area is numbed, the area will be shaved and the skin prepared with a solution that kills bacteria on the surface of the skin. Once the solution dries, the surgery begins with 1 or 2 half-inch long incisions on the underside of the scrotum. The vas deferens, the cord that carries sperm, is then located and either cut and tied off or cut and cauterized. Research shows that the use of cautery is the most effective, as it prevents the vas deferens from healing back together. 


The incision is then closed with sutures, which can be removed at the surgeon’s office in a week to ten days.

A vasectomy is chosen by over 600,000 American men annually, and as many as 30 million men worldwide. The vasectomy procedure is uncomplicated, is commonly performed in a doctor’s office and usually takes about 15 to 20 minutes.

All about vasectomy.

The simplest and safest vasectomy method is the No-Scalpel Vasectomy (NSV), which, as the name suggests, requires no scalpel, no incisions (only two tiny punctures in the skin) and no sutures. It is performed with a local anesthetic to numb the area. The No-Scalpel Vasectomy is rapidly becoming the procedure of choice among patients and is also favored by many doctors.

Urologists perform most vasectomies, although up to 30 % are performed each year by family practitioners, depending on the location. Costs range from $500 to over $1,000 and is reimbursed by many health insurance programs.

In Summary:

• A vasectomy is a safe and simple procedure.
• It is one of the most common means for permanent contraception.
• The procedure is over 99 % effective and intended to be permanent.
• The "No-Scalpel Vasectomy" method is popular with patients and doctors.
• It is usually performed in the doctor's office in less than 30 minutes.
• Urologists and general practitioners perform vasectomies.

The cost is low and is often reimbursed by health insurance.

Tubectomy

Tubal Sterilization is a permanent method of contraception where the fallopian tubes are blocked so that the ova or eggs are prevented from traveling to the uterus from the ovary.

general surgeons

and laparoscopic surgeons perform tubectomy.
The Fallopian Tubes are two in number and are attached on either side of the uterus at one end and the other end is open in the abdomen. The length of each Fallopian tube is about 10cm.When the ovum or egg is released from the ovary, it is picked up by Fallopian tube through which it moves into the uterus. If sperms are present in the Fallopian tubes, the ovum is fertilized and the resulting embryo is transmitted to the uterus where it is embedded. In short, we can say that Fallopian tubes are channels through which the eggs from the ovaries travel to the uterus. In Tubectomy the tubes are blocked or divided to prevent the eggs from entering the uterus. This prevents any future pregnancies to occur after the surgical procedure. 

The preferred method that is used commonly is to use a laparoscopic approach to identify the fallopian tubes on both the sides and apply plastic clips.

There are different surgical approaches for the tubal sterilization operations are

1. Laparoscopy
2. Microlaparoscopy
3. Laparotomy (concurrent with cesarean delivery)
4. Minilaparotomy
5. Hysteroscopy
6. Vaginal approaches.

Laparoscopy

The most popular is using a laparoscope; where the patient has just a couple of small scars and is discharged home the same day.

If laparoscopy is not available an open surgical operation may be required. Here the tubes are completely divided and a section is excised.

Local anesthesia is used for more than 75% of sterilizations worldwide. Laparoscopic sterilization in performed under general anesthesia. Spinal anesthesia is preferred for procedures done immediately after delivery of the baby

Local anesthesia is the standard for the hysteroscopic approach, and it may be supplemented by oral or IV sedation if needed.

The actual procedure is done in an operating room, either in a hospital or a surgical center.

Currently, Laparoscopy is the most popular method of female sterilization in nonpregnant women. It is performed under General Anesthesia. The surgery takes about half an hour.

1. In the Laparoscopy procedure, the abdomen is filled with carbon dioxide gas by introducing a needle so that the abdominal wall balloons away from the uterus and tubes.

2. The surgeon makes a small cut just below the navel and inserts a laparoscope, a small telescope-like instrument.

3. A second incision is made just above the pubic hairline to allow the entrance of another small instrument that can help with closure of the fallopian tubes.

