Viruses and viral products that block apoptosis

I was having study on apoptosis (pathology) and found that one of the stimuli triggering apoptosis is ” DNA damage”.  Since, The viral infections need the host DNA for replication means they are damaging the host DNA, So why doesn’t  apoptosis start cell death and clear all the infected cell ??

Yeah I know i am silly and i know there are also a lot of  dumb people like me who also don’t know about this phenomenon.. So i decided to let them know some thing regarding VIRAL INFECTIONS AND APOPTOSIS.

SOME OF VIRUSES PRODUCING PROTEINS THAT BLOCK THE APOPTOSIS IN DIFFERENT WAYS :

I may also let u know the Source was THIS RESEARCH.Download pdf

There are certain viruses which produce different proteins to prevent apoptosis.
yeah that was some thing i was searching for.
Among those proteins these are

• E1b 19k, E1b 55k, E3 14-7k (by adenovirus)
  E1B 19K and Bcl-2 are functionally interchangeable ; E1B 19K does not promote an elevation of Bcl-2 within cells, suggesting that it is a functional homologue of Bcl-2. In fact, E1B 19K interacts with three positive regulators of apoptosis from the Bcl-2 family: Bax, Bak and Bik. E1B 19K is also able to suppress cell death mediated by tumour necrosis factor alpha (TNF-a).

• LMW5-HL (by swine virus)
• P35, IAP (by baculovirus)
• CrmA ( by cowpox virus)
• core protein (by HCV )
• pX ( by HBV )
• FLIPs ( by gamma herpes viruses)
• E6 ( by HPV )

There mechanisms of these proteins that inhibit the apoptosis in host cell. You can download From Here.

In addition to that i may also inform you ” Viruses which are non-enveloped, and non-lytic can also induce cell death with causing inflammation ..but why ? I am also searching. may be for efficient dissemination of progeny.
But soon science will find out this. Thanks i hope it helped you
regards admin

Physiology Of Pain

Pain;

pain is defined as an unpleasant and emotional experience associated with or with out actual tissue damage. The pain sensation is described in many ways.

The word unpleasant comprises the whole range of disagreeable feelings from being merely inconvenienced to misery, anguish, anxiety, depression and desperation to ultimate cure of suicide. Pain may acute or chronic. Acute pain is a sharp pain of short duration with easily identified cause often its localize in small area before spreading to neighboring areas. Usually was treated by medication chronic pains. The intermediate or constant pain was different intensities. it last for long periods.

it is somewhat difficult to treat chronic pain and it needs professional expert care.

Pain is produced by real or potential injury to the body. Often its expressed in terms of injury, e.g. pain produced by fire is expressed as burning sensation, pain produced by

Severe sustained contraction of skeletal muscles expressed as cramps.

Phenomenon of pain;

1- Pain can occur without tissue injury or evident disease and can persist after injury has healed.

2- Serious tissue injury can occur without pain

3- Emotion (anxiety, fear, depression) is an inseparable co eminent of pain and can modify bois intensity and the victim’s behavioral response.

4- There is important processing of afferent nociceptive and other impulses in the spinal cord and brain.

appreciation that pain is a both a sensory and an emotional (effective) experienced has allowed clinicians to realize that to meet a complaint of pain automatically with a prescription alone is not appropriate response for there is always more to analgesia than analgesics. Pain that is not the subject of an analysis by the clinicians (and explanation to the patient) may be inadequately relieved because of lake of understanding that doctors do not provide adequate relief of serve pain by bad choice and by over using and also important understanding drugs and by defective relation with their patients has been & still is injustified and shaming criticism.

Components of pain sensation;

A pain stimulus produces two pain sensations

1- Fast pain

2- Slow pain

è Fast pain is the first stimulation when a pain stimulus is applied. Its experienced as an bright sharp and localized pain sensation.

Fast pain fallows show pain which is experienced as dull diffused, and unpleasant pain the receptors for both the components of pain are same i.e. the free none endings.

The relative abundance of various types of receptors differ greatly, e.g. pain receptor are 27 times more abundant then cold receptors, the cold receptors are nearly 10 times more abundant than heat or temperature receptors . The receptors are not distributed evenly over the entire surface of the body e.g. the finger tips have an abundance of touch receptors than skin of back.

