DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM

Histamines and antihistamines:
Histamine means tissue amine and is present in ample amount in the lung, skin and GI tract mucosa. Mast cells, basophils and platelets contain histamine in an inactive bound form. It is derived from the aa histadine by decarboxylation. Two functions are : control of microcirculation and secretion of HCl from the parietal cells of the stomach. It causes vasodilation. This can help in an immune response where the inc in capillary permeability can help in the movement of immunocompetent  cells and other immunological mediators to the site of injury.

Local release of histamine in the nasal pathway due to the stimulation by a pollen grain can lead to hayfever.
Release of histamine in the skin due to an insect bite can lead to urticaria.
Destruction of many cells by some cause can also lead to a release in the amount of histamine.

Histamine reacts with receptors to cause a response. Two types of receptors have been identified and are h1 and h2. the h1 receptor is found in the smooth muscle of the bronchioles and exocrine glands of the respiratory tract. The h2 receptor is found in the parietal cells of the stomach. Both the receptors are found in the CNS and heart, where the h2 receptor has a positive chronotropic effect whereas the h1 has both positive chronotropic and inotropic.

Chronotropic: something that alters the rate of heart beat
Inotropic: something that alters the force of contraction of the heart.

The term antihistamines are used for H1 blockers or antagonists. And for the h2 receptor there is the h2 blocker or antagonist. They not only block the histamine receptor but also inhibit the release of histamine from the mast cells. Initially all histamines were able to cross the bbb hence had the sedative effect. The main side effect being dry mouth and sedation. These are mainly used to treat allergies and anaphylaxis reactions.

Antiemetics: to treat Nausea and Vomiting:

Whatever be the cause of nausea and vomiting the vomiting center in the brain is involved. The treatment of this condition depends on the cause. Many of the cases of nausea and vomiting is a protective function of the Chemoreceptor Trigger Zone (CTZ) responding to a therapeutic drug. The ctz situated near the vomiting center in the medulla is protected by the bbb. Due to both a mechanical or a chemical stimulation of the GI tract vomiting can occur and both of these are protective mechanism.

Drugs used to treat Nausea and vomiting:
To treat vomiting suppositories are convenient whereas in the case of nausea the cause is determined and is prevented then being cured. When nausea and vomiting is due to the psychogenic factors involving the cortical center of the brain the use of benzodiazepine is useful as a sedative.

Antimuscarinic drugs:
The only antimuscarinic drug used to treat against emetics is hyoscine and is used in the treatment of motion sickness. It is available in various forms and is an effective way of treatment. It has a long lasting effect.

Antihistamines:
Any antihistamine will have an antiemetic property although only a few are used. They are better than antimuscarinic agents. They can be used for travel sickness and at the same time for other type of nausea such as Menieres disease and labyrinthitis. It can cause drowsiness which can be troublesome.

Phenothiazines:
In practice the only phenothiazine that is used is prochlorperazine and is mainly used to treat against motion sickness. It can cause extrapyrimidal symptoms and oculogyric crises as an adverse reaction. The drug induces photosensitivity if taken more than 4 times in 24 hours.

Metoclopramide and domperidone:
They reduce the stimulation of the CTZ and as a result prevent nausea and vomiting, they also inc the rate of gastric emptying and dec the sensitivity of the receptors in the pharynx and upper gut to noxious stimuli.

The setrons: ondansetron: are serotonin antagonists that are highly effective for 5 – HT3 receptors found on the afferent fibers of the vagus nerve and in the brain associated with the ctz. These receptors when blocked help to control chemically induced vomiting and nausea. These are used in controlling the vomiting associated with cytotoxic drugs. These are relatively free of side effects except for a mild transient headache and sometimes may cause diarrhea or constipation.

Nausea and vomiting In pregnancy is common in the first trimester and can be extended too. It is best treated with ginger and or pyridoxine but this has an implication of being teratogenic. The best used drug is an antihistamine doxylamine.

Drugs used to induce vomiting include emetine which is the active ingredient of ipecacuanha. It induces vomiting by irritating the upper gut and on absorption acts on the ctz.

Nausea and vomiting can occur whenever the stomach is overly irritated, stimulated or distended and are common non – specific features of disease or drug toxicity.

Drugs to know:
Metoclopramide - Dopamine antagonist
Chlorpromazine – phenothiazine
Prochlorperazine – phenothiazine
Promethazine - Antihistamine
Atropine - antimuscarinic
Odansetron – steron

There are specific receptors present in the two centers in the brain, in the vomiting center there are the muscarinic receptors and H1 receptors that are present and these are triggered when Ach and histamine bind to them respectively. In the CTZ there are the dopamine receptors and the 5HT3 receptors and these will be stimulated when dopamine and serotonin bind to them respectively leading to the trigger of the vomiting center leading to the emesis. The 5 HT3 receptors are also present in the pharynx, biliary tree and intestine.

Antiulcer drugs and antacids: upper GI tract drugs:
The most common problem associated with the stomach is the secretion of excess acid. the stomach is well protected with the mucosal cells from the acid and proteinase pepsin. When there is a damage of the mucosal layer erosion can occur in the gastric mucosa leading to a gastric ulcer. When this acid enters the duodenum it  can cause duodenal ulcer. In some cases there can be further erosion and the fluid can leak into the peritoneal cavity leading to life threatening peritonitis. When the acid enter the oesophagus a burning sensation is felt and this is commonly termed as a heart burn and is treated with an antacid.

Antacids:
Mechanism of action: are weak bases which readily combine with the HCl and neutralize it. They also raise the pH of the stomach and over a pH of 4 pepsin is inactive. There are usually basic compounds of Al, Na, Ca, Mg and K. normally used are AlOH and MgCO2 in combination. These are mixed in a correct proportion to nullify the effect of al causing constipation and mg acting as a laxative. E.g. hydrotalcite.

Aloh complexes with phosphate in the gut and is useful in the treatment of hyperphosphatameia that can result from renal failure. It can lead to hypophophatemaia.
Mgtrisilicate is found in some antacids and when neutralized with HCl produces a viscous jelly which is said to coat and protect the peptic ulcer promoting healing. When used alone it is not very protective.
Calcium carbonate: is used in several antacids and overuse can lead to high level of ca in the blood but cant cause hypercalcaemia, these can over a long period of time lead to calcification of the soft tissue and the development of kidney stones.

Sodium bicarbonate: baking soda: the release of carbon dioxide from the neutrilisation of sodium bicarbonate can lead to burping which many think to be a cure. The use should not be encouraged as sodium can exacerbate the pre – existing conditions of hypertension and also can lead to alkalosis by excessive absorption of bicarbonate ions.

Alignates: Gaviscon, Mylanta plus, meracote, aligcon: these are derived from a seaweed and when they react with the acid they form a jelly like substance that floats on the aqueous solution. This property gives these antacids the name raft antacids. It floats upto the top and prevent s a gastric reflux but in some positions it might float upto the cardia of the stomach and prevention of a gastric reflux will be tough.

Oxethazaine: is a local anaesthetic that is included in the preparation of the antacid Mucaine and is useful when the antacid alone do not relieve the pain of indigestion.

Cisapride: it is useful in the treatment of the UGI tract conditions caused by motility problem such as reflux oesophagitis and gastroparesis.
It is termed as a prokinetic drug as it accelerates the movement of the material through the stomach and the upper GI tract. It is highly selective cholinergic agent and works on the myenteric plexus and inc the release of Ach and this in turn stimulates the movement of the gut.

Peptic Ulcer:
There are three receptors in the stomach that needs to be stimulated for the production of acid they are H2 histamine receptor, muscarinic cholinergic receptors and gastrin receptors. Gastric ulcers are mainly due to a defect in mucus production whereas duodenal ulcers are due to excessive acid production. The use of colloidal bismuth in combination of two antibacterials for the treatment of gastric ulcer due to the cause of a bacteria is known as triple therapy.

Histamine H2 receptor antagonist:
Acid secretion is by the stimulation of the h2 receptor and hence an antagonist to this will prove to be helpful. E.g. Cimetidine there is a high relapse rate after discontinuation of the drug. Most common side effects are muscular pain, headache, dizziness.
It can slow down the metabolism of other drugs, resulting in an enhanced action
Other three H2 antagonists are ranitidine, nizatidine and famotidine. Similar to cimetidine but have no antiandrogenic activity.