4. Usually Falope rings or Filshie clips are placed on the fallopian tubes to block the tubes. Sometimes the tubes are cut and clipped

5. The skin incision is then closed with one stitch or a tape. The patient may feel well enough to go home from the outpatient surgery center in a few hours.

Advantages include small incisions, rapid access to the fallopian tubes and rapid recovery.

Disadvantages include the need for general anesthesia, the risks of injury to internal organs with needle insufflations. Difficulty associated with Laparoscopy in patients who are obese.

Micro-laparoscopy
Micro-laparoscopy involves use of micro endoscopes of smaller diameter with 5 to 7 mm suprapubic incisions being made. This surgery is possible because of improved technology in light transmission and fiber optic bundles.

There are some theoretical advantages such as even smaller scars, less pain, less cost, and faster patient recovery. However the difference is so marginal that it has never become very popular despite being available for almost 20 years.

Contraindications

1. The patient should make the request herself, be of sound mind, and not act under external duress.

2. During delivery of the baby some women opt for sterilization; however this should be deferred if maternal or infant complications are anticipated.

3. Surgery is contraindicated in patients with active infections like Pelvic Inflammatory Disease (PID)

4. The laparoscopic approach is also contraindicated in patients with severe heart or lung problems.

5. Surgery is deferred in patients with suspected pregnancy

Pharmacology Glossary

A
Anaphylaxis: serious and rapid allergic reaction usually involving more than one part of the body which, if severe enough, can be fatal. Usually associated with bee or wasp stings but is more common with food or drug allergies. Treatment: Epinephrine (im) is the drug of choice.
Autonomic nervous system: innervation of smooth muscle, glands and visceral organs, which are not normally under voluntary control. Subdivided principally into the sympathetic and parasympathetic efferent systems. Autonomic reflexes are reflexes that act through these efferent systems; their afferent pathways may be either the same as pathways that subserve conscious perceptions (as with salivation) or they may be different (as with baroreceptor reflexes). The afferent pathways are not distinctive in any anatomical way, and are not usually described as 'autonomic' except by association with particular reflex actions
Antagonism: The effect of two or more drugs such that the combined effect is less than the sum of the effects produced by each agent separately. The agonist is the agent producing the effect which is diminished by the administration of the antagonist. Antagonisms may be any of three general types:
1. Chemical: caused by combination of agonist with antagonist, with resulting inactivation of the agonist
2. Physiological: caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects
3. Pharmacological: caused by action of the agonist and antagonist at the same site ie. epinephrine and propranolol at beta-receptors
Aging: inhibition of acetycholinesterase (AchE) with organophosphates results in a increase in Ach levels. If allowed to associate with AchE for certain period of time a phenomenon called 'aging' occurs, involving the loss of a group attached to phosphorus and leading to the formation of a negatively charged irreversibly phosphorylated AchE enzyme. The aging process can be very short (ie. nerve gases, secs) or longer (ie. pesticides, hrs). Pralidoxime (2-PAM) can regenerate AchE from the organophosphate but only before the 'aging' process.
Area under the curve (AUC): The area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration. The area is conveniently determined by the "trapezoidal rule": the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed. The AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs.
Affinity (drug): the equilibrium constant of the reversible reaction of a drug with a receptor to form a drug-receptor complex; the reciprocal of the dissociation constant of a drug-receptor complex. Under the most general conditions, where there is a 1:1 binding interaction, at equilibrium the number of receptors engaged by a drug at a given drug concentration is directly proportional to their affinity for each other and inversely related to the tendency of the drug-receptor complex to dissociate. Obviously, affinity depends on the chemical natures of both the drug and the receptor. "Affinity" is not the same as "duration of action".
Activity, intrinsic: the property of a drug which determines the amount of biological effect produced per unit of drug-receptor complex formed. Two agents combining with equivalent sets of receptors may not produce equal degrees of effect even if both agents are given in maximally effective doses; the agents differ in their intrinsic activities and the one producing the greater maximum effect has the greater intrinsic activity. Intrinsic activity is not the same as "potency" and may be completely independent of it. Meperidine and morphine presumably combine with the same receptors to produce analgesia, but regardless of dose, the maximum degree of analgesia produced by morphine is greater than that produced by meperidine; morphine has the greater intrinsic activity. Intrinsic activity - like affinity - depends on the chemical natures of both the drug and the receptor, but intrinsic activity and affinity apparently can vary independently with changes in the drug molecule
B
Benign prostrate hypertrophy (hyperplasia) is an enlargement of the prostrate gland. This can often compress the urethra and partially block urine flow. Prostate enlargement adversely affects about half the men in their 60s and close to 80 percent of men in their 80s. The presence or absence of prostate gland enlargement is not related to the development of prostate cancer. Treatment: Alpha1 blockers such as prazosin or terazosin (Hytrin).
Belladonna alkaloids: group of alkaloids, including atropine and scopolamine, found in plants such as belladonna and jimsonweed. They are used in medicine to dilate the pupils of the eyes, dry respiratory passages, prevent motion sickness, and relieve cramping of the intestines and bladder.
Bioavailability: the percent of dose entering the systemic circulation after administration of a given dosage form. More explicitly, the ratio of the amount of drug "absorbed" from a test formulation to the amount "absorbed" after administration of a standard formulation. Frequently, the "standard formulation" used in assessing bioavailability is the aqueous solution of the drug, given intravenously.