The afferent nerve fibers are different, the fast pain sensation is carried by A8 fibers and the slow pain sensation is carried by C types of nerve fibers.

è Glutamate and substance P are the neuro-transmit secreted by the pain nerve endings. The A8 afferent fibers when transmit impulses of fast pain secrete glutamate. C type fibers which transmit impulse of slow pain secrete substance P.

Advantages or Benefits of Pain Sensation;

We know pain is unpleasant sensation but it has same proactive and beneficial or survival effects such as,

1- Pain gives alarming signals about the existence of a problem or threat, it also creates the awareness of injury.

2- Pain prevents further damage by causing reflex withdrawal of the boy from the source of injury.

3- Pain tell the person to acquired treatment to prevent the major damage.

4- It forces the person to rest or to minimize the activities thus enabling the raping healing of the injured part.

Pathways of Pain Sensation;

Pain

Pain sensation from various parts of body is carried to brain by different pathways which are,

1- Pathways from skin and deeper structures

2- Pathways from face

3- Pathways from viscera

4- Pathways from pelvic region

1- Pathways of pain sensation from skin and deeper structure;

Receptors;

The receptors of pain sensation are the face nerve endings which are distributed throughout the body

First order neuron;

First order neurons are the cells in the posterior nerve root ganglia which receive the impulses of pain sensation from the pain receptor through their dendrites. These impulses are transmitted to spinal cord through the axons of there neurons.

Fast pain fibers;

Fast pain sensation is carried by A8 type afferent fibers which synapse with neurons of marginal nucleus in the posterior grey horn.

Slow pain fibers;

Slow pain sensation is carried by C type afferent fibers which synapse its neurons of substentia gelatinosa of reelendo in the posterior grey horn.

Second order neurons;

The neurons of the marginal nucleus and substentia gelatinosa of palando from the second order neurons fibers from these escred in the form of the lateral spin thalamic tract.

Fast pain fibers;

Fibers of the fast pain arise from neurons of marginal nucleus. Immediately after taking origin the fibers cross the midline via anterior gray commissure reach the lateral white column of the opposite side and ascend, these fibers from the neospino thalamic fibers in lateral spino thalamic tract. These nerve fibers terminate in ventral posteo lateral nucleus of thalamus some of the fibers terminate in ascending reticular activating system of the brainstem.

Slow pain fibers;

The fibers of slow pain which arise from neurons of substantia gelatinosa cross the mid line and run along the fibers of fast pain as pateospinothalamic fibers in lateral spinothalamic tract. One fifth of these fibers terminate in ventral posteolateral nucleus of thalamus the remaining fibers terminate in any of the fallowing areas.

1- Nuclei of reticular formation in brainstem.

2-Tactum of mid brain

3- Grey matter surrounding aqueduct of sylvius.

Third order neurons:

The third order neurons of pain pathway are the neurons in

1-    Thalamic nucleous

2-    Reticular formation

3-    Tectum

4-    Grey matter around aqua duct sylvivs

Axons from these neurons reach the sensory area of cerebral cortex. Some fibers from reticular formation reach hypothalamus.

Center for pain sensation:

The center for pain sensation is in the post central gyrus of parietal cortex. Fibers reaching hypothalamus are concerned with the arousal mechanism due to pain stimuli.

Pathway of pain sensation from face:

Pain from face is carried out by trigeminal nerve. This nerve carries somato sensory information from face, teeth, tissue around teeth, oral cavity, cranial daura matter and major part of scalp to sensory cortex. It also conveys prprioceptive impulses from extrinsic muscles of eye ball.

Pathway of pain sensation from viscera:

The pain sensation from thoracic and abdominal viscera is transmitted by sympathetic nerves. Pain from esophagus, trachea, phyranx is carried by vagus and glassophyrrengial nerves.

Pathways of pain sensation from pelvic region:

Pain sensation from deeper structures of pelvic region is conveyed by sacral parasympathetic nerves.

Visceral pain:

Pain from viscera is un pleasant. It is poorly localized.

Cause f visceral pain:

1-Ischemia

The substance released during ischemic condition like bradykinnin and proteolytic enzymes stimulate the pain receptors of viscera.