Proton Pump Inhibitors:
The formation of HCl depends on a supply of hydrogen ions being produced in the parietal cells and these drugs stop this from happening. Omeprazole being the prototype. As a non - competitive inhibitor of the gastric ATPase enzyme they have a relatively long duration of action inspite of their short half lives. They need an acidic environment to be active hence act only in the stomach.

These drugs lead to hypochlorhydia which leads to an inc gastrin secretion. Can be considered as destroying the body defence mechanism against infection.

Prostaglandins:
Action of pg on the digestive functions are:
Inhibition of gastric acid pdtn, gastrin pdtn, pepsinogen pdtn, stimulation of mucus secretion, bicarbonate secretion and inc in mucosal blood flow.
The pg analogue misoprostol is the one usually considered and has been useful where the h2 antagonists have not been very useful. It can cause diarrhea, and can have some effects on the uterus where it can cause menorrhagia.
It is contraindicated in pregnancy as it can induce premature labor by increasing uterine contraction.

Sucralfate:
Is a complex of the sugar sucrose and an Al compound. Acts only in the presence of acid. It polymerises to form a thick – paste like substance which adheres to the gastric mucosa and protects it from the acid. its adverse reaction is constipation as it is poorly absorbed.

Drugs to know:
H2 receptor antagonist – cimetidine, nizatidine, ranitidine
Proton – pump inhibitor – omeprazole
Antacids – aloh, mgoh
Bismuth compounds
Sucralfate
Misoprostol – pg
Antibiotics necessary for the treatment against H. Pyroli

Anti – diarrhea drugs and laxatives:

 Laxatives: also called as aperients or purgatives. Prolonged bowel movement as in weekly cannot be termed as constipation if there is no pain associated with it and hence there is no need of a laxative, but when there is much pain associated with the bowel movement then it is termed as constipation and may require the use of laxatives.
Many drugs like antimuscarinic agents can slow down the bowel movements and lead to constipation. Narcotic analgesics can stimulate the mixing movement and as result of which there can be more water reabsorption leading to constipation.  Prolonged constipation can lead to impacted faeces.

Osmotic Laxative: act by physical mechanism. Small molecules are inefficiently absorbed by the small intestine thus creating a stronger solution in the colon where lot of water reabsorption takes place. The contents are hypertonic causing the water to be retained and if the osmotic pressure is great can pull the water from the bowel capillaries back into the bowel lumen , as a result there is a rise in the pressure and volume in the colon and rectum leading to stimulation of defecation. E.g. salts of magnesium and sodium, Epsom salts. These laxatives are contraindicated in persons with renal pathologies since there can be absorption and accumulation of the ions in the blood.

Carbohydrate osmotic laxatives:
Some sugar derivatives are not absorbed from the gut and hence can have an laxative effect. Lactulose a derivative of lactose is one of them. Some of this is metabolized by the bacterial flora of the gut into various acidic compounds which can also have a stimulant effect on the bowel walls. Glycerol when given as a suppository can also have an osmotic effect. Sorbitol also.
Flatulence and abdominal discomfort can occur with lactulose. And sorbitol can lead to diarrhea if consumed in excess.

Miscellaneous agents: used to completely empty the bowel prior to surgery. These contain large amounts of polyethylene glycols and non – electrolytes in combination with equivalent amount of normal electrolyte such as K, Na and Cl ions. This solution is isotonic and promotes no nett loss of electrolyte or of water but effectively cleans the bowel.

Stimulant laxatives: these have a direct effect on the walls of the small and large intestine and cause an increase in the peristaltic effect leading to defecation. Theories postulated include:
Interference with an enzyme system involved in ion transport
Inc the concentration of intestinal fluid leading to an osmotic effect.
Prevent water reabsorption into the colon and may promote water excretion directly from the intestinal cells into the lumen.
Irritate the smooth muscle of the intestinal walls leading to defecation

Adverse reaction is rebound constipation and this is since the intestine are strongly stimulated and then when the normal food stimulates it is not enough for the brain to cause enough bowel movements.
e.g. Bisacodyl – related to phenolphthalein
Castor oil -  not used much today – to be metabolized to ricinoleic acid that can stimulate the smooth muscle and act as a intestinal irritant.
Sennosides – group of plant pdts.

Faecal Softeners:
Also known as emollients, surfactants or stool softeners.
Sodium dioctyl sulphosuccinate – docusate. This compound has detergent – like properties and seems to act to hold the water molecules in the faecal material thus rendering them softer and easy to pass.
Poloxalkol – is an non – ionic complex organic polymer and having similar properties to the former.
These might have some stimulant properties. And they can enhance the activity of the drugs administered concurrently with them. They take several days for their action to be noticed. Can be hepatotoxic.

Lubricants: include mineral oil namely liquid paraffin. Physical action and the oils are relatively inert. Its mode of action is that it coats the intestinal mucosa and there by prevents the absorption of water, and hence its stool softening effect. It can interefere with the absorption of fat soluble vitamins.

Anti – diarrhea drugs:
Diarrhea is defined as an inc in volume, fluidity or frequency of bowel movements relative to the usual pattern for a particular individual. First line of treatment is rehydration and electrolyte replacement therapy.
Antibiotics are not used unless the cause is well identified. Travelers diarrhea is caused by a unknown strain of E. Coli and in some cases doxycycline or ciprofloxacine are recommended. The drugs used in the treatment of non – specific diarrhea usually slow down GI motility or help absorb the excessive fluid present in the colon.

Non – specific anti – diarrhoeal drugs:
Opiods: most of the narcotic analgesics can act on the opioid receptors in the gut and inc the mixing movement of the gut and simultaneously dec the peristaltic movement. This results in the slow down of the forward movemet, improved reabsorption and as a result inc viscosity correcting the diarrhea. Very low doses are needed hence chances of addiction are low. Codeine as a syrup is used. Morphine is also used. Lomotil is mixed with atropine to counterindicate the euphoric effect of the the narcotic. Loperamide is a synthetic narcotic which is used but since it does not cross the bbb it has a very low potential to be abused. Adverse effect : constipation associated with nausea, vomiting and abdominal cramping.

Adsorbents: bismuth salts, kaolin and pectin have the ability to absorb bacterial toxin that might be implicated in causing diarrhea.

Drugs to know:
Loperamide – immodium
Atropine
Kaolin
Methylcellulose bran
Lactulose
Senna
Docusate sodium
Phenolphthalein

DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM

The brain is responsible for all affective and cognitive process and is capable of coordinating corporeal functions. Sometimes there can be an imbalance in the mental functioning and can result in some of the disorders. The drugs used to treat the disorders are called psychotropic drugs, the mechanism of action is not well understood. These drugs act on chemical transmitter – receptor system within the brain.

Divisions of the brain:
1. Cerebrum consists of the two cerebral hemispheres, the cortex and the associated sub – cortical nuclei.
2. Diencephalon consisting of the thalamus and the hypothalamus.
3. Brain stem and the cerebellum where the brain stem consists of the mid brain, pons and the medulla oblongata and the cerebellum is posterior located between the pons and medulla.

Cerebrum: is responsible for precise perception, interpretation of sensation, initiation of skeletal muscle movement and communication. It is also the seat of intellect and abstract thought

Diencephalon: the thalamus acts as a relay center for the incoming sensory signals sort them and send them to the appropriate regions of the cortex for processing. It also relays motor impulses from the cortex to the lower motor centers. The hypothalamus is involved in visceral functions such as body temp, appetite, hormone pdtn and secretion, fluid levels and biological rythms.

Cerebrum – diencephalons interactions: these corporate in memory functions as well as in the control of the emotions and behaviour. This system is known as the limbic system and includes area of the cortex, hippocampus, amyglada, fornix, thalamus and hypothalamus.
Brain stem: acts as conduction p/w between the higher and lower centers of the brain of both the sensory and motor info. The medulla oblongata contains control centers for important   visceral functions such as heart rate, bp, respiratory center coughing and vomiting.

Brain stem – diencephalons – cerebrum : the brains stem , thalamus and the cortex cooperate and control level of consciousness by a system called the reticular activating system.

Cerebellum is involved in the maintenance of equilibrium and posture.

Motor pathways incorporate two discrete system: pyramidal and extrapyramidal p/w. The pyramidal p/w is responsible for the activation of skeletal muscle whereas the extrapyramidal p/w dampens and adjust voluntary muscle movement. It is also involved in the maintenance of muscle tone and balance as well as being concerned with the coordinated movement of the head and eye towards a visual stimuli.