Baroreceptor reflex:: baroreceptors found in the aorta arch and carotid sinuses, sense changes in blood pressure. As blood pressure goes up, the baroreceptors are stimulated and they deliver a higher rate of impulses to the vasomotor center of the brain. This causes a reduction in sympathetic tone and a stimulation of vagal tone. As a result, there is a reduction in heart rate, cardiac contractility, and vasodilation of blood vessels throughout the body which all contribute to lower blood pressure. If blood pressure goes down, baroreceptors reduce their rate of firing, causing the opposite effect. The baroreceptor reflex is more sensitive to rapidly changing pressure (standing up, or sitting down) than to a constantly elevated or depressed pressure. Baroreceptors will adapt to long term increased or decreased blood pressure.
Bioassay (biological assay): the determination of the potency of a physical, chemical or biological agent, by means of a biological indicator .The biological indicators in bioassay are the reactions of living organisms or tissues.
C
Cycloplegia: paralysis or loss of function of the ciliary muscle; this results in loss of accommodation (ability to focus).
Ceiling (drug): The maximum biological effect that can be induced in a tissue by a given drug, regardless of how large a dose is administered. The maximum effect produced by a given drug may be less than the maximum response of which the reacting tissue is capable, and less than the maximum response which can be induced by another drug of greater intrinsic activity. "Ceiling" is analogous to the maximum reaction velocity of an enzymatic reaction when the enzyme is saturated with substrate.
Clearance of a chemical is the volume of body fluid from which the chemical is, apparently, completely removed by biotransformation and/or excretion, per unit time. In fact, the chemical is only partially removed from each unit volume of the total volume in which it is dissolved. Since the concentration of the chemical in its volume of distribution is most commonly sampled by analysis of blood or plasma, clearances are most commonly described as the "plasma clearance" or "blood clearance" of a substance.
Coombs Test is used to detect auto antibodies against your own red blood cells (RBCs). Many diseases and drugs (e.g., quinidine,  methyldopa, and procainamide) can lead to production of these antibodies. The test is only rarely used to diagnose a medical condition but is essential for use by laboratories such as blood banks. Blood banks use the Coombs' test is to determine whether there is likely to be an adverse reaction to blood that is going to be used for a blood transfusion.
Cross-over experiment: A form of experiment in which each subject receives the test preparation at least once, and every test preparation is administered to every subject. At successive experimental sessions each preparation is "crossed-over" from one subject to another. The purpose of the cross-over experiment is to permit the effects of every preparation to be studied in every subject, and to permit the data for each preparation to be similarly and equally affected by the peculiarities of each subject.
D
Drug selectivity: the propensity of a drug to affect one receptor population in preference to others. ie. propranolol is a non-selective beta-blocker (blocks all beta-receptors equally), whereas metoprolol is a beta1-selective blocker in that it has a greater preference (affinity) for beta1- over beta2-receptors. Selectivity is generally a desirable property in a drug as it can minimize potential side-effects ie. potential of propranolol causing bronchospasm. Selectivity is not to be confused with "potency"; a potent drug may be non-selective or a selective drug may not be very potent.
Drug abuse: misuse of a drug under conditions considered "more destructive than constructive for society and the individual. The abuse potential of a drug depends on its capacity to induce compulsive drug-seeking behavior in the user, its capacity to induce acute and chronic toxic effects (and to permit occurrence of associated diseases), and upon social attitudes toward the drug, its use, and its effects.
Drug dependence: a somatic state which develops after chronic administration of certain drugs; this state is characterized by the necessity to continue administration of the drug in order to avoid the appearance of uncomfortable or dangerous (withdrawal) symptoms. Withdrawal symptoms, when they occur, may be relieved by the administration of the drug upon which the body was "dependent". Recommended as a term to be substituted for such words as "addiction" and "habituation " since it is frequently difficult to classify specific agents as being only addictive, habituating, or non-addicting or non-habituating. e.g., drug dependence of the barbiturate type.
Drug: a chemical used in the diagnosis, treatment, or prevention of disease. More generally, a chemical, which, in a solution of sufficient concentration, will modify the behavior of cells exposed to the solution.
Dose-effect curve: characteristic, even the sine qua non, of a true drug effect is that a larger dose produces a greater effect than does a smaller dose, up to the limit to which the cells affected can respond. While characteristic of a drug effect, this relationship is not unique to active drugs, since increasing doses of placebos (q.v.) can, under certain conditions, result in increasing effects. Distinguishing between "true" and "inactive" drugs requires more than demonstration of a relationship between "dose" and effect. The curve relating effect (as the dependent variable) to dose (as the independent variable) for a drug-cell system is the "dose-effect curve" for the system. For a unique system, i.e., one involving a single drug and a single effect, such curves have three characteristics, regardless of whether effects are measured as continuous (measurement) or discontinuous (quantal, all-or-none) variates:

1. The curves are continuous, i.e. there are no gaps in the curve and effect is a continuous function of dose. Some effect corresponds to every dose above the threshold dose, and every dose has a corresponding effect; there is no inherent invalidity in interpolating doses or effects from a dose-effect curve.

2. The curves are "monotonic". The curve may have a positive slope, or a negative slope, but not both if the system under study is unique. The slope of the curve may show varying degrees of positivity (negativity), but the sign of the slope stays the same throughout the range of testable doses. When monotonicity of a dose-effect curve does not obtain, one may infer that the system under study is not unique or singular: either more than one active agent or more than one effect is under study.
3. The curves approach some maximum value as an asymptote, and the asymptote is a measure of the intrinsic activity of the drug in the system.

Dissolution time: the time required for a given amount (or fraction) of drug to be released into solution from a solid dosage form. Dissolution time is measured in vitro, under conditions which simulate those which occur in vivo, in experiments in which the amount of drug in solution is determined as a function of time. Needless to say, the availability of a drug in solution - rather than as part of insoluble particulate matter - is a necessary preliminary to the drug's absorption.
E
Epinephrine reversal describes the response seen to epinephrine (EPI) in the presence of an alpha-blocker. The normal response to EPI alone is an increase in BP and HR. However in the presence of an alpha-blocker, EPI can now only activate the beta-receptors to cause a fall in BP with an increase in HR.
ED50: see Mean effective dose
Exocytosis: vesicular release of transmitter ie. NE storage vesicle migrates to and fuses with the plasma membrane to release NE (and other compounds within the vesicle ie. DBH) into the synaptic cleft. Non-exocytotic release includes the displacement of NE by amphetamine or tyramine, which can then leak across the plasma membrane in the synaptic cleft.
F
First-pass effect: all drugs that are absorbed from the intestine enter the hepatic portal vein and pass through the liver before they are distributed systemically. Some drugs (ie. propranolol) have a high degree of removal from the circulation on their first passage through the liver.
First-order kinetics: according to the law of mass action, the velocity of a chemical reaction is proportional to the product of the active masses (concentrations) of the reactants. In a monomolecular reaction, i.e., one in which only a single molecular species reacts, the velocity of the reaction is proportional to the concentration of the unreacted substance (C). see also Zero-order kinetics.