2-Chemical stimuli

The chemicals like acidic gastric juice leaks from ruptured ulcers into peritoneal cavity and produce pain.

3-Spasm of hollow organs

Spastic contraction of smooth muscles in GIT and other hollow organs of viscera cause pain by stimulating the force nerve endings.

4-Over distention of hallow organs also cause pain

Referred Pain

It is a pain that is perceived at a site adjuvant to away from the site of origin. The deep and some visceral pain are referred to other areas. But superficial pain is not referred.

Examples :

1-cardiac pain is felt at inner part of left arm and left shoulder.

2-Pain in ovary is referred to umbilicus.

3-pain from testes is referred in abdomen.

4-Pain in diaphragm is referred to right shoulder.

5-Pain in gallbladder is referred to epigastric region.

Mechanism of referred pain:

Dermitomal rule

According to this pain is referred to a structure which is developed from the same dermeterne from which the pain producing structure is developed.

A dermatome includes all the structures or parts of body which are innernated by afferent nerve fibers of one dorsal root. For example the heart, the inner aspect of left arm originates from same dermatome so the pain of heart is referred to left arm.

Gate contract theory:

This theory was proposed in 1965 to explain the pain suppression.

According to them the pain stimuli transmitted by afferent pain fibers are blocked by gate mechanism located at posterior gay horn of spinal cord. If the gate is opened pain is felt but if the gate is closed pain I suppressed.

Mechanism of gate control at spinal level:

1-    When pain stimuli is applied on any part of body , besides pain receptors, the receptors of other sensation such as touch are also stimulated.

2-    When all the impulses reach the spnal cord through posterior nerve root, the fibers fo touch sensation of apin pathway

3-    The impulses of touch sensation passing thorough these collaterals inhibit the release of glutamate and substance P from the pain fibers.

4-    This closes the gate nd the pain transmission is blocked.

Headache

Headache originating inside the skull may be due to destention of artries arising from circle of willis, or traction on dura matter.

Headache originating outside the skull is may be due to local stimulated muscle spasm.

Written by Ahmed Abdullah

Abnormal ECG

The normal ECG is composed of P wave QRS complex and T wave. 

P wave is caused by electrical potential generated when atria depolarized before artrial contraction begins.

The QRS complex is caused by potential generated when ventricles depolarizes before contraction that is as the depolarization wave spread through he ventricles thus both P wave and QRS complex are depolarization waves.

T wave is due to re polarization of ventricle muscles.

Abnormalities in P wave:

Variation in the duration, amplitude and morphology of ‘ P ’ wave helps in the diagnosis of several cardiac problems. such as .

1. Atrial fibrillation:

Mainly fibrillation means a small, local involuntary, muscular contraction due to spontaneous activation of single muscle cells or muscle fiber whose nerve supply has been damage or cut off. In these disease when the ECG of patient are taken, the P wave is not present .  Atrial muscle mass separated from the ventricular muscle mass by fibrous tissue. Therefor ventricular fibrillation often occur with out atrial fibrillation.

A frequent cause of atria fibrillation is atrial enlargemnt resulting from heart valve lesions (any patholological dis continuetity of tissue or loss of function of heart) that prevent atria from wmptying into ventricle. Or from ventricular failure with excess damming of blood in the atria.

Atrial fibrillation may be caused by hypertension. Diabetese millitus, congestive heart failure, age above 75 years.

Atrial fibrillation : P wave is not present.

B . Atrial proxysmal tachycardia :

To diagnose this disease in Ecg we must know following things.
1. Proxysmal: An arrhthmia (irregular heart beat) that suddenly begin and end

2. Tachycardia: Abnormal rapid heart rate usually 160-190/ min

When the ECG of patient which have atrial proxysmal     tachycardia disease is taken, a sudden ioncrease in heart rate from about 95-150 beat per minute . On close study of ECG during rapid heart beat an inverted P wave is seen before QRS –T complex and this P wave is partially superimposed onto normal T wave. This indicate that origion of proxysmal tachu cardia is in the atrium, but because of abnormal P wave shape , the origon is not near Sinus node.  