Chemical transmitters:
Noradrenalin
Adrenalin
Serotonin
Dopamine
Ach
Glutamate
Gamma aminobutyric acid.
Glycine and histamine have also been found.
These are involved in the function of neurotransmission and may also act as neuromodulators.

Neuromodulation: they alter the response of a nerve cell or a nerve circuit to its neurotransmitter to either enhance or suppress impulse transmission.

Ach: is thought to play a major role in cognitive functions and memory formation as well as motor control. Cholinergic nerves are associated with the pyramidal p/w. the motor p/w are essentially nicotinic whereas in cognitive function memory and consiousness, M1 muscarinic receptors predominate.

Dopamine: Behaviour, hormone release, motor control and emesis. Areas of the brain where dopaminergic receptors have been found are limbic system, extrapyramidal p/w, the ctz in the medulla and the p/w connecting the hypo and pituitary gland. There are four receptor subtypes that have been found.

Noradrenaline and Serotonin: involved in arousal, sleep, mood, appetite, termperature control and hormone release. Noradrenalin can stimulate the alfa and beta adrenergic receptors. There are two subtype receptors of serotonin found in the brain.

GABA: is distributed throughout the brain and the spinal cord. It is a major inhibitory nt and helps to modulate the excitatory p/w. it is formed from the excitatory nt glutamate. There are two types of receptors. Motor control, arousal, memory formation and consciousness are all inhibited by gaba. GABAa receptors are associated with the Cl ion channels and GABAb is associated with the k and ca channels. Activation of the GABAa receptor induces chloride ion influx into the neuron. This hyperpolarizes the neurons and makes it difficult to fire when stimulated by excitatory nt like glutamate. Drugs that enhance the action of GABA are used as sedatives and muscle relaxant.

Glutamate: distributed throughout the cns. It can be stimulated by a number of receptors such as NMDA, AMPA and kinate. It also performs a modullatory function on the cns.
Opioids are also nt present in the brain and in the rest of the body.

The drugs involved in the treatment of disorders containing the cns are antipyschotics, antidepressants, anxiolytics, hypnotics, sedatives, muscle relaxants, anticonvulsants, antiparkinsonian and CNS Stimulant.

How do Nt work?
Nt are made in the neurons and are stored in the synaptic vesicles, when the neuron is stimulated these nt are released from the vesicle into the synaptic arch between the two neurons or the effector tissue. Then the nt crosses the synapse and binds to the specific receptor triggering a response or act to pass on the message. Excessive nt are removed from the synapse either by a proton pump or by enzyme degradation.

Nt disease can occur either when there is too much neurotransmission or there is not enough of it.

Too much: means that the neurons are excited all the time e.g. seizures disorders e.g. psychosis

Too little: e.g. depression and parkinsonism.

When too little nt is present the drugs can be designed in the following way:
1. agonists
2. can be precursors for nt
3. can inhibit nt from being broken down
4. can inhibit the reuptake of nt.

When too much
1. anatagonist
2. can enhance the action of the inhibitory transmitters such as GABA or inhibit the action or release of the excitatory aa like glutamate.

Drugs and Parkinson’s Disease:

Some of the degeneration of the nervous system is caused genetically and other is due to an autoimmune system being triggered. There is progressive deterioration which is irreversible. Treatment is supportive and not curative.

Parkinson Disease:

It is characterized by a distinctive tremor of the extremities and head as well as difficulty in the coordination of fine muscle movements. The other imp feature is called hypokinesia an inability or slowness in initiating movement.

The defect in the PD is in the basal ganglia portion of the midbrain. On the corticospinal p/w there are muscarinic cholinergic fibers that are excitatory pyramidal p/w and there is another p/w thru the basal ganglia called the nigrostratial p/w which contains inhibitory dopaminergic fibers of the extrapyramidal p/w. There is always a homeostatic control between the excitatory muscarinic and inhibitory dopaminergic activity. In PD the dopaminergic fibers degenerate and as a result there is less depaminergic activity and excessive muscarinic activity. There are two methods that can be used to treat this:
Decrease the muscarinic activity
Increase the dopaminergic activity.

Decreasing the Muscarinic Activity: these help to control tremors and rigidity though they are not of much help in hypokinesia. By inhibiting the muscarinic receptors in the basal ganglia the imbalance between the pyramidal and extrapyramidal p/w will be reduced. They have unwanted antimuscarinic side effects like micturition, hallucination and confusion which are undesirable in the elderly.
e.g. benzotropine, biperidine, procyclidine and orphenadrine.
These are the drugs useful in the treatment of secondary parkinsonism.

Increasing the dopaminergic activity.

Increasing dopamine levels:
Levodopa: dopamine on its own does not cross the bbb. The immediate precursor of dopamine called levodopa or L – dopa can cross the bbb and then can be converted to dopamine.
It has some serious effects since it is converted into dopamine even by the peripheral mechanism. The enzyme that converts levodopa to dopamine is a decarboxylase. There are several inhibitors of this enzyme and of this two cannot cross the bbb and they are carbidopa and benserazide. By addition of any one of these compounds the peripheral conversion of levodopa is inhibited and thus allowing more levodopa to cross into the cns. This can reduce the side effects that are caused. Side effects include : nausea, depression, involuntary muscle movements of the extremities, head, lips and tongue, agitation and confusion, increased sexual activity, hypotension, delusions and dsyrythmias. The effect of levodopa decreases with time until no effect is produced. As the years proceed the drug dosing has to become more frequent. This progressive loss of drug activity is due to the continuous degeneration of the dopaminergic neurons.

Other peripheral inhibitors of levedopa conversion.
Entacapone and tolacapone belong to a class of COMT ( Catechol – O – methyltransferase) inhibitor. These enzymes are present in the synapse and are involved in the metabolism of certain nt belonging to the catecholamine group. These do not cross the bbb and therefore produce only a peripheral effect. Clients should be told that the urine may be reddish – brown during treatment. Inc in the liver enzymes and neuroleptic malignant syndrome can occur though very rare. The treatment with decarboxylase inhibitors with levodopa and COMT inhibitors enhances the effect of levodopa to a great extent but liver function should be monitored.

Inhibit the breakdown of Dopamine. This is done so as to achieve prolonged action of dopamine. MAO is an enzyme which is responsible in the degradation of noradrenaline as well as a dopamine and hence drugs used to inhibit the action of MAO are called MAOI’s and are also a class of antidepressants. This will result in a rise of the dopamine level. Care should be taken for drug – drug interaction and dietary restrictions. The enzyme present in the brain is different from the rest of the body and is termed as MAOb and Selegiline is an MAOb inhibitor. If given concurrently with levodopa smaller doses can be administered. Dry mouth being the only possible side effect. But dyskinesias can occur.

Stimulate the release of Dopamine:
Amantsdine inhibits the uptake of dopamine and increases and stimulates the release of dopamine. It also has a slight antimuscarinic effect. It by itself is not so potential but it can enhance the potential of levodopa or other antimuscarinic agents. It can cause postural hypotension, ankle oedema, insomnia, hallucinations. It is useful in diminishing tremors in the early stages of the disease.

Mimic Dopamine Action:
Bromocriptine can be termed as a dopamine agonist. Best use in conjunction of levodopa. Lisuride, cabergoline are drugs similar to bromocriptine and are derivatives of ergotamine.
Apomorphine is a non – ergot derivative but it is a derivative of morphine and is used in the treatment since it mimics dopamine.
They mimic dopamine on the pyramidal p/w by stimulating the dopamine receptors.
Side effect is nausea. Lisuride can cause hallucinations, delusions and confusions. Other side effects are vomiting, diplopia and dysrythmia.

Drugs to know:
Levodopa – addition of dopamine
Sinemet ( Levodopa + carbidopa)
Bromocriptine  - dopamine agonist
Benzotropine(Cogentin)
Orphenadrine

Antipsychotic Drugs:

There appears to be a disturbance in the catecholamine in the cns leading to disease like schizophrenia, severe agitation and some forms of dementia. Drugs used to treat pschoses are generally dopamine antagonist which rebalance the system but does not induce a cure. Some of the dopamine antagonist are very specific for the D2 receptor in the brain where the defect appears to be located.

The cause of schizophrenia is a mystery but can be determined genetically or is induced by the inc dopaminergic activity in the brain. Antipsychotic drugs either have a direct effect on the D2 receptors and are termed as typical, or the ones that have less affinity for the D2 receptors and are termed as atypical.

