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User:Nobody60/Nils/God and Enlightenment

<God

Find God Through the Path of Enlightenment
God is a mystery that can be seen and understood only by enlightenment. One can see God only in enlightenment. The Bible says: "Blessed are the pure in heart: for they shall see God." Who cleans his heart (his mind) with spiritual exercises, enters the dimension of God and sees God. With man's current reasoning capacities, he can describe God only in limited and finite terms. Science cannot explore more than circumstantial evidences for God. If one wishes to know if God exists, one must realize enlightenment.

1. Purify yourself with yoga and mantra yoga. Do yoga for beginners, easy yoga poses with mantra meditation, dynamic mantra yoga, fitness yoga or yoga with positive thinking. Practice the five principles of health.

2. Do kundalini yoga. Kundalini is a great power, which leads us to enlightenment. Read How to Get the Benefits of Kundalini Yoga. Pracice the sun meditation|sun meditation]].

3. Do the yoga of love. Send regularly all people light. All-encompassing love is the quickest way to a life in God. Read How to Be a Karma Yogi.

4. Connect daily with God or the enlightened Masters and follow the voice of your inner wisdom. Read in the holy books, pray or think a mantra as: "Om all enlightened Masters. Om inner wisdom. Please guide and help me on my way." You can change the mantra, so that it applies to your personal beliefs. Buddhists say: "Om Buddha". Christians can pray: "Dear God", or "Jesus Christ". Atheists can think: "Om inner wisdom". Find your personal word to connect with the enlightenment energy. Get help from the yoga oracle or the Angel oracle.

5. Think positive. Practice the five qualities inner peace, love, wisdom, self-discipline and happiness. Read Positive thinking. Become positive through forgiveness and thankfullness.

 * Spirituality is a way of working on oneself and his mind (spirit). Through spiritual techniques such as mental work (positive thinking) and meditation one can come into contact with a higher level of consciousness (God consciousness, unity consciousness). One sees the light in the world, in himself and in his fellow man. The most effective exercise is to rest, to practice (Yoga, meditation, reading) and to love all beings (to do good for others). You must center your life in inner happiness and find out how you can stay within and grow spiritually. The most important thing in spirituality is the inner voice. The inner voice is the voice of your own truth and wisdom. It is your feeling of rightness.
 * Video ShantiMayi: How to open up knots in the heart
 * Video What's my core message? (gangaji)

The Lord´s Prayer
The image refers us to connect the Lord's Prayer (Christian main mantra) with visualizations and thereby strengthen the spiritual effect considerably. To have a powerful effect, we should speak or think the prayer how it fits us best. We should interpret the images so that they are helpful to us. We can formulate the sentences of the Lord's Prayer in our own words. This can help us to come better into contact with the energy of the prayer. The Pater Noster picture divides the Lord's Prayer in eight areas.

1.Our Father in heaven,

(We visualize God as a light or a person in heaven above our crown chakra.)

2.hallowed be your name,

(We imagine a beautiful melody to our image of God.)

3.your kingdom come,

(We recognize our world as a paradise.)

4.your will be done, on earth as in heaven.

(We take all things in our lives as they are.)

5.Give us today our daily bread.

(We are grateful for everything positive in our lives.)

6.Forgive us our sins as we forgive those who sin against us.

(What do you want to forgive your fellow man or God / your life today?)

7.Save us from the time of trial and deliver us from evil.

(What false desires you want to let go of today?)

8.''For the kingdom, the power, and the glory are yours now and for ever. Amen.''

(Feel the power and the light of your spiritual role model flowing into you and filling you. Think Amen as long until you are one with the power of Jesus or God. Move one hand and send the light with the mantra Amen to all beings on earth. So you will come fully into the light.)

The Sermon on the Mount

 * Blessed are the poor in spirit, for theirs is the kingdom of heaven.
 * Blessed are they who mourn, for they will be comforted.
 * Blessed are the meek, for they will inherit the land.
 * Blessed are they who hunger and thirst for righteousness, for they will be satisfied.
 * Blessed are the merciful, for they will be shown mercy.
 * Blessed are the clean of heart, for they will see God.
 * Blessed are the peacemakers, for they will be called children of God.

Jesus meant „poor“ in terms of the inner self, and not the outer self. Outer poverty does not lead automatically to inner happines. Those who let go of outer attachments, can simply exist and find a way to inner contentment in God.

Suffering in and of itself does not lead to happiness. However, those who can take suffering in their lives and raise themselves through spiritual exercises, can find solace in inner peace. Mourning can help to let go, but one should not allow the self to be overwhelmed by grief. Grief is not the center of life, rather inner peace.

Those who can greet their fellow beings with non-violence and placidity, can live in a relaxed and peaceful way and relinquish into a cosmic consciousness. Those who are at peace with all things, are at peace with themselves.

Justice means correctness in the Bible. To long for a correct life, means to long for a life in the light. Those who long for happiness and search for it in the right places will receive it one day, in the form of inner peace.

Those full of empathy, will feel with the cosmos. Those who love their enemies will experience inner harmony. Those who experience the center of their existence as a love for all other beings will be rewarded by God with an all-encompassing love, peace, and inner happiness.

To dissolve inner tension, exercises for the body are required (going, meditation) and exercises for the spirit (reading, thought exercises). Those who exercise spiritually every day will reach a lasting happiness one day. Then one day the meaning of God will be found.

Those who let go of the ego, come into the light. Without a sacrifice, the breakthrough to enlightenment cannot be made. Those who live according to these teachings and therefore experience difficulty in their daily lives, provide the basis for such a spiritual sacrifice. To let go in a spiritual manner is an art. Those who do not go about this the right way create inner tension and conflict. We should not sacrifice too little or too much. Those who go about this the right way will be rid of their inner conflict.

A peacemaker is a person who makes peace within the self and the world. Those who are enlightened can be called holy, a son or daughter of God. Those who live in peace radiate peace into the world.

'''The central message of Jesus’ Mount Sermon is that a person cannot serve two lords. He cannot serve God (inner happiness) and money (the outer form of “happiness”). One has to decide for him or herself as to what form of happiness he or she will seek to attain. As a wise person, one must place the way of peace, serenity, love, and spiritual exercises as the central point of existence. In this way, he or she will one day find true happiness and live in the light.'''

Good and evil
We are beings of the light. We are children of the light. The cosmos is our great mother and our great father. We play games of happiness in God and thus grows the eternal happiness of all beings. The problem with most of our fellow creatures is that they can not distinguish between good and bad games. Bad games often make happy the short term and unhappy the long term. Bad games are all games who focus of worldly desires.

If we anchor ourselves in external things, we always long for more. We become tensed inside, our inner happiness decreases and it takes everyone down. We are allowed to live the external things. We can have relationships. We can play relationship games. We are permitted to make us the outside world beautiful. But we must bring the spirituality at the center of our lives. We need to play our life games out of the focus of spirituality. We have to play on the basis of wisdom, love and peace. Only those games benefits us.

This is difficult to understand. There are many little devils in the world playing negative games. Little devils are always poor devils. They lack wisdom and they end up harming themselves primarily. We need many angels in the world who can teach the little devils to play in the right way. If the angels are centered in wisdom, in their spiritual practices and in all-embracing love, then they win and that will be good games for everyone.

If we look closely at the Bible, we see that the Devil is not mentioned often. Moses reported of a snake who lived in paradise and wound itself around a tree. The snake is a symbol for the kundalini energy in yoga. This snake winds itself around the tree of enlightenment, the middle energy canal. The snake embodies the wisdom of activating the internal energy of happiness.

The Bible refers to a devil who came to Jesus as he sat for forty days in the desert and meditated. Shortly before Jesus came to enlightenment, the devil appeared to him. The devil wanted to stop him from destroying his ego and from attaining the point where he could live in the light. Before the tensions within a person dissolve, they strengthen for a time. A strong feeling of aversion to a spiritual life appears and the worldly pleasures appear for a time to be more important than God. They appear as a large source of confusion and temptation.

With a little imagination, the devil can be imagined. One can see the ego as a sort of inner devil who stops one in the path towards enlightenment. However, this devil is not a being, but a part of the individual’s own self. He is a visualized ego conflict. In the Bible it is described with an image, a presence, but this is not to be taken literally.

In Buddhism, the devil is called Mara. Before he achieved enlightenment, Mara came to Buddha. Buddha reached his hand towards the earth, activated his root chakra, and rid himself of this ego conflict. Mara and his entire army of temptation disappeared. After Buddha triumphed, the light of enlightenment flowed within. With Jesus, it meant that the angels came and served him, after he managed to overwhelm his ego and came to enlightenment.

There is no devil in reality. In its basic substance the universe is made of light. Everything is God. Everything is clean. One can only live things in the cosmos wrong. You can put your ego at the center of your life. The right path can be found with the principles of truth and love. With these two properties we can defeat the devil. Who's going through his full life consistently with wisdom and love, one day comes into the light (in a life of God, into the paradise).