The proxysmal tachycardia of ten result from an aberrant rhythm that involves the A-V node .

This usually cause almost normal QRS-T complexes but totally missinh or obscured P wave . Atrial or AV nodal proxysmal tachycardiaboth of which are called supraventricular tacchycardia , both of which  occure in young , other wise helathy people and they genrally grow out of the predispoition (a latent susceptibility to disease that may be activated by uinder certain condition ) to tachy cardia after adolescene ( the period b/w puberty and completion of physical growth from 11-19 years ) . a person tremendously and may cause weakness during the paroxysmal only seldom does permanent harm from the heart.

c. Hyperkalemia: P wave is small.

D. Sinoatrial Block:

Sinoatrial disease result form degeneration of the sinus node and is common in the elderly. It may present with palpitation ( subjective sensation of an rapind or irregular heart beat) , didzzy spells or syncope ( suddend loss of conscioussness, without warning due to cerebral anemia caused by obstruction to cardiac arrhythmia ) due to intermittent tachycardia , brady cardia or pauses (interpretation in the sinus rhthym , which is not exact in normal cardiac cycle) with no atrial or ventricular activity. In sinoatrial block P wave is absent.

SA block

E. Right atrial hypertrpohy :  P wave is tall

F. Left atrial hypertrpohy: P wave is tall and broad.

2. QRS complex:

It is causeed by potential generated when the ventrical depolarize before contraction i-e as the depolarization waves spread through ventricle
a. Purkinji system block:                                 When these fibers are bllocked the cardiac impulse must then be conducted by ventricle muscle instead of by way of the purkinji system. This decrease the velocity of the impulses conduction about 1/3^rd of normal. In purkinji system Block QRS complex are prolong.

B. Current of injury:

Many different cardia abnormalities specially those that damage the heart muscle cells itself, often cause part of the heart to remain partially or totallt depolarized all the time. When this occur curent flows b/w the pathologically depolarized and normally polarized areas even b/w heart beat. This is called current of injury. The effect of injury on heart muscle cause the random ECG especially QRS complex.

T wave : the T wave is caused by potential repolarization of ventricle after contraction.T wave become hyperaccute (Tall and broad) that reffer to acute myocardial ischemia, pericarditis, myocardial infraction.

P-R interval:

The distance b/w P and R waves  is very important for many diseases such as bradycardia in which heart is very slow less then 60 and the distance b/w P and R is large, and also in first degree heart block. 

The distance is very short in tachycardia , wolf- parkinson –white syndrome, duchene muscular dystrphy, lawn-levine syndrome and type two glycogen storage disease.

Ecg in tachycardia P-R interval is shortened heart rate is more then 100 per minute

Q-T interval :

This interval indicate the ventricular depolarization and ventricular repolarization. It is prolong in heper calcimia , hypocalcimia , myocarditis. It is shortened in isoelectric period.

S-T Segment:

S-T segment prolonged in hypocalcimia and it is shortened in hypercalcimia. The hypo calcim,ia is indicate the less amount of calcium, the calcium has important function in the contraction of cardia muscle. And Hypercalcimia mean large large amount of calcium. Variation in S-T segment that elevation occur in left bundle branch block anda cute pericarditis.

Written by Abid Abdullah
Student of First prof
Pharm-D

University of BAlochistan .
Hope it helped

Carbapenems resistance is threatning

CARBAPENEMS are a class of beta-lactum, broad spectrum antibiotics which act by inhibiting the cell wall synthesis and are known to be most effective against gram negative infections.

Carbapenems, often in combination with other agents, remain a mainstay of therapy in patients with serious hospital-acquired infection. 

Carbapenems can be grouped as (2),

Group 1 includes broad-spectrum Carbapenems, with limited activity against non-fermentative Gram-negative bacilli, particularly suitable for community acquired infections (e.g. ertapenem).

Group 2 includes broad-spectrum Carbapenems, with activity against non-fermentative Gram-negative bacilli that are particularly suitable for nosocomial infections (e.g. imipenem and meropenem).