Typical Antipsychotics:
Also called neuroleptics or major tranquillisers. The three common ones are phenothiazines, butyrophenones and thioxanthenes.  Their mode of action remains unelucidated. Their main action is to antagonize dopamine but they also have an antimuscarinic antihistaminic and antiseritonergic action as well as are alfa blockers. This inc their range of adverse effects.
E.g. of phenothiazine – metoclopramide, chlorpromazine
Adverse reactions: Extrapyramidal effects are often seen. There are four types:
1. drug induced parkinosonian symptoms
2. dystonic reactions which include facial grimacing, wry neck and spasticity of the limbs.
3. There is akathisia with restlessness being the most common.
4. there is tardive dyskinesia which severly affects muscle coordination. Occurs after prolonged treatment.

Rare but a serious result of an antipsychotic is neuroleptic malignant syndrome. This treatment involves the administration of a dopamine agonist like dantrolene and bromocriptine.

Dopamine antagonists can also cause lactation and when it is not post partum it is called galactorrhoea and it can also lead to gynaecomastia in the males. It can cause amenorrhoea in females and loss of libido in males.

When the phenothiazines accumulate in the skin they can result in abnormal pigmentation, skin rashes or utricaria. Also can induce photosensitivity.

Phenothiazines can be used to treat short term severe anxiety.
Antipsychotic also have the antiemetic properties and sometimes can make it difficult to evaluate the effect of other drugs causing nausea.

The thioxanthenes such as flupenthixol and zuclopenthixol are parenteral agents and have mood – elevating properties and can be given to flat patients or depressed.  Thiothixene is an thioxanthenes which is used in the treatment of schizo and has been good.

Atypical antisychotics:
These are less pronounced to producing extrapyramidal effects and this is due to their having differences in their affinities for various central receptors. These also have a tendency to cause weight gain. Chemical groups such as
Benzamides - amisulpiride
Benzisoxazoles ( Risperidone)
It is a selective antagonist for 5 – HT2 and D2 receptors. No affinity for the muscarinic receptors. Its affinity for the 5 HT2 receptors may be responsible for its having a lesser incidence of extrapyramidal effects as compared to other D2 receptor antagonist.

Dibenzodiazepines: Clozapine which is a dopamine antagonist and acts on the D1 and D4 receptors and not on the D2 receptor. It also has sympatholytic, antimuscarinic, antisertononergic, antihistaminic and arousal inhibiting effect.
It causes irreversible neutopenia a type of agranulocytosis.

Drugs to know are:
Chlorpromazine – typical
Fluphenazine – typical depot
Haloperidole – Typical
Clozapine – atypical
Olanzapine – “
Risperidone – “

Antidepressants and Mood stabilizers:

Depression is a state of profound sadness or melancholy. It includes lethargy, apathy, loss of appetite, insomnia, feeling of worthlessness, personal neglect and suicidal tendencies.

There are three types of depression:
1. Which occurs either in response to a life crisis or an adverse reaction.
2. Endogenous form
3. Bipolar affective disorder or manic – depressive state.

There is a link between the levels of the two brain nt NA and 5 HT and the depressed state. There is a depletion of the nt. The action of the antidepressant is aimed at inc the level of either one or both of these nt.
The purpose of the presynaptic receptor is to prevent the overstimulation of the postsynaptic receptor.

The major groups of antidepressants are:
1. Tricyclic Antidepressants TCA
2. Selective serotonin reuptake inhibitors SSRI
3. Monoamine oxidase inhibitor MAOI
4. Reversible inhibitors of Monoamine oxidase RIMA
5. Tetracyclic antidepressants
6. Noradrenalin – serotonin reuptake inhibitors (NSRI)
7. Selective serotonin receptor blockers
8. Selective noradrenalin reuptake inhibitors.

1. TCA: imipramine, amitriptyline, doxepin: they have got their name because of the three ringed structure of the drug molecule itself. The drug primarily acts by inhibiting the amine uptake pump on the presynaptic terminal and as a consequence the level of the nt inc. they are not termed as cns stimulant since they do not have stimulatory effects in a person who is not depressed. They have antimuscarinic, antihistaminic and antiadrenergic activity as a result they can lead to dry mouth, blurred vision, constipation, urinary retention and tachycardia. There can also be confusion and sedation. Also postural hypotension can be present. There is a major chance of individuals suffering from erratic moods and suicidal tendencies are at a greater risk of poisoning themselves. The bp needs to be monitored. The dose should be given at bedtime to assist compliance. They are not the first choice of drug treatment.

2. SSRI’s: Fluoxetine, paroxetine,sertraline, fluvoxamine,escitalopram and citalopram. They are considered as the first line of treatment for major depression. These block the amine reuptake pump but selectively affect only the serotonin reuptake and as a result there is an inc in the level of serotonin. They do not have muscarinic, histamininc and adrenergic affinity and hence they have comparatively lower side effects. They are non – sedative and also are not cns stimulants. The common side effects associated are headache, nausea, vomiting, tremor, insomnia, dizziness and diarrhea. There has been a fatal disease that has developed with the use of these and that is serotonin syndrome which can develop and this occurs due to hyperserotonergic state characterized by euphoria, drowsiness, abnormal muscle movements, sweating, intoxication, hyperthermia, diarrhea, loss of consciousness and possible death. These should not be given with TCA but should be accompanied with the MAOI or lithium carbonate.

3. Tetracyclic Antidepressants: Mianserin, maprotiline and mirtazapine are tetracyclic in their molecular structures. These are known as second generation antidepressants are also used in the first line therapy of drug treatment.
These act by blocking the presynaptic alfa 2 receptors and as a result there is an increase in the level of the nt.  Common adverse effects include headache, drowsiness, dry mouth and fatigue.  There is a risk of hematological toxicity and are contraindicated in cases such as heart or bladder disease.

4. MAOI – Irreversible and non – selective:
These act at the synaptic level by preventing the degradation of the nt by the MAO after its release. These include phenelzine and tranylcypromine. These are irreversible inhibitors. The side effects are less severe as compared to TCA but do include antimuscarinic and antiadrenergic effects. MAO is an enzyme which is used to metabolise tyramine. Tyramine is taken up by the amine pumps and result in a release of noradrenalin which is then broken down by the MAO enzyme when MAOI are used this breakdown is not possible and hence when food rich in tyramine is consumed it can lead to an excess of NA in the periphery and hence can cause life threatening cardiovascular stimulation.

5. RIMA’s: there are two isoforms of the enzyme MAO found. MAO type A is found in the brain, peripheral adrenergic nerve and the placenta and is involved in the breakdown of NA and 5ht. whereas MAO type B is found in the liver, brain and platelet and is involved in the breakdown of dopamine. Type A inhibitor is Moclobemide and is a competitive inhibitor of type A MAO and its effects are reversible. Common adverse rxn are nausea, dizziness and insomnia. Since it is a low toxic drug it has been included in the first line therapy of treatment.

6. NSRI: Venlafaxin: it is a phenythylamine and its mechanism of action closely resembles TCA. It basically blocks the uptake of NA and 5ht and to some extent also dopamine. Adverse rxn include nausea, headache, anorexia, sedation and dizziness.

7. SNRI’s: Reboxetine: this blocks the reuptake of NA but does not affect the uptake of serotonin and dopamine. Common Adverse reaction include headache, dry mouth, tachycardia, hypotension, urinary retention, constipation and insomnia.
8. Selective Serotonin Receptor blocker: Nefazodone: its action involves the inhibition of serotonin reuptake presynaptically and this would potentiate the level of serotonin in the brain. It also blocks the 5 HT2 receptors.

Mood stabilizers: mania is the opposite of depression and is characterized by an elevation of mood, lasting more than a week. The affected person is hyperactive and talkative. Inc experience of insomnia, inc sexual drive, and an inc flow of thoughts and ideas. There is also an inc in the synaptic level of noradrenaline. The person often suffers from cycles between mania and depression. When cycles occur more than four times a year it is known as rapid – cycling bipolar affective disorder. The best agents are lithium carbonate, carbamazepine and sodium valporate.

Lithium Carbonate: is mainly used to prevent mania and cyclic depressive states. Lithium has been known to enhance the action of the amine reuptake pump and hence also inhibit the release of noradrenaline. This results in dec of the nt within the synapse. It has a narrow therapeutic index and hence clients need to be monitored properly. It can cause Gi irritation, tremor, muscle weakness and polyuria. Due to its narrow therapeutic index there can be an exacerbation and can lead to tinnitus, blurred vision, ataxia, muscle twitches and altered consciousness.