Healing through the path of enlightenment
After five years of continuous stress associated with a difficult relationship I got 30 years ago a burnout. I wanted to heal me. I tried everything that the current medicine has to offer. But nothing helped. My theory is that the strong stress had caused many internal tensions. Healing would occur if these tensions are disassembled.

I tried to get rid of the tensions through systematic spiritual exercises. Some times I broke through to enlightenment. Then the burnout was gone and I was cured for a short time. Unfortunately, new tensions emerged. Then the enlightenment disappeared. But I can say that enlightenment is ultimately a way of healing. Therefore there is hope for you.

The main path of healing is, in my experience, to live in enough rest, make sufficiently spiritual exercises and to do good deeds (living in love to all). In addition you have to practise the five principles of health (healthy diet, avoid harmful substances such as smoking and alcohol, regular exercise, positive thinking, and enough sleep).

Basically you should spend no more energy in your life in outward things, as you have. If you live quietly enough, the life energy turns inward and heals a person. For me a variety of diseases disappeared over the years as a hermit. Thus it is described in the Hatha Yoga Pradipika, the holy book of Yoga. And here it seems to me to be your first problem. You have organized your life now so that you will grow in sickness and unhappiness. You are surrounded by things that rob you your energy.

This system must be changed. How, you may try out creatively for yourself. You should bring as much rest in your life that you are even get a little boring. It is precisely at this point, that your vital energy begins to turn inward and heals you. This is the great secret of rapid spiritual growth and inner healing.

Specifically, I recommend to you, because you have a job and a family, three hours each day of spiritual exercises. Feel what is right for you and what brings you to healing. Helpful are walking (running), yoga, to read in a spiritual book and to meditate.

Meditation is basically quite simple. Watch a video with spiritual exercises on the Internet, do the exercises, thus solve your energy blockages and activate your healing energy. Then sit relaxed or lie down and hear beautiful meditation music (for example, New Age music from the Internet). You lie or sit until you are completely relaxed and became positive inside. The combination of a short activation of the kundalini energy (healing energy) through yoga exercises (breathing, mantras, visualizations), followed by a long resting phase quickly take you into a good energy. You do that every day and get so over the years more and more healthy and happy.

What is a Christian?
ma.be (Jesus.de): What makes you a Christian?

Nils: There are many Christian groups. We should not fight each other. We should love us, respect us and work together. A Christian ist a person who recognizes Jesus as his spiritual role model, connects with him regularly and follow his commandments. This is especially the love to God and love for his neighbor (all people). You must not agree with every word of the Bible.

ma.be: Do you accept that you are a sinner and need forgiveness, to have fellowship with God.

Nils: What is sin? Sin is to have an ego. The ego makes you to fall out of the Paradise, out of a life in God and out of the Enlightenment. Everyone who is unenlightened is a sinner. His task is to overcome his ego with his spiritual exercises and to get into a life in the light. Our sins are forgiven us in the moment when we seriously begin to go our spiritual way. Then the grace will unfold at its time.

Chaya (Christian woman): What is the ego?

Nils: The ego is a phase of human development. In a material world you need a strong ego to survive as an individual. For the whole of humanity, a strong ego of its individual members is dangerous. If the people look too much on their individual interest and pay too little attention to collective interests, the human race can destroy itself. At the moment, we watch the madness that in a globalized world, few people are immensely rich and about a billion people are starving. For me this is an exaggerated egoism of the rich. The rich should give to the poor so much money, that all people can live well. The rich will do that, only if they understand that inner happiness and love is the center of man. Inner happiness grows when you overcome the selfishness and live in the all-embracing love. The inner happiness is blocked by the tensions in the body and in the mind of a man. This tensions can be dissolved through physical and mental exercises (yoga, walking, positive thinking, meditation). Tensions arise mainly from fears (rejection of suffering) and attachment to external pleasures. The ego is a result of internal tensions. The more a man purifies himself inwardly, the more his soul is healed, the smaller is the ego. When love and happiness in a man grow, the ego disappears on its own and the man gets into a cosmic consciousness (unity consciousness). Then one feels love to all beings and is in harmony with himself and the world.

Coming close to God
Mion (Jesus.de): I never really felt close to God. Perhaps this is yet to come.

Nils: You have only to find the way by which you can be close to God. There are many spiritual techniques. Find out what works for you. If you really want, you can find your way to God. I get into the light by thinking and visualizing: "I send light to .... (name). May all people be happy. May the world  be happy."

A good way to feel God's presence is to meet holy (enlightened) people. I went to Brother Roger of Taize, as he visited Germany. It was a great event in the exhibition halls. I sat in the back of the large hall. Brother Roger was sitting up front and surrounded by his monks. And suddenly the Holy Spirit came down from heaven and filled me. I gave the light to all people in the hall so that they could partake of the joy of God. I do not know if anyone has felt this. Anyway, I think that Brother Roger has enabled me to experience God. Maybe you should even go to Taize. Everyone can be there for a few weeks and enjoy the sacred atmosphere. Perhaps you experience God there. Or with other saint. There are so many holy people in the world. I got many times enlightenment energy in their presence.

---> Videos: Pope Highlights Work of Brother Roger (1 min.), The Taizé Community (2 min.)

Bede Griffiths
Bede Griffiths was born in 1906 in England and died in 1993 in India. He made lecture tours through the West and sparked waves of enthusiasm out there. He wrote many books. He was a great inspiration to many Christians today. At him they found the love and the authenticity that they had been looking for. His final words were: "I am so happy. I'm so full of love. This is my commandment, that ye love one another. In this is included the whole gospel."

Bede Griffiths wanted the adaptation of Christianity to the present day. He taught that the disclosures of all religions complete one another. All the holy books of all religions together give the whole thing. A spiritual person can and should learn from the books of all religions.

Bede Griffiths was, how many great saints, very uncomfortable for his church. He explained that the Catholic Church must change. She should find new ways to express the Christian message. She should make love, not the sin to the center of her faith.

Bede Griffiths advocated the abolition of compulsory celibacy for priests, the priesthood of women and to establish inter-religious communities. His ashram in India was visited by people from all religions. He sent his Christian students to other spiritual traditions, so that everyone could find just the personal right way for him to enlightenment.

Much like Bede Griffiths also represents David Steindl-Rast a pluralistic theology of religions. David Steindl-Rast grew up in Austria. He graduated from Vienna in art and got a degree in psychology, in addition, he studied anthropology. After receiving his doctorate in psychology in 1952 he emigrated to the United States. In 1953 he entered the Benedictine monastery of Mount Saviour in Elmira, NY. In 1965 he was one of the first monks after the Second Vatican Council, appointed by his abbot, to deal with the inter-religious dialogue between Christianity and Buddhism. He then practiced with several Japanese Zen masters. In the Internet Steindl-Rast founded the international network Grateful life. If he is not traveling on lecture tours, he lives as a hermit.

---> Videos: Bede Griffiths talks about the love of God (3 min.), Bede Griffiths talks about God (5 min.)

The Spiritual Daily Schedule
For Nils, the spiritual daily schedule is a central technique on the path to light. This is based on letting go of tension in the body and soul. When we live and practice spiritual exercises for the body and mind everyday, then we will reach enlightenment. The number of hours required on a daily basis to attain a life in the light (in happiness) varies from person to person, and their situation and abilities.

Nils meditates for six hours and goes for an hour walk twice a day. He practices Yoga for an hour and reads a spiritual book for one hour. He also works towards the happiness of others three to four hours per day. He exercises constantly. He divides these spiritual exercises in a way that enables him to constantly undergo the inner purification process.

A spiritual person know when he needs which technique. When the body is dull and lacking energy, he goes for a walk. When he or she feels restless, he or she practices Yoga or meditates. When the spirit seems to rebel against the spiritual way, a book on spiritual topics helps to bring back the conviction towards enlightenment. He senses the inner conflict and uses the proper techniques to dissolve the tension. That is usually what the body and soul wants the least at that moment. Wherever the neurotic tendency to feel repelled towards something is usually the way to the light. On the other hand, we need to sometimes give the body and soul what they would like, otherwise tension is built. The way to happiness requires a lot of wisdom and inner sensitivity.

ma.be (Jesus.de): I want to be myself and learn to sit in the sun in a lawn chair, because Jesus has done everything for us.

Nils: Jesus has done everything in which he has shown us the way. But we must go the way by ourselves. We can find the way only, if we interpret the Bible with inner wisdom and intuition. The path into the light (holiness, Paradise) consists of three main points. 1 The way of rest (lying relaxed in a lounge chair, living in the silence) 2 The way of practice (prayer, meditation) 3 The way of universal love (do good, take ones fellow man more important than oneself). All three points are important. Thus succeeds our spiritual path. They must all be practiced at the right moment, in the right time, in the right way and personally in the right proportions.