Group 3 includes Carbapenems with clinical activity methicillin-resistant Staphylococcus aureus

Amongst these the most widely used Carbapenems include:

• Meropenum
• Imipenum +Cilastin

Mechanism of resistance

• The stability of the carbapenems against gram-negative pathogens, which are resistant to other beta-lactams, comes from the protection against AmpC beta-lactamases and the extended-spectrum beta-lactamases (ESBLs). These enzymes can be produced by a variety of gram negative organisms (ie E. coli, Klebsiella pneumoniae, Enterobacter spp. and Serratia marcescens).
• When comparing wild-type and ESBL producing strains of E coli or Klebsiella, they found no increase or a one dilution doubling in MIC₉₀. Ertapenem MIC₉₀ increased by two to three doubling dilutions for ESBL producing isolates and a four doubling-dilutions for AmpC beta-lactamase isolates. By the Clinical and Laboratory Standards Institute (CLSI) breakpoints, ertapenem still maintained susceptibility to these organisms. another scientist conducted a similar study observing AmpC beta-lactamase producing strains of Enterobacter spp. and Serratia marcescens. Similar results were found for imipenem/cilastatin, meropenem and doripenem as the previous study. This in vitro data suggest that ertapenem is less stable than the other carbapenems to the beta-lactamase enzymes and may confer resistance more rapidly in vivo.
• P. aeruginosa has become resistant to many of the beta-lactam antibiotics. It remains fairly sensitive to the carbapenems, excluding ertapenem. Ertapenem lacks pseudomonal activity and is a niche of this agent. P. aeruginosa is associated with increasing MICs of the imipenem, meropenem and doripenem but needs an AmpC beta-lactamase to become resistant. The mechanisms for the increase of MICs is associated with loss of the porin Opr D, combined with activity of chromosomal beta lactamase (Amp C); in addition, overexpression of multi-drug efflux pumps is considered to confer meropenem and doripenem resistance. Meropenem and doripenem are thought to maintain more antipseudomonal activity than imipenem/cilastatin because of the multiple mechanisms of resistance required to cause resistance to P. aeruginosa. Another consideration is the enzymes referred to as “carbapenemases.” These enzymes hydrolyse all penicillins and cephalosporins, but may also lead to rapid hydrolysis of carbapenems.
• Although the carbapenems spectrum of activity is broad, some gram positive organisms exhibit intrinsic resistance. Methicillin-resistant S. aureus (MRSA) and Enterococcus faecium have intrinsic resistance to the carbapenems. All the carbapenems have poor binding affinity for PBP 2a (found on MRSA) and PBP 5 (found on E. faecium). Imipenem/cilastatin and doripenem have more potent activity against gram positive aerobic bacteria. Imipenem/cilastatin also demonstrates lower MICs for E. faecalis compared with the other carbapenems.
• In clinical practice, it is relevant to consider the in vitro mechanisms of action and each agent’s mechanism of resistance. If treating a P. aeurginosa, which has demonstrated some resistance to other beta-lactam antibiotics, it is critical to monitor isolates for MIC “creeps” and be aware that some isolates may mount resistance to the carbapenems. Pathogens such as Stenotrophomonas maltophilia and Aeromonas spp., may also produce carbapenem resistant strains (ie due to production of metallo-beta-lactamases production). When treating polymicrobial infections, it is essential to remember the intrinsic resistance to MRSA and E. faecium to the carbapenems and choose other first-line gram positive antibiotics for these organisms.
  hope it helped you

Source

Protein Kinase and Cancer

Protein kinases are enzymes within cells that act by attaching phosphate groups to the amino acid residues of various proteins. This process of phosphorylation serves two primary roles: as a molecular on-off switch to trigger a cascade of cellular events and as a “connector” that binds proteins to each other. Therefore, protein kinases play a primary role in the complex signaling systems that transfer information between and within cells. They are generally classified into two groups:
A. Based on their specificity for target amino acids:
– Serine- or threonine-specific kinases— Catalyze the phosphorylation of groups on serine and threonine residues
– Tyrosine-specific kinases— Catalyze the phosphorylation of tyrosine residues
– Mixed function kinases— Catalyze serine, threonine, or tyrosine phosphorylation

B. Based on their structure and cellular localization:
– Receptor kinases— Defined by a hydrophobic transmembrane domain that passes through the plasma membrane, an extracellular ligand-binding domain, and a cytoplasmically located kinase domain. The extracellular ligand-binding domain is typically glycosylated and conveys ligand specificity.
The three main families are

1. erbB (HER)
2. platelet-derived growth factor receptor (PDGFR)
3. vascular endothelial growth factor receptor (VEGFR).