Carbamazepine and sodium valporate are useful in the treatment of bipolar affective disorder. Their exact mechanism of action is unknown however it is thought to enhance the activity of the GABA

The common side effects of the TCA and MAOI include anti – cholinergic effects such as dry mouth, blurred vision, constipation , problem in voiding urine and tachycardia. Antihistaminic effect  - sedation and confusion. Antiadrenergic effect – postural hypertension.

Anticonvulsants or antiseizure drugs:

These are used in the treatment of seizures and in a particular the condition characterized by recurrent seizure – epilepsy.

A seizure is the manifestation of an intense transient electrical discharge across the surface of the cerebral cortex. Can involve only one area and is called focal or can arise at different parts of the cortex and is called diffuse. Cause can be either a biochemical imbalance or a structural abnormality.

Antiseizure drugs are based on their chemical structure and their mechanism of action and include:
Hydantoins
Succinimides
Benzodiazipines
Barbiturates

General mechanism of action:
They achieve control by the following ways:
1. Directly stabilizing the nerve membranes
2. Altering the movement of sodium through the membrane channels.
3. Enhancing the activity of nt like GABA
4. Inhibiting the action of glutamate.

Common adverse effects include: GI disturbance, ataxia, headache, nystagmus, mental confusion, skin rash, myelosuppression (inhibition of blood cell pdtn) and sedation.

Most of the antiseizure drugs with the exception of benzodiazepines are suspected teratogens.

Drugs that affect the movement of Sodium across the membrane Channels:
Hydantoins: Sodium phenytoin: it act to promote the intracellular sodium removal during the refractory period of the action potential, as a result it stabilized the cortex nerve against hyperexcitability, especially those located in the motor cortex and prevents discharging neurons from repeated firing. It is useful in the treatment of tonic – seizures and also other seizure. It is also an antidysrythmic agent and a co – analgesic in the treatment of neuralgia but it is not the first choice of drug. Additional adverse rxn include gum overgrowth and liver damage. Phenytoin decreases the effectiveness of hormonal contraceptives.

Carbamazepine: it is a tricyclic compound and is related to imipramine. It has an antiseizure effect different from phenytoin. It is the choice of drug in symptomatic partial seizures. It promotes sodium efflux across the nerve membrane. It reduces neuronal excitability, especially repeated firing of the same neuron. This does not have much effect on the motor cortex. Severe cardiovascular, altered micturition, liver and kidney dysfunction are the adverse effects.

Oxcarbazepine: used in tonic – clonic seizures: they block the voltage gated sodium channels and as a consequence they inhibit the hyperexcitability of the neurons, nerve impulse transmission is reduced and repetitive firing is inhibited. There is also evidence that it enhances K efflux and Ca influx which may support the drug action.

Drugs that stabilize the nerve membrane directly:
Succinimides: ethosuximide: treatment of childhood absence seizures: stabilizes neuronal excitability thereby raising the threshold to uncontrolled cerebral discharge, especially within the motor cortex. Adverse reactions include alopecia and muscle weakness.

Drugs affecting the activity of GABA:
Benzodiazepines: Diazepam, clobazam, clonazepam: Diazepam is used to control status epilepticus. The mechanism of these agents is to inhibit the firing of the hyperexcitable neurons thru the enhancement of the action of the inhibitory transmitter GABA. This nt is present everywhere is the cns. These drugs induce fatigue, muscle weakness, hypersalivation and vertigo. Sedative effect and produce tolerance hence cant be used for long term therapy.

Barbiturates: phenobarbitone long acting and short acting amylobarbitone: Depress the activity of the hyperexcited neuron by the enhancing the action of the inhibitory GABA. Have a narrow therapeutic index and hence are quite toxic.

Vigabatrin: used when seizures are not well controlled by other drugs: this drug is an irreversible inhibitor of the enzyme that degrades GABA and as a result there is an inc amt of GABA in the cns. Weight gain is common adverse reaction and psychotic behavious has also been reported.

Tiagabine: inhibits the action of reuptake of the GABA and therefore there is prolonged action of the inhibitory nt. It is well absorbed in the gut and should be taken with food and is subjected to significant metabolism in the liver and has a half life of 8 hours. Common adverse reactions include dizziness, tiredness, nervousness and diarrhea.

Other Antiseizure drugs and drugs with combined mechanism of action:
 Valporic Acid: Sodium valporate: mechanism is to trigger the release of GABA within the brain and inhibit Na channels that change in voltage during depolarization. Major concern is hepatotoxicity.

Lamotrigine: has a two fold effect: inhibits passage of Na thru the voltage sensitive channels and reduces the release of the excitatory nt glutamate as a result the uncontrolled and repetitive firing of the neurone in the affected area of  the cortex is suppressed. Common rxn is skin rash.

DRUGS AFFECTING THE HEART AND CARDIOVASCULAR SYSTEM

Antihypertensive Drugs

Hypertension is a vascular disease with an elevated level of bp recorded over a period of time.
There are three types of hypertensions:
1. primary / essential : age related changes in the nervous, cv and endocrine systems. Two common symptoms that are noted are nocturia and headache.
2. Secondary : is due some other consequence such as pregnancy, artherosclerosis or renal disease.
3. Malignant: in this case hypertension develops quickly and can be severe enough to cause a cerebral oedema. These can be caused due to some agents such as MOAI or eclampsia.

Chronic hypertension leads to the thickening of the walls of the artery and arterioles and also leads to the narrowing of the lumen. Other layers of the wall undergo fibrosis. This damage induces an inflammatory response that increases the permeability of the vascular endothelium.

The aim of the antihypertensive drugs is to lower the bp and prevent damage to major body organs and other tissues. This is rarely achieved by monotherapy and hence a combined therapy is common and can lead to an increase in the complexity of the drug regimen and incidence of adverse effect and can lead to non – compliance of the drug treatment.

Two factors determine the bp that is cardiac output ( stroke vol x heart rate) and systemic vascular resistance (SVR) of the vasculature. It is regulated by the interaction of the nervous, humoral and renal system.

The bp is measured by the sensory receptors located in the walls of the artery which are sensitive to change in pr and chemistry of the blood. These receptors are found in the aortic arch and in the common carotid arteries. These receptors relay their information to the vasomotor centers in the medulla via the afferent fibers associated with the glossopharangeal cranial nerve. The vasomotor center is part of the sns and its function is regulated with the help of alfa2 – adrenergic receptors. The efferent fibers descend the spinal cord and enter the periphery between the T1 and L2 levels. These fibers stimulate the smooth muscle causing vasoconstriction and as a result inc SVR and cardiac output as a result there is inc bp. The medulla also contains fibers that stimulate the force of contraction of the heart and heart rate thereby leading to an inc in bp.

Humoral control system:
Endocrine – renal interactions
These comprise of hormones and other vasoactive substance which are either secreted from the glands or from the walls of the blood vessels and either cause dilation or constriction of the blood vessels.
Most imp humoral mechanism is the rennin – angiostensin system, which regulates renal blood flow. When there is a dec in bp of the renal blood flow rennin an enzyme is released from the renal arterioles. This converts the plasma protein angiostensinogen into angiotensin I, which then converted into an active vasoconstrictive product angiotensin II with the help of angiotensin converting enzyme, this inc the blood flow thru the kidney and as a result there is an inc in bp.
Vasopressin known as an antidiuretic also has an effect of inc the bp by inc the absorption of water.
Adrenaline and noradrenalin also inc bp by vasoconstriction.

Endothelial vasoactive substances: are endothelins, pg’s, and nitric oxide. Endothelin acts as a locally acting vasoconstrictor. Pg’s and nitric oxide are potent vasodilators

Antihypertensive therapies:

There is the ABCDE therapy: as follows:
A : ACE inhibitors
B: beta blockers
C: Ca Channel blockers
D: Diuretics
E: Endothelin receptor antagonist.

ACE Inhibitors: these drug group act on the rennin – angiostensin system by preventing the conversion of angiostensin I to angiostensin II as a result of which there is a dec SVR and hence lowered bp. Angiostensin also stimulates the aldosterone, sodium and water retention are also diminished. It also prevents the breakdown of a vasodilator peptide called bradykinin which makes a further contribution to the dec in vascular resistance. The reduction of bp is brought about without lowering the cardiac output. It is the choice of drug for congestive heart failure since it reduces the work load of the heart without reducing the cardiac output. Captopril is the prototype and is prodrug which is converted into its active form once absorbed and this is so since the drug on its own is poorly absorbed. Common side effects are hypotension, dizziness and headache.
Induce cough and hyperkalaemia.