Living in the light of God
Elizabeth: "Here I'll describe my path who led me into the light and gave me the love (...) I am a nurse by profession. At the age of 38 an illness struck me, the Firbomyalgie syndrome. And everything I had built up myself was lost. I was so desperate that I nearly gave up my life. (...) I began to think about death. How would that be like. Then I thought about life. What was the meaning of life? Was it the sense to be born, to struggle through his life, only to die then. (.. .) And there it was again the question: who was I anyway?

I thought about the people. Why were they so unhappy? No one saw the beauty of nature. (...) I made a long walk throug a forest nearby. Suddenly I had to stop. I saw a flash coming down out of a tunnel from above. And something penetrated me. I got a wonderful feeling within myself. A feeling of warmth, love and hope. (...) I did not really understand what had happened. But I felt an incredible peace, an incredible satisfaction. I was so happy as never before in my life. And it was as though a veil pulled from my eyes. Everything was suddenly brighter and clearer, as if I would see better. Everything seemed so clean and pure. As if I would see a new world. I saw the light of God in the word. And this has remained until today. I always live in the light of God.

Now I was the one I've always been. A woman of quiet tones. And everything is gotten better since then. My illness has disappeared since then more and more. (...) It was remarkable also, that I understood at once the words of Jesus and the Bible. (...) And I knew now what love is. Love is not dependent on people, but solely from oneself. (...) And then I suddenly knew what God is. It is the energy that is everywhere and everything. And this energy is pure consciousness. And this consciousness is shaped to all that which is. And this light came to me and brought me love. (...) And I more and more got aware what was been given to me."

What are you thankful for? Practice today a ritual of gratitude. Fill you with the energy of gratitude. "I am thankful for ..."


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User:Egm6936.f10

EGM 6936 Seminar, Fall 2010 Prof. Loc Vu-Quoc

University of Florida  Licensing info

= Topics: Uncertainty quantification =

Articles (work under progress)
Probability concepts

Zeros of polynomial equations

Orthogonal polynomials

Stochastic systems

Generalized polynomial chaos

Stochastic Galerkin method and collocation method

Spectral Methods in UQ for Fluid Simulations

Stochastic 1-D heat problem

= Important links =

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license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: User:Egm6936.f10


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User:Egm6936.f10/Uncertainty quantification

We document some concepts in Uncertainty Quantification (UQ) here.

= Uncertainty quantification and propagation =

Spectral methods
germ

$$S(\xi) = \sum_{k=0}^\infty S_k \Psi (\xi)$$

$${\mathbf A}, \boldsymbol A$$ (slanted)

= Spectral expansions =


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Pharmacokinetics

Pharmacology
As defined in the Merriam-Webster dictionary pharmacology is: "1: The science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology 2: the properties and reactions of drugs especially with relation to their therapeutic value"

By studying drug action on living organisms,  mechanisms of action, biological distribution and processing, and both therapeutic and non-therapeutic effects it provides a better understanding of the underlying physiology.. A drug is an exogenous or endogenous chemical entity that causes a specific change in a biological function in an organism. Drugs can be of a variety of sources: elemental compounds (i.e. Lithium, Oxygen, Calcium (Ca2+), a molecule (i.e. Nitrous Oxide), an endogenous compounds given exogenously ( i.e. hormones, immunoglobulins), and other compounds ( i.e. plant alkaloids, minerals, synthetics).  Drugs are formulated to conveniently deliver a precise dose intended to affect a short or long-term predictable, therapeutic biological change. Compounds which are exogenously administered and have medicinal properties are considered pharmaceuticals or colloquially "medicines" or "drugs".

Interactions of a drug within the body can be divided into two major principles: Pharmacokinetics and Pharmacodynamics ; the former deals with absorption, distribution, metabolism and elimination of a given substance by the organism and the latter deals with the interactions of the substance with biological processes (i.e. receptor-binding, signaling pathways..).

PHARMACOKINETIC PROCESSES
Time, needed for achieving of maximal effect, its duration and intensity depends on route of administration, rate of catabolism (metabolism, breakdown to inert compound) and elimination of active and/or inactive drug. So it is necessary to consider peculiarities and principles of different introduction methods, while choosing. They are divided to enteral, passage through the digestive tract (i.e. oral, rectal, gastronomy, feeding tube in stomach, small intestines) and parenteral, bypassing digestive tract (i.e. intravenous (IV), arterial, intramuscular (IM), subcutaneous (subQ), sublingual (can be considered enteral), topical, inhalation, subdural, epidural...).