–> Other well-known receptors include IGF-1R, KIT, and mutant FLt-3 receptors.
– Nonreceptor kinases— Unlike the receptor kinases, these agents have no transmembrane or extracellular domains and may be associated with the cytoplasmic surfaces by membrane localization via a lipid modifi-cation that anchors them to the phospholipid bilayer or by noncovalent binding to a membrane receptor. Examples include the ABL, JAK, FAK, and SRC kinases.

FUNCTIONS OF PROTEIN KINASES
The function of protein kinases is to provide a mechanism for transmitting information from a factor outside a cell to the interior of the cell without the initiating factor having to cross the cell membrane. For example, growth factors and polypeptide hormones in the extracellular milieu can exert a regulatory effect on cells by activating specific gene transcription in the nucleus of target cells without passing through their cyto-plasmic membranes. By this mechanism, protein kinases help regulate cellular func-tions such as proliferation, cell-matrix adhesion, cell-cell adhesion, movement, apoptosis control, transcription, and membrane transport

ROLE OF PROTEIN KINASES IN CANCER

Protein kinases can play major etiologic roles in the initiation of malignancy and may contribute to the uncontrolled proliferation of cancer cells, tumor progression, and the development of metastatic disease. It is thought that cancer cells depend almost entirely on signaling by protein kinases for their continued proliferation, whereas normal cells rarely invoke these pathways.
Protein kinases can be altered in two main ways in tumor cells as described below.

• Mutations in Protein Kinases

A number of examples in which specific kinases have become mutated in cancer cells are known. For example, a mutation of the protein kinase ABL (i.e., BCR-ABL) is the etiologic agent in CML. The cytoplasmic tyrosine kinase BCR-ABL, which is constitutively active, is present in 15% to 30% of cases of adult acute lymphoblastic leukemia (ALL) and virtually all cases of CML. This mutation has been put to good use in the design of imatinib (kinase inhibitor). A second example can be found in patients with multiple endocrine neoplasia (type 2), in which mutations in RET tyrosine kinase may be responsible for development of the disease. Finally, EGFR mutations with enhanced kinase activity have been detected in several human tumor types.

• Overexpression of Protein Kinases

Expression of EGFR and its associated primary ligands epidermal growth factor (EGF) and transforming growth factor α(TGF-α) has been studied in several human malignancies with coexpression of EGFR and EGF observed to have both prognostic significance and a possible role in the pathogenesis of several human cancers. Specifically, overexpression of EGFR and EGF in several tumor types significantly reduces patient prognosis.
For example, members of the EGFR kinase family (EGFR, ErbB-2, HER2/neu, ErbB-3, and ErbB-4) are known to be overexpressed in some types of breast tumors. The HER2/neu RTK has been found to be amplified up to 100 times in the tumor cells of approximately 30% of cancer patients with invasive breast disease, and its presence is also associated with poor prognosis. Similarly, over expression of PDGF and PDGFR has been reported in meningioma, melanoma, and neuroendocrine cancers as well as tumors of the ovary, pancreas, stomach, lung, and prostate. Elevated levels of SRC kinase activity have also been noted in colon cancer specimens, implying that over expression may also be important in this disease.
Source : chemistry and pharmacology of anti cancer drugs 5.2 kinase inhibitors page 96
hope it helped you

Diabetes and deafness

Diabetics, who were warned for years that their illness could cause blindness, are in for more bad news, as doctors have claimed that the patients are more likely to lose their hearing, too.

Japanese research has found that hearing problems are far more common in diabetics than their healthy counterparts, even when other factors such as ageing and a noisy environment are taken into account, the Daily Mail reported.

Lead author of the study, Chika Horikawa of Niigata University, said: “We found that people with diabetes had more than two times higher prevalence of hearing impairment than those without diabetes.”

Several studies have investigated the relationship between diabetes and hearing impairment but their findings were inconsistent.

However, links have been made between hearing loss and other conditions such as dementia and depression.