Angiostensin receptor antagonist:
Losartan, irbesartan, candesartan… they are similar in action to the ACE I and cause a dec in SVR and an dec in the release of aldosterone. They do not inhibit the formation of angiostensin II, they rather produce the effect by blocking the interaction of angiostensin II with the specific receptor. The common side effects are dizziness, headache, hypotension and GI disturbances.

Alfa 1 antagonist: are designed to block the alfa 1 receptor located on the arteriole and venule. These receptors mediate vasoconstriction hence blocking them lowers the SVR. Common side effects are postural hypotension, nasal congestion, pupil constriction, fatigue, inhibition of ejaculation and diarrhea.

For all the three types the diuretics are withheld when the course of the drug is being started.

Beta – blockers: though have been used for a long time their mechanism is unclear. It takes about a weak or two to manifest . it is suggested that the rennin release in mediated by the beta 1 receptors and hence blocking of these receptors results in a dec in pdtn of angiostensin II and also aldosterone resulting in a  dec in the SVR and also bp. Common adverse effects include bradycardia, hypotension, cold extremities, vivid dreams and constipation. Blocking of the beta 2 receptors leads to bronchoconstriction and hence can cause an asthma attack.

Calcium Channel Blockers: management of angina pectoris and cerebral ischaemia, selected cardiac dysrhythmias and hypertension.
Ca channels regulate the influx of ca across the membrane of the muscle cells. They play a particular role in the heart and vascular smooth muscle. Ca channel antagonist dec the influx of ca across the membrane and as a result dec the amt of ca even in the heart and blood vessels and ca ions are required for the contraction of the muscles. Cardiac contractility, conduction and tone is affected.  These are divided into three subtypes:
Nifidipine like agents: nifidipine, felodipine, amlodipine: also known as dihydropyridine. These are relatively selective for vascular muscle
Diltiazem : depresses heart and vascular muscle and
Verapamil : depresses cardiac and vascular muscle as awell as atrioventricular node.

Common side effects are hypotension, headache, facial flushing and skin rash, can lead to bradycardia and other cardiac dysrythmias. These are not recommended for long term management of people with heart failure.

Drugs with a combined action: labetalol and Celiprolol are sympathetic depressants that peripherally block all the adrenoreceptors. The adv is that there is resultant dec in bp at the alfa and beta sites but the disadv that the adverse effects of both will occur. Common side effects are hypotension, dizziness and bradycardia.

Diuretics : lower bp by reducing the vol of blood and this is achieved by inc the amount of water excreted as urine. The problem associated with this is dehydration, hypotension and electrolyte imbalance.  Thiazide diuretics, potassium – sparing diuretics and diuretic drug with a mixed action (indapamide), loop diuretics ( frusemide)

Hypertensive emergencies and second line hypertensive therapies:

Peripheral vasodilators are used in the treatment of second line hypertensive therapy. These reduce the total peripheral resistance by relaxing the vascular smooth muscle. Minoxidil, sodium nitroprusside are vasodilator substances. All these induce dilation of arterioles, causing a lowering of the SVR. Na nitroprusside is the only one that causes dilation of both arteries and veins, the other effect only arterial vessel. As a consequence it causes a dec in the cardiac output and has a more profound effect in decreasing the bp.
Glyceryl trinitrate can also be used in the treatment of hypertension and it acts as a venodilator, but also affects the smooth muscles reducing both venous return and peripheral resistance. It is used with hypertension related to surgery and post operative situations. Main side effects are hypotension, headache, peripheral oedema and allergic rash.

Centrally acting agents:
These act by stimulating the alfa2 receptors situated presynaptically in the vasomotor center of the medulla and these are involved in inhibiting the release of noradrenaline from the adrenergic nerve terminals. Either there is a decrease in the SVR or cardiac output. Methyldopa is involved in reducing SVR whereas Clonidine is involved in reducing cardiac output. Methyldopa is a like a prodrug. And is an analogue of L – dopa from which adrenalin, noradrenalin and dopamine are released, and it is converted into the false transmitter methylnoradrenaline.
Clonidine acts directly as a partial alfa 2 agonist.

Recommended combinations are:
1. A diuretic with a  b – blocker or ACE inhibitor
2. Ca Channel blocker , with either a b – blocker or an ACE inhibitor.

Drugs used to promote tissue perfusion:

Angina pectoris – means chest pain.

Drugs used to relieve this are:
Peripheral vasodilators
Selective coronary dilators
Beta – adrenergic antagonists
Ca Channel Blockers

Their mode of action
Inc the secondary messenger
Blocking ca entry
Hyperpolarizing the cell membrane.

Peripheral vasodilators:
Act both on the arterial and veins to reduce the work load of the heart. They cause the dilation of the arteries as a result there is a dec in the peripheral resistance which the ventricles have to overcome to eject blood into the circulation. Venodilation results in there being a pool of blood and less blood is returned back and as a result less work has to be done by the heart.
Mainly are a group of nitrates such as glyceryl trinitrate, isosoride dinitrate, mononitrate.
The nitrate is absorbed by the endothelial cells and is converted into nitic oxide via the sulfhydryl dependent catalyst which increases the intracellular level of cGMP and in turn alters the availability of ca ions within the muscle cell. As a result there is dilation of the blood vessel. It more marked on the venous side. Common side effects are reflex tachycardia, hypotension, facial flushing, syncope and migraine like headache.

Coronary vasodilators: dipyridamole is used as a prophylactic agent to reduce the frequency of attacks and the requirement for glyceryl trinitrate treatment. It inhibits the phosphodiesterease which results in an inc in the secondary messenger cAMP as a result there is vasodilation of the coronary artery. It selectively causes vasodilation of the coronary vessels as a result there is an inc blood flow to the heart and an inc oxygen supply, it can worsen ischaemia in some cases. Adverse reactions are mild and include dizziness, headache, skin rashes and GI upset

B Blockers – reduce heart rate and workload of the heart.

Ca Channel blockers covered before… but it depends on which ca channel it affects.

Potassium Channel openers:Nicorandil is a derivative of nitrates. It relaxes the vascular smooth muscle of the veins. It opens the potassium channels and allows a efflux of potassium as a result of which it hyperpolarizes the membranes and in turn prevents the ca channel from opening. The unavailability of the ca produces arterial vasodilation. Common side effects are headache, facial flushing, nausea, vomiting, dizziness and weakness.

Anticoagulant, thrombolytics and antiplatelet drugs:

Anticoagulants: persons prone to blood – clots, it is possible to use drugs that interfere with normal blood coagulation processes and thus help to prevent thrombus formation. Over inhibition will lead to bleeding disorders. Blood clotting involves two procedures: the adherence of platelets to each other resulting in a platelet plug. The second being the actual process of blood clot itself due to fibrin formation.  Since the second is the major cause of blood clot the anticoagulation treatment is geared towards the partial inhibition of this process. Heparin and Warfarin.

Heparin: is a polysachharide that occurs naturally in the lungs where its function is not known. Strong ionic compound which is lipophobic and hence cannot be given orally. It is given subcutaneously for slow action or iv for fast action. It enhances the action of the natural inhibitor of coagulation antithrombin III. At high doses leads to the inactivation of all the clotting factors but at low doses only Xa is affected. Bleeding is the only side effect and to counter this problem protamine sulfate is used. Since they are available as high mol wt heparin and this can cause thrombocytopenia and hence we also get low mol wt heparin such as enoxaparin, dalteparin and these can also be used during pregnancy.

Warfarin: is the mainstay of the long term anticoagulant therapy and is a member of the coumarin group. It is structurally similar to vit k which is involved in the synthesis of prothrombin and other factors in the liver. The vit k is reduced since it acts as a coenzyme and needs to be oxidized into its active form before it can be reused again and this is done with the help of epoxide reductase. Warfarin inhibits this enzyme and hence prevent coagulation. Vit k in excess can serve as an antidote for warfarin toxicity. It takes time for its action since all the amount of active vit K has to be depleted and all the enzyme has to by inhibited by warfarin. It is almost devoid of adverse effect.
Drug – food interaction and drug  - drug interaction should be monitored when taking warfarin as it is known to have either an overactivity or underactivity under the influence of certain foodstuff and other drugs.