Enteral route include oral, subglossal, and per rectum administration. Oral way is the most easy, convenient, and widely used way of administration. But a lot of factors influence on absorption and bioavailability of the drug. Bioavailability is the ratio of unchanged drug reaching the systemic circulation to the given dose (in percentage). For an intravenous dose of the drug, bioavailability is equal to unity (100%). For example, if bioavailability of drug is 50 %, its mean that 50 % of ingested dose reach the serum. For a drug administered orally, bioavailability may be less than 100% for two main reasons - incomplete extent of absorption and first-pass elimination. The last one is mean that following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall, but most commonly in the liver that is responsible for metabolism before the drug reaches the systemic circulation. The hepatic first-pass effect can be avoided to a great extent by use of sublingual route and by use of rectal suppositories. Sublingual absorption provides direct access to systemic - not portal - veins. This route is facile; the onset of action is fast; but the duration of action is short. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, partially drugs achieve superior hemorrhoidal that lead to the liver. In addition the absorptive ability of rectum mucosa lower than of small intestine. Thus, only about 50% of a rectal dose can be assumed to bypass the liver. To parenteral routes we consider injections, inhalations, and transdermal route. The first one includes injection under the skin, intro the muscles (i.m.), in veins (i.v.) and arteries. The effect appears quickly, especially in case of intravenous injection, and provides precision of dosage. Bioavailability for intravenous route is 100 %. After intravenous injection the onset of action is quicker, but duration is shorter than during intramuscular or subcutaneous injection. It is not recommended to use the drugs with strong irritate action subcutaneously and intramuscularly. Also it is prohibited to use intravenously insoluble substances and oily solutions, because of embolism risk. Lack of these routes is tissue damages, necessity of sterility, and risk of non-specific reactions (shock, collapse, cramps). Gases and aerosols are introduced using inhalations. Therapeutic effect is reached quickly. Predominantly this route is desirable for the treatment of diseases of breathing ways. It causes topical action mainly. Lack of this method is irritation followed by spasm of larynx, bronchi. Through the skin are introduced the oil-solved substances (in the form of ointments and liniments) and electrolytes (by electrophoresis). The transdermal route provides direct access to systemic - not portal – veins and prolong the duration of drug absorption. In digestive tract drug absorption depends on many factors. Ionized forms of drugs are poorly dissolved in lipids and poorly absorbed. Salicylates in the stomach (pH 1,0 - 1,5) are poorly ionized and are absorbed to a great extend in the stomach. Alkaloids are better absorbed in intestine (pH in duodenum is ~ 6,6), due to the poor ionization in alkaline medium. It is necessary to consider, that pH in the stomach is the lowest during and just after meals, and the highest - 1 hour before and 1,5 - 2 hours after meals. So acid substances is necessary to administrate while or just after eating, alkaline substances - 1 hour before and 1.5 - 2 hours after eating. Quantity and character of meals, that can change pH of surrounding, also considerably influence on drug's absorption. For example, tetracycline forms stable compounds with calcium, which are not absorbed. That’s why simultaneous using of tetracycline and milk that contain calcium can decrease the rate of tetracycline absorption. In the same time, lipids increase the absorption of fat-dissolved drugs (vitamins A, D, K, E, etc.). Alkaline promotes ionization of acid substances and impedes their absorption and vice versa. Also drugs absorption in intestine considerably depends on motility of digestive tract. Substances that decrease motility of intestine (spasmolytics, cholinolytics, etc.) promote absorption; substances, hastening motility (cholinomimetics) impede absorption. Drug's form has a great meaning while oral administration. The most common rule is, that liquid forms are absorbed better, than powders, absorption of which depends on it's dispersion; powders are absorbed better then tablets, dragees and granules. So, bioavailability of drugs while enteral administration depends on many factors, various greatly and difficulty predicted. After parenteral administration drugs are absorbed into the blood circulation from subcutaneous tissue, muscles and cavities (depending of injection types), from alveoli (during inhalations). Physician can easier predict serum's level of drug and it's effective dose. However, in the case of bloodstream delay the absorption after subcutaneous and intramuscular injections can decrease. Choosing the route of administration it is important to consider some basic factors: (1) stability of drug in digestive tract; (2) possibility of absorption through the walls of digestive tract and bioavail¬ability; (3) goal of therapy (in emergency cases parenteral route of administration, espe¬cially intravenous is preferred). In organism drugs permeate through the various barriers that separate different compartments, e.g., gut, brain. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that comprise the wall of the intestine, the walls of the capillaries that perfuse the gut, and the "blood-brain barrier," the walls of the capillaries that perfuse the brain. Drug permeation proceeds by four primary mechanisms. 1. Passive or lipid diffusion due to gradient of substance's concentration. Passive diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. This way are transported the lipophilic substances. It occurs without energy using. 2. Filtration or aqueous diffusion is appear across epithelial membrane through pores that permit the passage of small molecules. Filtration is depends on the concentration gradient of the permeating drug. In this way are transported small hydrophilic molecules and some ions. 3. Active transport is provided by special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes (e.g., peptides, amino acids, glucose). Active transport needs energy, which occur due to decomposition of ATP molecule. 4. Pinocytosis is the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane. This process is responsible for the transport of large substances. There are many biological (blood-histological) barriers in organism, except mentioned above blood-brain barrier. They are placental, blood-follicular, blood-testicular, and epithelium of mamma's glands. Blood-histological barrier is the capillary wall that consists of endothelium cells, basal membrane, enzymes, and small pores. Lipophylic substances easily pass through cellular membranes, hydrophilic substances pass through basal membrane and pores. Substances with molecular weight smaller than 5000-6000 Da easily pass through capillary wall also. Blood-brain barrier (BBB) consists of cerebral capillaries and astrocytes (neuroglia cells). It possesses selective permeability. Ionized molecules cannot pass trough it. In the case of inflammatory process brain BBB become more permeable; and brain is subjected by harmful influence of different substances. Placental barrier protects fetus from xenobiotics (not endogenous substances). Drugs with molecular weight smaller than 400 Da easily pass trough placenta by the way of passive diffusion. Permeability of placenta depends on many conditions and gradually increases to 33-35 weeks of pregnancy. Thus, it is necessary care administration of drugs especially in first trimester of pregnancy (period of fetus organ appearing). Blood-follicular and blood-testicular barrier protects sexual cells from action of xenobiotics. They consist of lipoprotein membranes and are easily passed by lipophylic non-ionized molecules (narcotics, alcohol, etc.). So, genetic material may be damaged (mutagenic effect). Epithelium of mamma glands is easily passed by lipophilic substances. If drugs, used by mother are toxic or may cumulate in breast milk, nursing have to be stopped or the drug have to be changed. Distribution of drugs in organism is done by blood and lymph circulation. There are three fractions of substances in organism: (1) free fraction in serum and tissues; (2) connected with serum proteins; (3) fixed in different tissues. These fractions are in dynamic balance and constantly remove from one form to another. Only free fraction is biologically active, because it could be transformed and excreted. So, the high level of free fraction is associated with strong, quick, but short action. Level of free fraction in blood depends on albumin content. In case of low protein levels (diseases of liver, kidneys, starvation) concentration of free fraction considerably increases, that may cause strengthening of effect. Some drugs may be deposited in tissues, forming extra-cellular and cellular depots. It occurs due to connection with proteins and phospholipids. Durability of connection is various. Some drugs (e.g., substances for narcosis) form not durable complexes with phospholipids and are quickly deleted from fat depots. Other (sulfanilamides of prolonged action, salts of heavy metals) form durable connections with proteins and for a long time stay in tissues. Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug in blood or plasma. Drugs with very high volume of distribution have much higher concentrations in extravascular tissue than in the vascular compartment. Mostly it is prefer for the drugs with high selectivity of action. Serum concentration is sum of free and connected with proteins drugs fractions. It shows different phases of pharmacokinetic: absorption, distribution and elimination of substance. Curve shows time from drug's administrat¬ion to appearance of primary effect (latent period of action), time from first appearance to minimal therapeutic effect (duration of action). Biotransformation (chemical drug conversion) occurs, basically in liver, and also in kidneys, lungs, wall of intestines and other organs. Most part of drugs are biotransformed in organism, except drugs for narcosis and hydrophil non-ionized substances that are excreted non-transformed. Result of biotransformation is converting of lipid-soluble substances to water-soluble and their excretion. Metabolic products are often less pharmacodynamically active than the parent drug and may even be inactive. There are two main phases of biotransformation - metabolism and conjugation. Metabolism (I phase) is occur due activity of oxidase's systems, basic components of which are cytochrome P-450 and NADP. At this phase reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Metabolic transformation is done by oxidation, restoration and hydrolysis. For example, imipramin, ephedrine, and aminazine are subjected to oxidation; levomycetin and nitrazepam are metabolized by restoration; complex ethers (e.g., novocaine, atropine) are hydrolyzed. Most part of substances are metabolized by oxidation for which oxygen is necessary. So, changes of blood circulation, hypoxia sharply lower metabolism of drugs. An interesting feature of some drugs (e.g., barbiturates, rifampicin) is their ability, on repeated administration, to "induce" cytochrome P-450 by enhancing the rate of its synthesis or reducing its rate of degradation. Induction results in an acceleration of metabolism and usually in a decrease in the pharmacologic action of the inducer and also of coadministered drugs. However, another drugs (e.g., valproic acid, cimetidine) inhibit activity of cytochrome P-450 that can result in an increasing of action of coadministered drugs. Parent drugs or their phase I metabolites that contain suitable chemical groups often undergo conjugation (coupling) reactions with an endogenous substance to yield drug conjugates. For example, histamine and noradrenaline are methylated; sulfanilamides are acetylated; morphine and bilirubin bind with glucuronic acid, etc. In general, conjugates are polar molecules that are readily excreted and often inactive. Conjugate formation involves high-energy intermediates and specific transfer enzymes (transferases). Excretion of drugs occurs basically via kidneys. Some drugs are excreted with bile into the lumen of intestine, via lungs, mammary glands, sweat and sebaceous glands. Drugs are excreted in changed form (metabolites, conjugates) and in unchanged (non-transformed) form. Almost all drugs are filtered at the glomerulus. If a drug is in a lipid-soluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by simple passive diffusion. If the goal is to accelerate excretion of the drug, it is important to prevent its reabsorption from the tubule. This can often be accomplished by adjusting urine to make certain that most of the drug is in the ionized state. As it is mentioned above, acids in acidic medium are poorly ionized and are easily reabsorbed. Alkaloids are better reabsorbed from alkaline urine. Thus, weak acids are usually excreted in alkaline urine; weak bases are better excreted in acidic urine. Also blood circulation in kidneys (hypotension diminish glomerular filtration), pathological processes in kidneys play an important role in excretion. It is necessary to remember that some drugs (e.g., tetracyclines, glycosides), which are excreted with bile, partially are reabsorbed in intestine. Some substances are excreted through stomach and intestine (morphine, salts of heavy metals). Drugs excretion into breast-milk has especial meaning. Most part of the drugs, used by mother, are found in breast-milk and may cause side effects at infant. If the drug is excreted into milk and is dangerous for infant, feeding has to be avoided. Elimination is the process of drug inactivation in result of biotransformation and excretion. It values by half-life of the drug, constant of elimination, and clearance. Half-life (t1/2) is the time required to change the amount of drug in the body (usually in blood) by one-half during elimination time. Constant of elimination is the drug quantity (in %), that was excreted by organism during period of time (usually during 1 day). Total clearance of a drug is the ratio of the rate of elimination by all routes to the concentration of drug in serum. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ.

title: Pharmacokinetics


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Talk:High School Biology

Please Do  Not  Put  ANy  Test  Edit On  Page Here. If You   Do They  Will  Be  Deleted  By Me. Or I WIll  Talk  To  You. Happy Learnin. 173.178.93.250 13:33, 27 March 2011 (UTC)

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title: Talk:High School Biology


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Talk:High School Biology/Students

It Does  Not Take You To  Wikipedia .--173.178.93.250 13:38, 27 March 2011 (UTC)

title: Talk:High School Biology/Students


text:
Pharmacodynamics

PHARMACODYNAMIC PROCESSES

 * It is a part of pharmacology that study mechanisms of action, pharmacological, therapeutical and side effects of drugs. :

The therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules' biochemical or biophysical activities. This idea is embodied in the term receptor. In general, receptor is a structural protein molecule on the cell surface or within the cytoplasm that binds to a specific factor, such as a hormone, antigen, or neurotransmitter. This interaction initiates the chain of biochemical events leading to the agent's observed effects. The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors often limits the maximal effect a drug may produce. Many drugs and endogenous chemical signals, such as mediators, regulate the function of receptor macromolecules as agonists (mimetic); i.e., they change the function of a macromolecule as a more or less direct result of binding to it. They possess affinity and intrinsic activity. Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into two classes. Partial agonists produce a lower response, at full receptor occupancy, than do full agonists.

Antagonists (lytics, blockers), however, bind to receptors without directly altering their function. Thus, they prevent the binding of agonist molecules and block their biologic actions. The two classes of receptor antagonism are known. In the presence of a fixed concentration of agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response. Conversely, sufficiently high concentrations of agonist can completely surmount the effect of a given concentration of the antagonist. Some receptor antagonists bind to the receptor in an irreversible fashion, i.e., not competitive. The antagonist's affinity for the receptor may be so high that for practical purposes, the receptor is unavailable for binding of agonist.