G
Glaucoma is a group of eye diseases that are associated with a rise in intraocular pressure (IOP) that can cause blindness if untreated. Vision loss is caused by damage to the optic nerve. The two main types of glaucoma are open angle glaucoma (chronic, primary open angle glaucoma (POAG), and angle closure glaucoma (narrow angle).
Generic drugs: formulations of identical composition with respect to the active ingredient, i.e., drugs that meet current official standards of identity, purity, and quality of active ingredient. Drug dosage forms considered as "generically equivalent" are more properly considered as "chemically equivalent" in that they contain a designated quantity of drug chemical in specified stable condition and meet pharmacopoeial requirements for chemical and physical properties
H
Horner's syndrome is characterized by an interruption of the sympathetic nerve pathway somewhere between its origin in the hypothalamus and the eye. The damage can either to the pre- post-ganglionic sympathetic fibers. The classic clinical findings associated with Horner's syndrome are ptosis (eyelid sagging), pupillary miosis and facial anhidrosis. Treatment: depends upon the identifying and treating the cause, in many cases there is no treatment that improves or reverses the condition.
Half-life (drug): period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. The given concentration or amount need not be the maximum observed during the course of the experiment, or the concentration or amount present at the beginning of an experiment, since the half-life is completely independent of the concentration or amount chosen as the "starting point".
I
Intrinsic sympathomimetic activity: Beta-blocker that has partial agonist action. Has potential to prevent bradycardia or negative inotropy in resting heart (if b₁ partial agonist) and to prevent bronchoconstraction (if b₂ partial agonist). Pindolol is prototype agent.
Indirect amine (agent): compounds that can cause displacement of NA from storage vesicles (ie. amphetamine, tyramine). Note agents that inhibit neuronal uptake (uptake 1) can diminish the actions of indirect amines by preventing their uptake into the nerve terminal.
Indirect parasympathomimetic: agent that causes inhibition of acetyl cholinesterase (AchE) to elevate Ach levels (ie. organophosphates).