Thrombolytic or fibrinolytic drugs:
A blood clot that is formed prevents the loss of body fluid and entery of outside material into the body but the clot itself undergoes dissolution at the site of injury once the tissue repair starts taking place. This process involves the bodies fibrinolytic process. The proenzyme plasminogen can be converted into plasmin and this degrades the fibrin present in the clot, this conversion takes place at the site of the clot and is due to the release of plasminogen activators from various cells. By using this mechanism and overstimulation of the release of plasminogen there can be dissolution of clots in the cases of thromboses and thus prevent the ischaemia in the blood – starved tissue.

Three types of drugs:
Streptokinase: is an enzyme prepared from b – haemolytic streptococci and is a potent activator of plasminogen. Without directly enzymatically cleaving plasminogen into plasmin it acts by binding to plasminogen and this complex in turn acts on other molecules of plasminogen converting them into plasmin molecules. If there is an excess of the plasmin in the circulation it can cause a degradation of the clotting factor leading to an haemorrhagic episode. Since it is of a bacterial origin it can stimulate an imminoresponse.

Tissue Plasminogen Activator tpa:
Is of human origin and is made by recombinant DNA tech. it is clot specific and activates plasminogen that is within clots thus minimizing the haemorrhagic episodes. Should be given immediately after an MI and within six hours to be effective. Altepase, tenecteplase and reteplase are the three forms of this enzyme.

Antiplatelet Drugs:
This is related to the formation of platelet plug. Platelets bind to the exposed collagen fibers and release various chemicals including the one called thromboxane. This inhibits the enzyme adenylate cyclase which is needed to make cyclic AMP. cAMP inhibits platelet adhesiveness and this is destroyed by the enzyme phosphodiesterase. Any drug that alters the amount of cAMP will have some effect on the platelet plug. Most pg’s have this function but asprin has the most because of its non – competitive action.

Asprin: it is a member of the salicylates and is acetylsalicyclic acid and the acetyl group react chemically with the enzyme cyclo – oxygenase which is needed for the synthesis of thromboxane. It is a non – competitive inhibitor of this enzyme and thus makes this enzyme completely inactive rendering the platelets functionless for the rest of their lifespan.

Diuretics
Are a group of drugs that promote water loss from the body into urine. They have a principal action at the level of nephrons. Some of the diuretics also act elsewhere in the body.

Loop Diuretics:
Frusemide, ethacrynic acid and bumetanide.  These drugs act on the ascending limb of the loop of henle of the nephron. They inhibit the reabsorption of Na and Cl ions from the loop into the interstitial fluid. This results in the fluid to become very hypotonic as a result there is a high concentration of ions over here so water will flow thru the interstitial fluid and from there into the blood stream. By altering the permeability of the collecting duct good water control is achieved and this is done in the presence of an antidiuretic hormone ADH released from the posterior pituitary. A slight change in balance will upset the normal functioning of the kidney and a hypotonic interstitial fluid will result in diuresis. These diuretics have a high efficacy. Major adverse reaction is the loss of electrolyte from the body. Loss of K can lead to hypokalaemia and this turn can lead to cardiac dysrythmias and death. K supplements need to be given and there needs to be an high intake of K in the diet.

Thiazides or thiazide like drugs: these act on the ascending loop of henle of the nephron. They dec Na reabsorption and as a result the fluid entering the collecting ducts is concentrated and hence less water is absorbed leading to diuresis. They have an effect on the peripheral artiole and this results in vasodilation. Adverse reaction sodium and K loss hence supplementation is required. Can cause hyperglycaemia hence care needs to be taken. Lactation can be suppressed. They contain a sulfonamide group hence persons allergic to this group should not be given this medication. Photosensitivity can also result.

K – sparing diuretics: these are not very powerful diuretics and hence are given in combination with either of the two above mentioned diuretics. There are two type aldosterone dependent and aldosterone independent.

Aldosterone antagonist  - spironolactone – the meachanism of this is to inhibit the action of aldosterone on the distal convoluted tubule of the nephron. Aldosterone is the sodium retaining hormone that is secreted from the adrenal cortex. If it acts on the distal tubule then more Na is retained by the body and this will result in loss of K. If the aldoseterone is blocked K is retained and Na is lost with a  slight inc in diuresis. For every 2 molecules of K retained 3 molecules of Na is lost. It is this phenomenon that induces diuresis since more ions are lost than retained. It is of tremendous use in the treatment of Congestive heart Failure chf. The adverse reactions are hyperkalaemia and hyponatraemia. In men it can produce gynaecosmastia (breast development in men) due to its estrogenic effect.

Osmotic Diuresis: these work directly by interfering with osmosis. Any substance that enters the body in large quantities and is excreted via the kidney will lead to water being kept in the renal tubules and this will lead to water loss. This is due to the maintenance of high osmotic pressure in the tubules. The osmotic diuretics should be non – toxic, be excreted quickly and should not be reabsorbed from the glomerular filtrate. These substance have to be highly soluble in water and hence cannot be given orally and have to be given iv else will have a osmotic laxative effect.  Adverse effects include dehydration and electrolyte imbalance.  Commonly used in Mannitol. It is a sugar alcohol derived from mannose.

Drugs used to treat Cardiac insufficiency.

Myocardial Infarction predisposes a person to dysrythmia and heart failure.
Heart failure is the impairment of the pumping ability of the heart. When the right side fails blood accumulates in the venal circulation causing organ congestion and peripheral tissue oedema. When the left side fails there is accumulation of blood in the pulmonary circulation resulting in pulmonary congestion and fluids in the lungs. When the left side of the heart is affected the condition is termed as congestive cardiac failure.

The current recommendation for treating heart failures is to treat with ACE inhibitors a diuretic and peripheral vasodilators and in some cases drugs that inc cardiac contractility are also used. There may also be a role for b – blockers in the long term management of this condition.

Inotropic Agents :
Cardiac Glycosides: Digoxin: they work by affecting the movement of ions in and out of the myocardial fibers, as well as altering the activity of ans. Ions most affected are Ca and Na.  these drugs inhibit the action of the enzyme associated with the Na pump, ATPases and exchange between Na and Ca is  impaired. Stores of Ca are released from the myocardial cells and the membranes become more permeable to this ion, as a result there are elevated levels of Ca. this result in stronger contraction of the heart since elevated levels of ca is associated with stronger contraction of the heart. Stronger myocardial contraction improves cardiac efficiency, boosting cardiac output. These enhance the psns stimulation of the heart and directly alter the responsiveness of the sinoartrial node. This results in dec heart rate and that is what we want since the sympathetic stimulation causes an inc in heart rate and can lead to an irregular pulse. The common adverse effects are forms of dysrhythmia such as tachycardia, fibrillations, ectopic depolarization and AV blockade. They trigger the CTZ zone in the brain leading to nausea and vomiting. Anorexia and diarrhea are consequences of direct GI irritation by these drugs. High levels of K reduce the effectiveness of these drugs. They have a relatively low margin of safety.

DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM

The ans is part of the peripheral nervous system and regulates the involuntary activities such as heart rate, bp, respiration and digestive tract function.

The ans consists of two parts:
Sympathetic nervous system (sns)
Parasympathertic nervous system (psns)

1. sns: this is involved in the flight / fright/ fight response to stress or arousal.
It stimulates the nervous system hence inc in heart rate and bp, dilation of the bronchioles hence inc the blood flow to the lungs hence an inc in supply of oxygen. The muscles are well supplied with blood vessels and there is a dec of blood supply to the digestive system.

2. psns: stimulation here is in the opposite way as compared to the sns. It is a state of rest and repose. Dec in heart rate and bp, less oxygen supplied to the lungs and the bronchioles are constricted. There is an inc blood flow to the digestive system with concurrent stimulation of peristalsis and inc secretion of digestive secretion such as saliva.

Drugs that stimulate the sns are called sympathomimetics i.e. they mimic the action of the neurotransmitters that are involved in the sns and produce an sns response.

Drugs that suppress the activity of the sns are called sympatholytics they block the sns response.

Mode of action of the ans drugs:
Neurophysiology:
1. a nerve cell (neuron) receives an input at the specialized end called the dendrites.
2. The message from the dendrites is passed down to the axon and from there to the terminal branches.
3. this stimulates the release of specialized chemicals called neurotransmitters which are released in a gap called the synaptic cleft or synapse
4. these then attach to the either the dendrites of another neuron or to a tissue such as a muscle or gland which are termed as effectors.