Mechanisms of drug's action may be connected with enzyme's inhibition. For example, proserine, which inhibits acetylcholinesterase, preserves acetylcholine from enzymatic decomposition, in result - tonus of cholinergic system increases. Mechanism of action of some drugs is connected with blockade of ionic channels in cellular membranes, e.g., for example, antagonists of calcium channels. Another drugs cause the exhaustion of mediator reserves in neural fibers in result of synthesis breach or reverse neuronal seizure (e.g., tricyclic antidepressants).

Types of drug's action.

There are local, reflective, and resorptive action. Under local action one can understand the drug's action in place of administration. It is used seldom. Reflective action appears in result of irritation of neural fibers that transmitted through CNS or by axon-reflexes. It may appear both: during local and resorptive action (e.g., reflective action of mustard plaster and cytitone). Resorptive action is observed after drug achievement of blood.

There are some types of resorptive action: direct and indirect, basic and side, selective and general, convertible and non-convertible. Direct action occurs in the place of drug contact with tissues, e.g., cardiotonic action of cardiac glycosides. Indirect action appears in result function changes, e.g., increased diuresis during administration of cardiac glycosides. Basic action is the main goal of drug's administration, e.g., lowering of blood pressure during administration of octadine. Side action is an additional effect to basic action. As the rule, side effect is unfavorable. For example, octadine can cause dyspeptic disorders.

Selective action alters function of certain organ and system. Usually it is related with action on functionally determined cytoreceptors (e.g., salbutamol, pilocarpine). General action is non-specific action in different organs and tissues (action of narcotic substances and alcohol). Convertible (reversible) action disappears just after drug's elimination. Non-convertible (irreversible) action appears in result of strong connection of drug with receptor (usually covalent) that cause irreversible breaking off it functions (e.g., proserine cause convertible inhibition of acetylcholinesterase, phosphacol causes non-convertible inhibition of acetylcholinesterase).

Factors that influence on drug's action. They may be divided into 3 groups:

1. Features of drugs;

2. Factors related with whole organism;

3. Environmental factors.

To the first group we refer structure of drug, it's physical and chemical features, pharmaceutical form, and doze. Chemical structure of drug determines its mechanism of action and toxicity. The molecular size, shape, and electrical charge of a drug determine whether it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, animal, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug's affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects. Drug's dissociation, solubility in lipids and water, permeation through biological barriers and membranes as well as pharmaceutical form and way of administration determine drugs action also. Strength and duration of effect, possibility of toxic action depends on the doze of drug. There is direct correlation among doze and drug level in serum. Dose is the quantity of a drug to be taken. It can be expressed in milliliters, grams, and international unites. It can be moment dose (for one time use), daily dose (the total amount of a remedy that is to be taken within 24 hours), curative dose (quantity of any substance required to effect the cure of a disease). Minimal (threshold) therapeutical dose is the smallest amount of a drug that will produce a desired therapeutic effect in an adult; maximal therapeutical dose is the largest amount of a drug that an adult can take with safety; median therapeutical dose is the dose that produces the desired therapeutic effect in majority of patients. Initial (loading) dose is a comparatively large dose given at the beginning of treatment to get the patient under the influence of the drug; maintenance dose supports the effect of drug therapy.

For evaluation of activity and safety of drugs therapeutical index is used. It is a ratio of doze that causes death in 50% of laboratory animals to doze that cause desirable effect in 50% of animals. Also it can be expressed as a ration of dose, which evoke toxic effect in 50% of patients, to dose, which evoke favorable effect in 50% of patients. Another data of drug's safety is wideness of therapeutical action - difference between threshold and maximal therapeutical doses. That drug is safer, which has large wideness of therapeutical action. To factors related with whole organism of patient we consider age, sex, genetic features, condition of patient, and biological rhythms. Age of patient considerable influences on the drug action. This factor is especially important in children and old patients. Most part of protective mechanisms in child organism is poorly developed. It is necessary to refer possibility of cramps, allergic reactions, slow biotransformation and excretion of the drugs, unripeness of biological barriers, high absorptive ability of skin and mucosa coats. In children of first 3 years drugs connection with serum proteins is lowered and level of free fraction is increased. In addition, children possess higher sensitiveness to drugs.

Old patients, especially over 75 years characterized by higher sensitiveness to drugs, which suppress CNS and lower sensitiveness that cause opposite effect. Tonus of vegetative nervous system, endocrine gland lowers. Inclination for thrombus formation increases, and it is dangerous to use coagulants. Level of serum albumins is lower and level of free fraction is higher. Biotransformation in liver and excretion by kidneys are delayed. So, in old patient, dose is smaller and administration is more careful.

Also it is necessary to consider condition of patient. Weakened and exhausted patients are needed for lowering of the dose. During shock and bleeding the sensitiveness for oppressing drugs increases (narcotics, neuroleptics, etc.). It is necessary to consider the additive diseases. For example, hepatic disease has been shown to reduce the clearance and prolong the half-life of many drugs.

Biological rhythmus is alternation of process's activity through determined interval of time. Dependence of drug action from biological rhythmus and their influence on them are studied by chronopharmacology. Biorhythmus may have seasonal, monthly, and daily (circadian) character. Knowledge of rhythmus is necessary for choosing of drug’s optimal regimen. For example, it is ascertained that maximal production of hormones in adrenal cortex occurs in the morning and sensitiveness of tissues for those hormones increases in that time also. So, using of corticosteroids in the morning increases efficacy of therapy and lowers risk of complications.

Some effects of drugs are concerned with genetic factors. These problems are studied by pharmacogenetics, part of medical genetics. For instance, metabolism of isoniazid and apressin occur due to their acetylation in liver. People are divided into “slow acetylators” with slow drug’s acetylation and “quick acetylators”. One of genetically determined reactions is idiosyncrasy, which is appears as abnormal reaction to a drug. It is characterized by redness, edema of skin and mucous, disorders of breathing and blood pressure, fever, and other disorders up to shock. Usually these reactions are related with congenital insufficiency of enzymes (enzymopathies). For example, in case of glucose-6-phosphate dehydrogenase of erythrocytes insufficiency sulfanilamides and derivatives of nitrofurane cause hemolytic anemia and jaundice. Pharmacogenetics is also studying mutagenic effects of drugs. It has great significance for individualization of treatment and prognoses efficacy and safety of pharmacotherapy.

Factors of environment also have determined influence on drug's action. They are social conditions that may cause psycho-emotional strain, strong noises, vibration, radiation, ecological problems, fluctuation of temperature, etc. Prolonged and excessive influence of these factors increases the drug's action on the CNS especially of narcosis substances, soporifics and neuroleptics. Some drugs (sulfanilamides) increase sensitivity of the skin to sunlight that named as photosensitization.

Changes in drug's action while repeated administration. In many cases drugs are used for prolonged therapy that can strengthen or weaken their action. Strengthening of effect may be stipulated by its cumulation both material and functional. Material cumulation is the accumulation of drugs (e.g., digitoxine, strychnine) that are slowly excreted from organism. Functional cumulation is the accumulation of drug's effect (alcohol, caffeine, etc.). It means that after the drug's excretion it effects still present As a result, toxic effects may appear.

Tolerance (accustoming, adaptation) is the ability to endure or be less responsive to the drug, especially over a period of continued exposure. Tolerance can be explained by accelerated of biotransformation and excretion, lowered of receptor's sensitiveness. For overcoming of the tolerance you need to increase doses of the drug that sometimes cause intoxication. Usually tolerance for one drug is accompanied by developed tolerance to pharmacologically similar compounds. Tachyphylaxis is a rapid appearance of progressive decrease in response following repetitive administration of a pharmacologically or physiologically active substance (e.g., while using ephedrine).

Dependence (drug abuse, addiction) is characterized by constant and repeated wish of drug using. Usually it is indicated by withdrawal symptoms (abstinence) that develop when use of the substance is terminated. Psychologic dependence is manifested by compulsive drug-seeking behavior in which the individual uses the drug repetitively for personal satisfaction. Cigarette smoking is an example. Abstinence is characterized by mental depression that include depressed or irritable mood, loss of interest in usually pleasurable activities, sleep and appetite disturbance, fatigue, suicidal thoughts, hopelessness, and guilt. Physiologic dependence is present when withdrawal of the drug produces symptoms and signs that are frequently the opposite of those sought by the user. It has been suggested that the body adjusts to a new level of homeostasis during the period of drug use and reacts in opposite fashion when the new equilibrium is disturbed. For example, symptoms of opioid withdrawal include lacrimation, sweating, weakness, chills, nausea and vomiting, muscle aches, hyper- or hypotension.

Drugs interaction.