Idiosyncratic Response:  qualitatively abnormal or unusual response to a drug which is unique, or virtually so, to the individual who manifests the response. "Idiosyncratic Response" usually applies to a response which is not allergic in nature and cannot be produced with regularity in a substantial number of subjects in the population , and which is ordinarily not produced in a greater intensity in an individual, or in a greater fraction of the population, by the expedient of increase in the dose. In other words, were frequency or intensity of idiosyncratic response used as a measure of effect in constructing a dose-effect curve, a curve might indeed be constructed, but its slope would be found to be 0 (zero), indicating that effect was not significantly a function of dose.
L
Latency period: the period of time which must elapse between the time at which a dose of drug is applied to a biologic system and the time at which a specified pharmacologic effect is produced. In general, the latent period varies inversely with dose; the relationship between dose and latent period for a given agent is described by a time-dose or time-concentration curve.
Loading (priming) dose: a larger than normal dose (D*) administered as the first in a series of doses, the others of which are smaller than D* but equal to each other. The loading dose is administered in order to achieve a therapeutic amount in the body more rapidly than would occur only by accumulation of the repeated smaller doses. The smaller doses (D) which are given after D* are called "maintenance doses".
M
Membrane-stabilizing activity (Local anesthetic action): Beta-blocker that has the ability to decrease electrical conductance, particularly in heart (Quinidine-like effects).
Malignant hyperthermia (MH) is a pharmacogenetic disease of skeletal muscle.  When exposed to inhalation anesthetics (those which are gases ), muscle metabolism increases with a rapid rise in body temperature which if left untreated can lead to death. Triggering agents include succinylcholine (NMJ depolarizing blocker) and volatile anesthetic. Treatment: Drug of choice is Dantrolene (inhibits Ca++ release).
Mean effective dose (ED50): The dose of a drug predicted (by statistical techniques) to produce a characteristic effect in 50 percent of the subjects to whom the dose is given. The median effective dose (usually abbreviated ED50) is found by interpolation from a dose-effect curve. The ED50 is the most frequently used standardized dose by means of which the potencies of drugs are compared. Although one can determine the dose of drug predicted to be effective in one percent (ED1) or 99 percent (ED99) of a population, the ED50 can be determined more precisely than other similar values. An ED50 can be determined only from data involving all or none (quantal) response; for quantal response data, values for ED0 and ED100 cannot be determined. In analogy to the median effective dose, the pharmacologist speaks of a median lethal dose (LD50), a median anesthetic dose(AD50), a median convulsive dose (CD50), etc.
N
Neuromuscular Junction (NMJ): The junction between the terminal of a motor neuron and a skeletal muscle fiber is called the neuromuscular junction. It is simply one kind of synapse. Nerve impulses travel down the motor neurons and cause the skeletal muscle fibers at which they terminate to contract. This is part of the Somatic (Voluntary) Nervous System.
O
Orthostatic (postural) hypotension: The gravitational stress of sudden standing normally causes pooling of blood in the venous capacitance vessels of the legs and trunk. The subsequent transient decrease in venous return and cardiac output results in reduced BP and can cause the individual to faint. Baroreceptors in the aortic arch and carotid bodies sense the change in BP and activate autonomic reflexes that rapidly normalize BP by causing a transient tachycardia and vasoconstriction in the lower limbs. Agents that interfere with this reflex response can cause orthostatic (postural) hypotension ie. alpha-blockers, ganglionic blockers and guanethidine.
P
Pharmacokinetics the science and study of the factors which determine the amount of chemical agents at their sites of biological effect at various times after the application of an agent or drug to biological systems. Pharmacokinetics includes study of drug absorption and distribution ("biotranslocation"), study of the chemical alterations a drug may undergo in the body, ("biotransformation"), and study of the means by which drugs are stored in the body and eliminated from it. Simply put, pharmacokinetics considers how drugs move around the body and how quickly this movement occurs. This includes the processes which control the absorption, distribution, metabolism, and excretion of drugs (A.D.M.E.).

Pharmacodynamics the study of the relationship of drug concentration to drug effects

Pharmacogenetics the study of how people respond differently to medicines due to their genetic inheritance. The term has been pieced together from the words pharmacology (the study of how drugs work in the body) and genetics (the study of how traits are inherited). An ultimate goal of pharmacogenetics is to understand how someone's genetic make-up determines how well a medicine works in his or her body, as well as what side effects or toxicity are likely to occur.