The binding of the nt at a specialized site on effector is termed as a receptor. Receptors are selective and specific. There are two types of receptors that are associated with the ans i.e. adrenergic receptor and cholinergic receptor.

Adrenergic receptor:
The nt noradrenaline binds only to the adrenergic receptor. These receptors are found in the sns and the drugs that mimic the action of noradrenalin and bind to these receptors are called adrenergic drugs / adrenergic agonists.  These drugs will result in increased heart rate, inc bp, inc brochodilation and dec digestive action. Conversely adrenergic antagonist are the ones that will bind to the receptor and will not allow the nt to bind as a result of which there will be dec heart rate, dec bp and dec brochodilation and an increased action of the digestive system.

Cholinergic receptors:
Nt acetylcholine binds to the cholinergic receptors. These are found in the psns and hence drugs that bind the cholinergic receptor and mimic the action of acetylcholine are called cholinergic agonists.  That is there will be a dec in heart rate, dec in bp, dec in bronchodilation and inc activity of the digestive tract.
Conversely cholinergic antagonist will lead to an inc in heart rate, inc bp, inc bronchodilation and dec in the GI tract activity.

Therefore:
Adrenergic agonist = cholinergic antagonists
Adrenergic antagonist = cholinergic agonists.

Removal of the nt from the synaptic cleft: is imp to avoid restimulation of the neurons by the nt.
There are two main mechanisms used for this:
1. Re – uptake of the released nt e.g. noradrenalin is taken up by the amine re – uptake pump.
2. Enzymatic breakdown of the nt: is achieved with the help of an enzyme e.g. acetylcholine esterase is an enzyme used in the breakdown of acetyl choline.

If the drug blocks the enzyme in the breakdown of the nt. The result of this Is prolonged stimulation and hence further stimulation of the sns or the psns.

Key aspects of nt and how this relates to the drug action:
1. nt transmits a response between two neurons or between an neuron or a neuron to an effector. Drugs may mimic the action of the nt or affect the nt concentration
2. nt bind to specific receptors. The drug may bind to the receptor and either mimic the action of nt or block the receptor.
3. nt vary between the different nerve tracts. The key ones in the ans are noradrenalin and acetylcholine and depending on the shape of the drug it might bind to these receptors  and this makes its action more specific.
4.since each nt is removed after release by a specific process the drug can alter this process.

Adrenergic Pharmacology:

Adrenergic agonists: inc heart rate, inc bp, bronchodilation, dec GI tract activity. They also stimulate the release of hormones like adrenalin and noradrenaline from the adrenal medulla.
Adrenergic antagonists: dec heart rate, dec bp, reduced bronchodilation and inc GI tract activity. They block the site of the receptor and hence reduce the sns reponse.

Drugs to know:
Adrenalin
Noradrenaline
Salbutamol
Ephedrine
Pseudoephedrine
Dopamine
Methylpoda
Clonidine

Adrenergic pharmacology refers to the drugs tht mediate their effect via the adrenergic receptors. These are found in the sns and also in the brain and cns.

There are different subsets of adrenergic receptors which allows the body to modify the stress response depending on the circumstances. This property of the adrenergic receptors allows the drugs to be more selective in their mode of action.

The receptors are as follows:
Alpha1 receptors: are located in the blood vessels and effect both bp and tissue perfusion
Alpha2 receptors: located presynaptically

Beta1 receptors: found in heart muscle, adipose cells, sphincters and smooth muscle of the GI tract and renal arterioles.

Beta2 receptors: found in the smooth muscle of the bronchioles, skeletal muscle and blood vessels supplying the heart, brain, liver, uterus and mast cells.

For treatment of asthma this selective property of the adrenergic receptor is useful else it would lead to cardiovascular trouble if we concentrated on bronchodilation. For asthma the best would be to have a selective action on the beta2 receptor compared to having an action on the others. This will avoid harmful effects such as palpitations. E.g. of drugs used for asthma are Salbutamol and terbutaline.

Lot of the adrenergic drugs are not selective in that they can bind to both the type of receptors the alpha and the beta receptors e.g. adrenaline, ephedrine and pseudoephedrine.

Dopamine is a nt found in the cns but is also found in the sns and react with the beta 1 at low doses and alpha 1 at high doses. It structurally resembles the adrenaline and noradrenaline. Specific peripheral dopamine receptors are found in the blood vessels of the brain, heart, kidney and mesentery and is involved in vasodilation. It is used in restoring circulation and tissue perfusion in a cardiac shock.

Adrenergic side effects:

These occur as a result of drug action on the adrenergic receptors at sites other than where the desired effect is wanted. E.g. drugs used to treat asthma can cause palpitations.

Some of the adrenergic agonist can cause the bbb and react with the adrenergic receptors in the brain and this can result in a fight / flight response leading to restlessness, insomnia, hyperactivity and anxiety.

Presynaptic and postsynaptic receptors:

If the receptor are found after having crossed the synapse they are called postsynaptic receptors whereas if the receptor is present on the presynaptic terminal that is the place from where the nt is released is called a presynaptic receptor.

Alpha1, beta1 and beta2 are found postsynaptically.
Alpha 2 receptors are found presynaptically and these are found on all adrenergic nerve terminals. Binding of the nt noradrenaline to the alpha 2 receptor leads to inhibition of further release of nt from the same axon terminal. This is a feed – back mechanism. This is also the mode of action of the antihypertensive drug clonidine which is a alpha 2 agonist.

Cholinergic Pharmacology is the drugs that act either as cholinergic agonists or antagonists and either mimic or inhibit the nt acetycholine.

Drugs to know:
Acetylcholine
Nicotine
Atropine
Cogentin ( Benztropine)

Different places in the body where the cholinergic receptors are found:
1. psns
2. the sympathetic fibers to the sweat gland and blood vessels of skeletal muscles are cholinergic.
3. all preganglionic synapses of the ans are cholinergic
4. these are also found in the pns and contols the voluntary skeletal muscle action.
5. they are also found in the cns.

Hence cholinergic drugs can have an effect on the ans, cns and the voluntary neuromuscular movements.

Drugs that mimic acetylcholine are said to be cholinergic and antagonists are said to be anticholinergic.

Cholinergic effect:
Acetylcholine is released in a cholinergic synapse and it diffuses across and binds to postsynaptic cholinergic receptors and this will trigger an appropriate effector response.
Autonomic ganglion: continuation of impulse to post ganglionic fibers in both sympathetic and parasympathetic fibers.
Psns: rest and repose response
Sns: only the cholinergic fibers – vasodilation in the skeletal muscle and sweating.
Neuromuscular junction – somatic nervous system – skeletal muscle contraction and inc muscle tone
CNS – varies – alertness, stimulation, relaxation and well being.

Acetylcholine is broken down by the enzyme acetylcholine esterase.

The drugs involve:
Cholinergic agonist
Cholinergic antagonists
Acetylcholine esterase inhibitors – these are the drugs that block the action of the
Acetylcholine esterase and as a result of which there is more concentration of acetylcholine and there is more of the cholinergic effect seen.

Cholinergic receptors:

Two types:
Nicotinic receptors : respond to stimulation by nicotine
Muscarinic receptors: these respond to muscarine. These are further divided into M1, M2 and M3.

Muscarinic receptors are found in the psns effectors and the cholinergic sympathetic effectors.

Nicotinic receptors are found in the neuromuscular junction of the somatic ns controlling the voluntary muscle contraction. Also found in the preganglionic neuron of the ans.

Nicotinic receptors: in the ans – preganglionic effect inc both the sns response such as bp and psns such as GI tract activity. It also leads to an inc in the amount of adrenaline and noradrenaline hence inc heart rate.
In the cns there is a feeling of wellbeing and relaxation.

Muscarinic receptors:
Ans – psns

M3 effect: inc Gi activity, inc insulin secretion, bronchioconstriction and inc mucus secretion, pupils contract and promotion of defecation

M2 effect: dec heart rate and force of contractions

M1 effect: inc GI tract activity and secretion.

Sns
M3 effect – vasodilation in skeletal muscle sweating

Cns – m1 effect – improves memory enhanced cognition.

Anticholinergic side effects:

Disipal and cogentin are anticholinergic drugs used to control the tremors in parkinsons. It is due to the action on the cns.

Adverse effects are dose related and include dry mouth, blurred vision, problems passing urine and constipation, these are all anticholinergic side effects and are muscarinic in origin.