Combined therapy is used for the treatment of majority diseases. Thus, it is necessary to know more about drugs interaction. There are two types of interaction: pharmaceutical and pharmacological. Pharmaceutical interaction may appear between incompatible drugs while their production, storing or mixing in solution. It can lowers components activity and increases their toxicity. For example, it is not recommended to mix in one-syringe vitamins B1, B6, and B12. Pharmacological interaction occurs on the level of pharmacodynamic and pharmacokinetic processes. Interaction on level of pharmacokinetic processes can be observed during absorption, transport, biotransformation, and excretion of drugs. For example, activated carbon, which has adsorbentive properties, decreases the extent of intestine absorption of concomitant drug. Competition for binding with serum proteins may develop between drugs, e.g., salicylates replace butamide, which decrease the blood glucose concentration, that may cause hypoglycemic coma. Drugs interaction on the biotransformation level may appear due to inducing or inhibiting effects on microsomal enzymes of the liver. As it is mentioned beyond barbiturates increase the enzyme's activity that is accompanied by hastened biotransformation of other drugs. Cimetidine has opposite effect. Interaction on the stage of excretion may cause hastening and slowing of drug's excretion from organism (see beyond). So, alkaline drugs (sodium bicarbonate) hasten excretion the acid substances (salicylates) and on the contrary. This interaction may be used during poisoning, e.g., administration of sodium bicarbonate during poisoning by salicylates and barbiturates.

Drugs interaction on the pharmacodynamic level appears in form of synergism or antagonism. Synergism is a coordinated or correlated action of two or more agents so that the combined action is greater than the effect of each acting separately. It can be in two forms: summation (additive) and potentiation. First one is a simple sum (addition) of effects, e.g., combination of agents for narcosis. Potentiation is an interaction between two or more drugs or agents resulting in a pharmacologic response greater than the sum of individual responses to each drug or agent, e.g. combination of sedative drugs with alcohol. Synergism may be direct, when drugs act on the same substrate, and indirect, when drugs act on different substrates.

Antagonism is the situation in which the combined effect of two or more agents is smaller than the solitary effect of any one of the factors. It can be physiological, chemical, physico-chemical and physical. Physiological antagonism appears on level of biological substrate. It may be direct and indirect. Interaction of cholinomimetic and cholinolytic is an example of direct antagonism. Indirect antagonism is stipulated by interaction of drugs with different mechanism of action. For example, pilocarpine narrow pupil through the stimulation of M-cholinoreceptors of sphincter pupil; adrenaline widens pupil due to stimulation adrenoreceptors of pupil's radial muscle. Chemical antagonism is a type of chemical reaction that results in loosing of initial pharmacological activity of agents and in formation of non-active substance (e.g., binding of unithiol with metals). Example of physico-chemical antagonism is neutralization of heparin (anticoagulant) by protamine sulfate, in result of electrostatic interaction. Physical antagonism is stipulated by physical features of drug, e.g., activated carbon adsorb on own surface molecules of many substances.

Types of drug's therapy.

Basic types of pharmacotherapy are prophylactic, etiotropic, pathogenic, and symptomatic. Prophylactic drug is an agent that acts to prevent a disease, e.g., chloridine for malaria prevention. Etiotropic therapy is directed against the cause; etiotropic agent is a remedy that attenuates or destroys the causal factor of a disease, e.g., antimicrobe drugs. Pathogenic therapy is directed on the pathologic, physiologic, or biochemical mechanism resulting in the development of a disease or morbid process, e.g., uses of cardiac glycosides during heart insufficiency. Finally, symptomatic therapy is directed on removing of symptoms of a disease (analgesics, stimulators of breathing, etc.).

Complications of drug therapy.

Together with therapeutically action drugs may cause unfavorable side (adverse) effects. There are different types of side effects. It may be complications related with absolute drug’s overdose – exceed of maximal therapeutical dose. Comparative overdose can appear in a result of fast intravenous injection of drug, during hard diseases of the liver, kidneys that delay drug’s elimination and increase drug’s concentration in the blood. Unfortunately, many drugs possess toxic action on human organs and tissues. For example, aminoglycosides are ototoxic (vestibular and auditory damage) and nephrotoxic, levomycetin commonly causes bone marrow depression (anemia, leukopenia).

Mutagenic, teratogenic, embryotoxic, and carcinogenic effects of the drugs engage prominent place in nowadays medicine. Mutagenic effect is a promoting of the changes in the chemistry of a gene that is perpetuated in subsequent divisions of the cell in which it occurs. It may be a result of drug's action on sexual cells (e.g., anticancer drugs). Mutagenic action may lead to congenital diseases like Daune’s syndrome. Teratogenic action of the drugs appears after its administration during pregnancy. It is characterized by the disturbed growth processes of fetus that lead to the formation of growth anomalies and malformed neonate. The most dangerous period is the first trimester of pregnancy (2-3 months) during formation of organs and systems. That’s why, administration of drugs in this period of pregnancy must be especially careful. In 60-s years of XX century it was so-called "thalidomide catastrophe". Using of thalidomide during pregnancy was accompanied by numerous developments of congenital defects in fetus. Nowadays, any drug cannot be proposed for sale and using without observing on teratogenic features.

Negative action on fetus can appear in growth retardation also. If this effect appear during first 12 weeks of pregnancy, it is named embryotoxic, if later - fetotoxic.

Allergic reactions are the most spread complications of pharmacotherapy. They are stipulated by formation of antibodies to the drugs that possess antigen features or to their metabolites. Increasing of organism's sensitivity to drugs is named sensitization. Hypersensitivity can be classified, as immediate or delayed depending on the time required for clinical symptoms to become manifest following exposure of the host to the sensitizing antigen. The most dangerous is anaphylactic shock.

title: Pharmacodynamics


text:
Medicine/First Aid/Materials

Poisonings may be caused by any kind of chemical compounds or liquids for technical used adopted in technique, agriculture and household. Medicines may cause poisonings too. All poisonings are divided into professional, household and medical ones. We are going to overview the first aid in cases of medical poisonings. But they are effective in other cases too.

Most frequent medical poisons are sleeping pills, analgesics, neuroleptics, antiseptics, cardiac glycosides, anti-cholinesterase agents etc. The pattern and severity of poisoning depends on its agent action. Thus, anti-cholinesterase agents poisoning (caused by phosphoorganic compounds) is characterized by cholinergic system enhanced symptoms. Alcohol, sleeping pills and drug intoxications are characterized by deep CNS depression.

Organism conditions and the way of poison entrance (oral, inhalation, skin, and mucous coat absorption) determine the severity of symptoms as well as the way of first aid. Children and elderly people are extremely sensitive to poisons and demonstrate the cases of the most severe poisonings. Environmental factors like temperature, humidity and atmospheric pressure influence the poison activity too.

There are general and specific first aid means. They are designed to achieve the following results.

•	Prevention of further poisons absorption

•	Chemical neutralizing of the absorbed poison or its elimination with a specific antidote

•	Enhanced poisons extraction

•	Normalizing of organisms function by symptomatic therapy

The sooner you begin the first aid, the more chances of success you have. Each case may need the adjustment of therapeutic pattern depending on the type and severity of poisoning. Thus, abrupt respiratory depression claims urgent restoring of the gas exchange system functions. In the treatment of poisonings an important place is engaged by antidote. Antidote is an agent that neutralizes a poison or counteracts its effects. There are a few types of antidotes. Chemical antidote is a substance that unites with a poison to form an innocuous chemical compound (unithiol, chelating compounds). Mechanical antidote is a substance that prevents the absorption of a poison (activated carbon). Physiologic antidote is an agent that produces systemic effects contrary to those of a given poison.

Prevention of poisons absorption

The pattern of these actions depends on the way the poison entrance into the organism. Inhalation poisonings (caused by carbon monoxide, nitric oxide, insecticides aerosols, petroleum evaporations) claim immediate removal of patient from the danger zone. Poisons should be removed or washed away from skin and mucous coats. Oral intake of poisons is managed by stomach rinsing (lavage). The early it is done, the more effective it is. Repeated rinsing help in cases of poisoning with hard-soluble powders and tablets that stay in stomach for a couple of hours.

Inactivation and binding of the poison in the stomach should be performed simultaneously to rinsing. Potassium permanganate, tannin, activated carbon, egg whites and milk are used for these purposes.

Potassium permanganate causes the oxidation of organic poisons. However it is unable to react with inorganic compounds. Its water solution ratio is from 1:5000 to 1:10000. It should be removed from stomach right after the rinsing due to its irritating properties.

Activated carbon (charcoal) is a universal adsorbent. Water suspension, containing 20-30 g of activated carbon, is to be poured into the stomach. After the interaction with poison the suspension should be quickly evacuated with the help of laxatives due to possible release of poison.

Tannin sediments various poisons especially alkaloids. 0.5% solution of tannin is usually used. Removal of the suspension due to possible poison release is necessary also.

Eggs white form insoluble complex with poisons. Milk acts in the same way but it is contradicted in case of poisonings by fat-soluble agents. Vomiting agents may be used in cases of impossibility of the gastric rinsing. Apomorphine hydrochloride (0.5-1 ml of 0.5-1% injected subcutaneously) is used most frequently. It is contradicted in case of patients unconsciousness.

Salt laxatives (sodium and magnesium sulfate) are used for poison removal from intestines. Sodium sulfate is better then magnesium sulfate, because the latter causes CNS depression.