Pheochromocytoma is a rare tumor that arises from tissue in the adrenal gland. The tumor increases production and release of epinephrine (adrenaline) and nor epinephrine (noradrenaline), which raises blood pressure and heart rate. Most pheochromocytomas are removed surgically, individuals are initially stabilized with alpha-blockers (ie. phenoxybenzamine) or alpha/beta-blockers (labetalol or carvedilol). Beta-blockers alone should never be given alone prior to administration of an alpha-blocker.
Prototype drug is the 'lead agent' in a drug class (family). ie propranolol is the prototype of the beta-blockers and metoprolol is the prototype of the beta1-blockers. These are common agents used in exam questions.
Prodrug: has no pharmacologic activity until converted into an active compound. ie. alpha-methyl dopa is converted to the biologically active agent, alpha-methyl-nor epinephrine (alpha2-agonist). The change may be a result of biotransformation, or may occur spontaneously, in the presence of, e.g., water, an appropriate pH, etc.
Placebo (effect): Latin: I will satisfy. A medicine or preparation with no inherent pertinent pharmacologic activity which is effective only by virtue of the factor of suggestion attendant upon its administration.
Potency: a measure of drug activity established by determining the dose of a drug required to produce a standard effect. Potency varies inversely with the magnitude of the dose required to produce a given effect. Thus, if twice the dose of drug "X" is required to produce analgesia equivalent to that produced by a dose of aspirin, it may be said that drug"X" is half as potent as aspirin.
Potentiation: a special case of synergy in which the simultaneous effects of two or more drugs is greater than the sum of the independent effects of these drugs. For example. although physostigmine has no acetylcholine-like activity of its own, it potentiates the actions of acetylcholine by inhibiting the enzymes responsible for the destruction of acetylcholine. Intensity of effect may be potentiated, duration of effect may be prolonged: potentiation and prolongation are independent phenomena, but frequently occur together.
Pharmacology: is the study of drugs in all their aspects. Pharmacy, although often confused with pharmacology, is, in fact, an independent discipline concerned with the art and science of the preparation, compounding, and dispensing of drugs. Pharmcodynamic, which in common usage is usually termed "pharmacology", is concerned with the study of drug effects and how they are produced. The  pharmacologist, identifies the effects produced by drugs, and determines the sites and mechanisms of their action in the body. The pharmacologist also studies the physiological or biochemical mechanisms by which drug actions are produced and investigates those factors which modify the effects of drugs, i.e. the routes of administration, influence of rates of absorption, differential distribution, and the body's mechanisms of excretion and detoxification, on the total effect of a drug. Pharmacotherapeutics is the study of the use of drugs in the diagnosis, prevention, and treatment of disease states.
Q
Quantitative Graded) dose-effect relationships: graph of the relationship between dose and response (effect) wherein all possible degrees of response between minimum detectable response and a maximum response are producible by varying the dose or drug concentration, i.e., the curve is continuous.
Quantal (All-or-none; binary) dose-effect relationships: relationship between dose and effect that describes the distribution of MINIMUM doses of drug required to produce a defined degree of a specific response in a population of subjects. Only two responses are allowed: Yes or No; 0 or 1. The purpose of the plot is to allow predictions about what proportion of a population of subjects will respond to given doses of the drug or toxin.
R
Raynaud's syndrome: condition in which small arteries, most commonly in the fingers and toes, spasm and cause the skin to turn pale or a patchy red to blue on exposure to cold or even the thought of cold. Although Raynaud's is usually a mild condition, it can have serious direct consequences, such as gangrene serious enough to warrant amputation.Treatment: Treatment: simple exercise may suffice (ie. swinging your arms around like a windmill), however if attacks are frequent or severe, dilating agents, such as nifedipine, calcium channel blocker may be prescribed.
Rate-limiting step: this is slowest point in a series of reactions (ie. uptake of choline into the nerve terminal in the synthesis of Ach) or where the enzyme involved is subject to regulatory control (ie. Tyrosine hydroxlase involved in NA systhesis)
Rebound effects: discontinuation of an agent my cause exacerbation of previous symptoms to a level which is greater than before, and than that which would have been expected. ie. sudden discontinuation of clonidine leads to rebound hypertension, tachycardia and angina (see also Super sensitivity)
S
Septic shock: serious condition that occurs when an overwhelming infection leads to low BP and low blood flow. Vital organs, such as the brain, heart, kidneys, and liver may not function properly or may fail. Treatment: Dopamine (iv) is the drug of choice.
Super sensitivity: when a some receptors are deprived of the actions of their agonists, they can become hypersensitive (increased affinity) to the agonist. ie. blockade of beta-receptors leads to super sensitivity such that if the beta-blocker was suddenly discontinued, an enhanced response to the agonist would be seen. Thus discontinuation from beta-blockers should be gradual. (see also Rebound effects).
Side effects: effects which are not desirable or are not part of a therapeutic effect; effects other than those intended. ie treatment of peptic ulcer with atropine, dryness of the mouth is a side effect and decreased gastric secretion is the desired drug effect. If the same drug were being used to inhibit salivation, dryness of the mouth would be the therapeutic effect and decreased gastric secretion would be a side effect.