“The association of hearing impairment with diabetes is controversial, but it is believed that over time, high blood glucose levels can damage vessels [causing hearing loss]” Horikawa said.

It’s thought that glucose damages the nerves and tissues in the ear, diminishing the ability to hear.

“Our results propose that diabetic patients be screened for hearing impairment from earlier age compared with non-diabetics, from the viewpoint of prevention of several health problems such as depression and dementia caused by hearing impairment,” Horikawa said.

Around a third of over-60s have significant permanent hearing loss, rising to about two-thirds of 70-year-olds.

American research published earlier this year found that women in particular are likely to suffer from hearing loss if they are diabetic and their condition is not well controlled with medication.

The findings are set to be published in the Journal of Clinical Endocrinology and Metabolism.

Copy pasted from Times of India.com

Dopamin ( A short Pharmacological review)

As a biogenic amine, 3, 4-dihydroxyphenylethylamine, dopamine belongs to a group of substances produced in the organism by de-carboxylation of amino acids. Besides dopamine and nor-epinephrine formed from it, this group includes many other messenger molecules such as histamine, serotonin, and γ-amino butyric acid.

Dopamine actions and its pharmacological implications.

In the CNS, dopamine serves as a neuro-mediator. Dopamine receptors are also present in the periphery. Neuronally released dopamine can interact with various receptor subtypes, all of which are coupled to G-proteins.

Two groupings can be distinguished:

• The family of D1-like receptors (comprising subtypes D1 and D5)
• The family of D2-like receptors (comprising subtypes D2, D3, and D4).

The subtypes differ in their signal transduction pathways. Thus, synthesis of cAMP is stimulated by D1-like receptors but inhibited by D2-like receptors.

Released dopamine can be reutilized by neuronal reuptake and re storage in vesicles or can be catabolized like other endogenous catecholamines by the enzymes MAO and COMT.

Various drugs are employed therapeutically to influence dopaminergic signal transmission.

• Antiparkinsonian agents:

In Parkinson disease, nigrostriatal dopamine neurons degenerate. To compensate for the lack of dopamine, use is made of L-dopa as the dopamine precursor and of D2 receptor agonists.

• Prolactin inhibitors:

Dopamine released from hypothalamic neurosecretory nerve cells inhibits the secretion of prolactin from the adenohypophysis. Prolactin promotes production of breast milk during the actuation period; moreover it inhibits the secretion of gonadorelin.

D2 receptor agonists prevent prolactin secretion and can be used for weaning and the treatment of female infertility resulting from hyperprolactinemia.

The D2 agonists differ in their duration of action and, hence, their dosing interval; e. g.

• Bromocriptine 3 times daily,
• Quinagolide once daily,
• Cabergoline once to twice weekly etc

• Antiemetics:

Stimulation of dopamine receptors in the area postrema can elicit vomiting. D2 receptor antagonists such as metoclopramide and domperidone are used as antiemetics.

In addition they promote gastric emptying.

• Neuroleptics:

Various CNS-permeant drugs that exert a therapeutic action in schizophrenia display antagonist properties at D2 receptors; e. g., the phenothiazines and butyrophenone neuroleptics.

Dopamine as a therapeutic agent

• When given by infusion, dopamine causes a dilation of renal and splanchnic arteries that result from stimulation of D1 receptors. This lowers cardiac after load and augments renal blood flow, effects that are exploited in the treatment of cardiogenic shock. Because of the close structural relationship between dopamine and nor epinephrine, it is easy to understand why, at progressively higher doses, dopamine is capable of activating β1-adrenoceptors and finally α1-receptors.
• In particular, α-mediated vasoconstriction would be therapeutically undesirable (symbolized by red warning sign). Apomorphine is a dopamine agonist with a variegated pattern of usage. Given parenterally as an emetic agent to aid elimination of orally ingested poisons, it is not without hazards (hypotension, respiratory depression). In kinetic motor disturbances, it is a backup drug.
• Taken orally, it supposedly is beneficial in erectile dysfunction.

Source : Color Atlas of  Pharmacology (3rd edition,) revised and expanded
Heinz Lüllmann, M.D.

Hope it helped you

Regards Admin