Chemical neutralization of the absorbed poison and usage of specific antidotes

There are certain compounds capable for neutralization of poison toxicity by chemical binding or functional antagonism. They act by chemical or functional interaction with poisons. Unithiol, sodium thiosulfate, complexones, methemoglobin-formers and demethemoglobin-formers are the examples of chemical concurrence interaction.

Unithiol (dimercaprol) can bind metal ions, metalloids and cardiac glycosides molecules due to it two sulfhydryl groups (-SH), which can donate electrons for coordination with the poison. Such bonding effectively prevents interaction of the metal with similar functional groups of enzymes, coenzymes, cellular nucleophiles, and membranes. Usually this medicine is used in cases of poisonings by arsenic, mercury and gold. It is less effective against bismuth, cobalt, cooper, zinc, nickel, polonium and cardiac glycosides. Complex of unithiol and poison is excreted by kidneys. Given intramuscularly, unithiol is readily absorbed, metabolized, and excreted by the kidney in complex with poison within 4-8 hours. Adverse effects include hypertension, tachycardia, vomiting, salivation, fever (particularly in children), and pain at the injection site.

Sodium thiosulfate is an antidote in arsenic, mercury, lead, and cyanide poisoning. Sodium thiosulfate forms with metals nontoxic sulfites and with cyanides less toxic substances. Its 30% solution is injected intravenously.

Complexons make chelate compounds with most of metal ions and radioactive isotopes. These substances have low toxicity and are being extracted by kidneys. Tetacine-calcium (EDTA, edetate calcium disodium), the calcium chelate of edetate (ethylenediaminetetraacetate) disodium, is a chelating agent (complexon). The calcium in calcium EDTA can be displaced by divalent and trivalent metals, particularly lead, to form stable soluble complexes which can then be excreted in urine. Administration of calcium EDTA chelates greatly increases the urinary excretion of zinc, cadmium, manganese, iron, and copper. The manufacturer recommends that calcium EDTA injection be diluted with 0.9% sodium chloride or 5% glucose injection for intravenous administration. Calcium EDTA is used for the reduction of blood and mobile depot lead in the treatment of acute and chronic lead poisoning and lead encephalopathy. Agent may also be beneficial in the treatment of poisoning from other heavy metals such as chromium, manganese, nickel, zinc, and possibly vanadium. The principal and most serious toxic effect of calcium EDTA is renal tubular necrosis, which tends to occur when the daily dose is excessive and may result in fatal nephrosis.

Penicillamine is a monothiol-chelating agent, which is a degradation product of penicillins. Penicillamine chelates copper, iron, mercury, and lead to form stable soluble complexes, which are readily excreted by the kidneys. Copper is chelated by the combination of 2 molecules of penicillamine with 1 atom of the metal. Penicillamine is readily absorbed from the GI tract. Penicillamine is used to promote excretion of copper in the treatment of Wilson's disease (hepatolenticular degeneration). Also it is used in the treatment of the active stage of rheumatoid arthritis. The mechanism of action of penicillamine in the treatment of rheumatoid arthritis is not known but may be related to inhibition of collagen formation. Adverse reactions include allergic reactions, nausea, leukopenia, and proteinuria.

Deferoxamine chelates iron by binding ferric ions to its molecule. Deferoxamine-iron complex is formed in many tissues, but mainly in plasma; this complex is stable, water soluble, and readily excreted by the kidneys. Deferoxamine appears to have a specific affinity for iron; this affinity is greater than that of other chelating agents for iron. Deferoxamine is used in the treatment of acute iron intoxication as well as chronic iron overload.

Demethemoglobin-formers are the substances capable of converting methemoglobin to hemoglobin. They are methylene blue (as a chromosmone medicine) and cystamine. Methylene blue reduces methemoglobin to hemoglobin. It is administered to patients who have been exposed to methemoglobin-forming compounds (e.g., aniline, nitrites, local anesthetics, sulfanilamides) and whose methemoglobin levels exceed 20 to 30%. However, in higher doses methylene blue promotes methemoglobin forming that can be used for the treatment of cyanide poisoning.

Physiologic antidote as it is mentioned above is an agent that produces systemic effects contrary to those of a given poison. Antidotes can concurrent with poison for the same substrate e.g., receptor, enzyme (functional antagonism). For example phosphoorganic substances inactivate an enzyme acetylcholinestarase that leads to exceed accumulation of acetylcholine. Cholinesterase reactivators (dipyroxime, isonitrosine) bind with phosphoorganic substances and release acetylcholinesterase. Cholinoblockers (atropine) remove cholinomimetics (muscarine, pilocarpine) on M-cholinoreceptors; thus atropine is useful during muscarine poisoning. The same concerns histamine and anti-histamine substances, adrenoblockers and adrenomimetics, morphine and nalorphine.

Enhanced poison extraction

That is achieved by organisms purifying. Large amounts of liquid and diuretics are to be taken (forced diuresis). It causes the dilution of poison in tissues and decreases its concentration while osmotic diuretics and furosemide enhances its renal excretion. Drinks are given to conscious patients; unconscious ones receive 5% glucose solution or isotonic sodium chloride solution intravenously. This method is effective only when kidneys are still capable of excretion. Alkaline diuresis may aid in increasing renal clearance and reducing the elimination half-life of salicylates and phenobarbital (acids), because the reabsorption of acids at alkaline pH is lower. And on the contrary, alcohol and amphetamine (alkaline compounds) are better excreted with acidic urine that can be achieved by using of ammonium chloride. Extracorporeal techniques include hemodialysis, hemoperfusion, etc that are used for different kinds of poisonings.

During the procedure hemodialysis of soluble substances and water from the blood by diffusion through a semipermeable membrane is appearing. The separation of cellular elements and colloids from soluble substances is achieved by pore size in the membrane and rates of diffusion. Hemodialysis is especially effective in case of kidney insufficiency (sulema poisonings). It promotes the evacuation of poisons with small molecular weight.

Hemoperfusion (hemosorption) is a detoxicative method. It consists of blood passage through columns of adsorptive material, such as activated charcoal (carbon), to remove toxic substances from the blood. It is active against poisons, diluted in blood. Hemoperfusion is useful for intoxication with a drug known to be metabolized to a more toxic one and a drug known to produce delayed toxicity.

Peritoneal dialysis is a removal from the body of soluble substances and water by transfer across the peritoneum, utilizing a dialysis solution which is intermittently introduced into and removed from the peritoneal cavity. Transfer of diffusable solutes and water between the blood and the peritoneal cavity depends on the concentration gradient between the two fluid compartments. Acute peritoneal dialysis is used principally to treat patients with acute renal failure.

Supportive care (symptomatic therapy) Morbidity and mortality following an overdose are reduced by intensive appropriate symptomatic supportive therapy, which includes restoring of vital functions (cardiac status, airway, and mental status).

Respiratory depression claims endotracheal intubation, bronchial cleaning and artificial lung ventilation. Respiratory centre depression is managed by analeptics (camphor, bemegride). Respiratory depression caused by morphine is can be treated by naloxone or nalorphine. Pulmonary edema is treated with complex therapy according to blood pressure rate. Spirit and antifoamsilane inhalations are performed to manage the foam; glucocorticoids, diuretics and ganglioblockers are given depending on the indications. Bronchospasm can be managed by broncholytics (adrenomimetics, cholinoblockers, euphylline, etc). Hypoxia is managed by oxygen inhalation and special apparatus for respiration and blood circulation support.

Cardiac insufficiency claims glycosides with a quick onset of action (strophantine, corglycon); antiarrhythmics are used in cases of arrhythmia.

Vascular tonus and blood pressure are decreased during most of poisonings. Hypotonia causes tissue nutrition disorders, hypoxia, and poison retention. Hypotonia is managed with adrenomimetics (e.g., dopamine, ephedrine, adrenaline, mesatone, and noradrenaline). Hypertension (poisoning by vasoconstrictors) is the indication for the using of clopheline, magnesium sulfate, phentolamine, benzohexonium, furosemide, etc.

Cholinomimetics and CNS agitators often cause cramps. They are managed with narcosis agents, tranquilizers (diazepam), barbiturates (thiopental), muscle relaxants, and magnesium sulfate.

Allergic reactions and especially anaphylactic shock first aid is urgent injections of adrenomimetics (adrenaline), glucocorticoids (prednisolone), anti-histamines (dimedrol), broncholytics (euphylline), and cardiac glycosides (strophantine). Coma is the symptom of severe poisonings. It is prefer for the poisoning by CNS depressants. Treatment is designed to support vital functions. Analeptic use should be extremely cautious in these cases. Pain syndrome claims narcotic analgesics, which can inhibit the respiratory centre on the other hand.

The support of acid-base balance and liquid-salt balance are extremely important in cases of poisonings therapy. Acidifying and alkalinizing agents, salt solutions are discussed in chapter “Plasma substitutes and deintoxication solution”.