Somatic nervous system: controls all voluntary systems within the body with the exception of reflex arcs. This system is comprised of the afferent nerve network, which include all sensory nerves leading to the brain, and the efferent nerve network, which includes all motor nerves leading from the brain to the muscles (NMJ). The somatic system is generally associated with all body movement and is not part of the Autonomic NS (involuntary).
Synergy: the summing of the simultaneous effects of two or more drugs such that the combined effect is greater than the effect of either of the drugs when they are given alone.
T
Tyramine - MAOIs interaction: certain foods (ie. aged cheese, red wine, figs, fermented and otherwise processed meats, fish and soy products) contain large amounts of the amino acid tyramine which can interact with MAOIs to dramatically raise HP and HR. The tyramine induces the release of large amounts of the stored neurotransmitter, NA from the nerve terminals. The reaction, which often does not appear for several hours after taking the medication, may also include headache, nausea, vomiting, possible confusion, psychotic symptoms, seizures, stroke and coma.
Tone (Autonomic): under resting conditions most organs of the body receive a low but steady release of NA or Ach (tonic release) to modulate tissue activity. In the heart the basal release of NA contributes about +5 bpm and the release of Ach about -10 bpm to the resting heart rate. This is why beta-blockers such as propranolol can cause a fall in HR as they prevent the action of the tonic release of NA. Likewise the muscarinic antagonists, such as atropine can cause an increase in HR as it prevents the action of Ach. Usually one division of the autonomic NS dominates under resting conditions, GI-tract, eye, heart (parasympathetic) and vasculature (sympathetic).
Tolerance - Tachyphylaxis: Continual use of an agent can result in diminished response. In some cases this can appear in mins-hrs or dose to dose and is termed tachyphylaxis (ie. amphetamines). In other cases it appears more gradual over days-months and is termed tolerance. (ie. opioids).
Therapeutics: the science and techniques of restoring patients to health. A single drug may have two or more therapeutic effects in the same patient at the same or different times, or in different patients. Drugs may be used prophylactic ally to prevent disease or to diminish the severity of a disease should it occur subsequent to or during treatment; such a use of drugs is commonly called "prophylactic therapy". Drugs are sometimes used to measure bodily function and contribute toward the diagnosis of disease.
Therapeutic index: a number, LD50/ED50, which is a measure of the approximate "safety factor" for a drug; a drug with a high index (ie. aspirin) can presumably be administered with greater safety than one with a low index (ie. digoxin).
Toxic effects: responses to a drug which are harmful to the health or life of the individual. Almost by definition, toxic effects are "side effects" when diagnosis, prevention, or treatment of disease is the goal of drug administration. Toxic effects are not side-effects in the case of pesticides and chemical warfare agents. Toxic effects may be idiosyncratic or allergic in nature, may be pharmacologic side effects, or may be an extension of therapeutic effect produced by over dosage.
Toxicology: the scientific discipline concerned with understanding the mechanisms by which chemicals produce noxious effects on living tissues or organisms; the study of the conditions (including dose) under which exposure of living systems to chemicals is hazardous.
V
Volume of distribution of a drug; the size of the "compartment" into which a drug apparently has been distributed following absorption.
Z
Zero-order kinetics: mechanism of chemical reaction in which the reaction velocity is apparently independent of the concentration of all the reactants. Typically, in biological systems, one reactant (X) is present in a concentration greatly exceeding that of the other (Y), but is capable of undergoing change, while the concentration of Y, in contrast, does not undergo substantial change during the course of the reaction (see First-order kinetics also).