Thus, first aid means depend on the kind of poisoning and patients state.

title: Medicine/First Aid/Materials


text:
Drugs affecting function of Uterus

They are divided on (1) substances, strengthening of uterus rhythmic contractions, (2) substances, lowering tonus of cervix uteri, (3) substances, increasing tonus of myometrium, and (4) substances, weakening uterus contractions. These drugs are used for regulation of labor activity and stopping of uterus bleeding. Drugs, strengthening rhythmic contractions of uterus This group include oxytocin, desaminooxytocin, pituitrine, hyphotocine, dinoprost, dinoprostone, pachycarpine, and proserine. They are indicated during weakness of labor activity, for normalization of uterus involution in postpartum period, during hypotonic uterus bleeding. Oxytocin is a hormone secreted by the neurons of the hypothalamus and stored in the posterior pituitary in mammals. Commercially available oxytocin preparations are prepared synthetically. Oxytocin stimulates contraction of uterine smooth muscle by increasing the sodium permeability of uterine myofibrils. High estrogen concentrations lower the threshold for uterine response to oxytocin. Uterine response to oxytocin increases with the duration of pregnancy. In the term uterus, oxytocin increases the amplitude and frequency of uterine contractions, which in turn tend to decrease cervical activity producing dilation and effacement of the cervix and to transiently impede uterine blood flow. Oxytocin elicit milk ejection in lactating women. Also it produces vasodilation of vascular smooth muscle, increasing renal, coronary, and cerebral blood flow.

In pharmacologic doses, oxytocin can be used for induction and augmentation of labor. It can also be used for control of postpartum uterine hemorrhage. Oxytocin is administered intravenously or intramuscularly. It has a circulating half-life of 5 minutes. Contraindications include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture. Desaminooxytocin is a synthetic analog of oxytocin. It is act longer than parental agent and is used subglossal.

Pituitrine and hyphotocine are the extracts of bovine pituitary gland. They contain two posterior pituitary hormones: vasopressin and oxytocin. Pituitrine and hyphotocine possess the activity of oxytocin, which is described beyond, and vasopressin that cause vasoconstriction and hypertension. These agents have the same indications as oxytocin. Hyphotocine contain less vasopressin than pituitrine, thus hyphotocine is more prefer, especially in patients with hypertension.

Prostaglandins are the class of physiologically active substances present in many tissues, with effects such as vasodilation, vasoconstriction, stimulation of intestinal or bronchial smooth muscle, uterine stimulation, and antagonism to hormones influencing lipid metabolism. Prostaglandins as well as leukotrienes and thromboxanes are synthesized from arachidonic acid via a cascade pathway. Prostaglandin F2α (dinoprost) and prostaglandin E2 (dinoprostone) possess expressed influence on contractility of myometrium.

Dinoprostone stimulates uterine and GI smooth muscle. Although it is believed that the drug exerts its uterine effects via direct myometrial stimulation, the exact mode of this and other actions has not been fully elucidated. Dinoprostone increases the amplitude and frequency of uterine contractions throughout pregnancy, but uterine response to the drug increases with the duration of pregnancy. In early pregnancy, the uterus is more responsive to dinoprostone than to oxytocin. Dinoprostone-induced uterine contractions are usually sufficient to cause evacuation of both the fetus and the placenta. The drug also produces cervical dilation and softening. Dinoprostone causes stimulation of the circular smooth muscle of the GI tract, causes bronchodilation, and increases permeability of the vessels. Large doses of dinoprostone may cause vasodilation and hypotension.

Dinoprostone is widely distributed in the mother and is rapidly metabolized in the maternal lungs, kidneys, and other tissues. Dinoprostone is used intravenously to induce abortion during the second trimester of pregnancy (beyond the 12th week of gestation) and to improve cervical inducibility (cervical "ripening") near or at term in pregnant women for labor induction. Adverse GI effects (e.g., diarrhea), phlebitis, fever are the most frequent adverse reactions of dinoprostone. Since dinoprostone, like dinoprost, is metabolized rapidly, discontinuing administration of the drug and supportive therapy are usually adequate treatments for serious adverse effects. Dynoprost is similar in structure, action and uses to dynoprostone. It is administered intravenously, vaginally, and as intra-amniotic injection. Dynoprost, unlike dynoprostone, causes bronchospasm. That’s why it is not recommended during bronchial asthma.

Pachycarpine hydroiodide is a ganglion-blocking agent. It increases the tonus and force of the uterus contractions. Agent lowers blood pressure, so it can be administered during labor in patients with hypertonia. It is used intramuscularly, subcutaneously and orally. Pachycarpine is indicated for the weakness of labor. Anti-cholinesterase substances (proserine) and β-adrenoblockers (anapriline) also stimulate activity of the uterus.

M-cholinolytic (atropine sulfate), prostaglandins (dynoprost, dynoprostone), and narcotic analgesic (promedole) are used for the relaxation and softening of cervix uteri, and bettering of labor current. Drugs, increasing tonus of myometrium

These drugs (ergot alkaloids, cotharnine, oxytocin, and pituitrine) are used basically during atonic uterus hemorrhages and for fastening of uterus involution in postpartum period. Mechanism of bleeding stop is related with stable increasing of uterus tonus and pressing due to it of small vessels in myometrium.

Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grain - especially rye - under damp growing or storage conditions. Ergot alkaloids are the derivatives of lysergic acid. The main alkaloids are ergotamine and ergometrine. Their effects include agonist, partial agonist, and antagonist actions at α-adrenoreceptors and serotonin receptors. Ergotamine and related compounds constrict most human blood vessels in a predictable, prolonged, and potent manner. In the same time they blockade the response of α-receptors to other agonists including noradrenaline. Dihydro derivatives of ergot alkaloids have much more selective α-receptor-blocking actions and they cause vasodilation.

Ergot alkaloids possess stimulant action on the uterus. The uterus at term is more sensitive to ergot than earlier in pregnancy and far more sensitive than the nonpregnant organ. These drugs induce powerful and prolonged tonic contraction of the uterus. Ergometrine is more selective than other ergot alkaloids in affecting the uterus and is the agent of choice in obstetric applications of these drugs. Ergometrine can be administrated enterally and parenterally. The onset of action is 10-15 minutes after ingestion and lasts a few hours. Certain of the naturally occurring alkaloids are powerful hallucinogens. Lysergic acid diethylamide (LSD, "acid") is the ergot compound that most clearly demonstrates this action.

Even moderate ergot doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor. Their use at that time to accelerate delivery caused an asphyxia and fetus death. Therefore, ergot derivatives are useful only for control of late uterine bleeding and should never be given before delivery.

In medical practice are used: Galen’s (extract of thick ergot), neo-Galen’s drugs (ergotal) and pure alkaloids (ergometrine maleate, methylergometrine, ergotamine hydrotartrate). Ergotamine is used for the treatment of migraine. Favorable effect of ergotamine is related with weakening of cerebral vessel’s pulsation and lowering of irritation of the cerebral cover’s receptors. Ergot alkaloids are contraindicated during angina pectoris, atherosclerosis, and spasm of peripheral vessels. They are excreted in breast milk, so they are not to be used during feeding.

The accidental ingestion of ergot alkaloids in contaminated grain as well as overdosing ergot agents causes ergot poisoning (ergotism). The most dramatic effects of poisoning are hallucinations and convulsions, prolonged vasospasm and damage of endothelium that may result in gangrene, and stimulation of uterine smooth muscle, which in pregnancy may result in abortion.

Cotharnine chloride also increases tonus of uterus and administered orally and parenterally during uterus bleeding. Expressed action during atonic uterus bleeding is exhibited by oxytocin, pituitrine and prostaglandins that are discussed beyond. During atonic uterus bleeding some plant drugs are used in form of extracts, decocts and tinctures: tincture of barberries, water paper, etc. Drugs, weakening contractile activity of myometrium

Those drugs are used, basically, for stopping of premature labor and weakening of labor activity during fastened labor, for preventing of labor ways traumas. For those purposes β2-adrenomimetics (fenoterol), magnesium sulfate, narcotic substances are used. Partusisten (fenoterol) is a β2-adrenomimetic. It causes tocolytic (uterine relax) action. Also it leads to bronchodilation. Agent is effective drug for prevention of premature labor and doesn’t cause negative action on fetus. It is administered intravenously by drops and orally in tablets. It may cause tachycardia, muscular weakness, tremor, and hypotension. It is contraindicated during cardiac defects, arrhythmia, thyrotoxicosis, and glaucoma.

Magnesium sulfate during parenteral administration decreases uterus contractions. It acts as calcium antagonist. Also agent possesses sedative, hypotensive effects. In higher doses – soporific, anticonvulsive, and narcosis effects are occur. Substances for narcosis (nitrogen oxide, phtorotane, sodium oxybutirate, etc.) and tranquilizers (sibazone) as well as progesterone, tocopherol (vitamin E) inhibit contractile activity of uterus.

title: Drugs affecting function of Uterus


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