Pharmacology

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Questions Received:

  1. Please send me information about drugs and alcohol which affect our co-ordination system.

  2. What do drugs do to the male reproductive system?

  3. How does aspirin work?

  4. I need to know if there is desmopressin for oral administration - now I use Minirin spray but I want to know the name of this oral drug.

  5. Can you explain the way in which the drug cyclizine hydrochloride works in the body please?

  6. Streptokinase: pharmacokinetics and pharmacodynamics. As a student nurse, I am doing a group seminar on drugs used in the treatment of myocardial infarction. I am looking at streptokinase, and was hoping someone could explain the above areas in a more user-friendly way than my books.

  7. Please can you give me any information on the use of antipyretic drugs.

Responses:

Please send me information about drugs and alcohol which affect our co-ordination system.

5th May 1999

It is not clear what is meant by the term, "co-ordination system". If this refers to the central nervous system - brain and spinal cord - then all central nervous system depressant drugs have an effect, i.e. sedative-hypnotics, anaesthetics, alcohol, tranquillisers and narcotic analgesics. If the question refers to drugs which adversely affect co-ordination, i.e. balance, the list would be more restricted and include drugs which affect vestibular function, for example Streptomycin. Certain drugs may affect balance and co-ordination by inducing Parkinson-like symptoms, notably anti-psychotic drugs like Chlorpromazine (Largactil) or certain chemical analogues of Amphetamine. Conditions in which co-ordination may be affected, such as motion sickness or Meniere’s disease for instance, may be improved by the use of particular anti-histamine drugs e.g. Perchlorphenazine, Stematil.

Our thanks to Geryk John, Lecturer in Pharmacology and Biochemistry, for providing this answer.

What do drugs do to the male reproductive system?

4th May 1999

With the possible exception of Viagra, drugs if they have any effect on the male reproductive system tend to have a negative one. Viagra seems to work indirectly by boosting levels of nitric oxide (NO), a substance which acts as a neurotransmitter and permits erection to occur via neuronally mediated vasodilatation. Evidence that particular substances can act as aphrodisiacs in terms of their effect on the male reproductive system tends to be anecdotal and of dubious scientific merit. Classically alcohol "stimulates desire but takes away from the performance" (William Shakespeare). On the other hand, there are plenty of drugs which have a negative effect on male reproductive function dating back to the early use of ganglion blocking drugs such as Hexamethonium and Mecamylamine for the treatment of hypertension in the 1950s. (Parasympathetic blockade prevents erection and sympathetic block prevents ejaculation). Alpha-methyldopa (Aldomet) also used nowadays for treating high blood pressure adversely affects male sexual function via its effect on the sympathetic nervous system.

Other groups of drugs may affect the male reproductive system via an effect on spermatogenesis. Since this process is stimulated by gonadotrophin (FSH) release from the pituitary, inhibition of FSH release should in theory block the production of sperm. Synthetic oestrogens and progestogens have been shown to produce this effect experimentally and recently great interest has been shown in this area by scientists in terms of developing a male contraceptive pill. Handelson’s team in Australia has produced promising results in terms of male contraception using a combined pill containing testosterone and a synthetic progesterone like substance called progestin. It appears to act by forcing the pituitary to switch off FSH production which in turn causes the testes to stop sperm production. Trials of this male contraceptive are ongoing. Synthetic oestrogens such as Ethinyloestradiol have been shown to reduce male reproductive function. Medically this has been employed in the treatment of prostatic cancer where oestrogens can suppress its enlargment. Recent studies have shown that synthetic oestrogens in the environment may be having a negative effect on human male sperm counts and there are numerous reports of the so-called feminization of male fish due to the presence of oestrogens in river water.

Finally some synthetic steroidal compounds may have an anti-androgen effect (anti-male sex hormone) by blocking receptors for testosterone. Such chemicals include Cyproterone and Danazol. The latter substance is chemically related to the anabolic steroid, Stanazol, which has been used by some athletes to enhance their performance. Anabolic steroids have been implicated in reducing male fertility although the claims are somewhat controversial and more research is required in this area for the situation to become clearer.

Our thanks to Geryk John, Lecturer in pharmacology and biochemistry, for this answer.

How does aspirin work?

17th May 1999

The actions of aspirin in relieving pain and inflammation can all be linked to its effect in blocking the production of prostaglandins. These are hormone-like substances which are produced by most cells in the body and which can indirectly transmit pain signals to the brain. Specifically, aspirin blocks the enzyme cyclo-oxygenase which is involved in a major pathway of prostaglandin synthesis. Prostaglandins are produced at sites of inflammation (such as tissue injury) and aspirin reduces their production and ultimately relieves pain and inflammation. A third beneficial effect of aspirin i.e. to reduce fever (anti-pyresis) is probably linked to preventing increased levels of prostaglandins in the brain.

Two other effects of aspirin are consequences of action on prostaglandin synthesis. Vane (1971) discovered that aspirin is a powerful inhibitor of platelet aggregation. This was caused by an effect of aspirin on the production of thromboxane, a prostaglandin-like substance which encourages blood platelets to aggregate. This action forms the basis of the prophylactic use of aspirin to prevent heart attacks and strokes in patients. Clinical trials have shown that low dose aspirin (75-150 mg daily) cuts the risk of heart attacks by a third.

However one of the major side-effects of aspirin is to cause irritation to the stomach lining and in severe cases, gastro-intestinal bleeding. This is again due to affecting prostaglandins. Normally prostaglandins inhibit gastric acid secretion and also have a protective effect on the gastric lining via the production of mucus. Aspirin may act to block these prostaglandins and hence produce the harmful effects. In about 6% of people these effects can be severe enough to make aspirin use inadvisable.

Reference

I need to know if there is desmopressin for oral administration - now I use Minirin spray but I want to know the name of this oral drug.

27th May 1999

An oral version of desmopressin (1-deamino-8-D-arginine vasopressin, or DDAVP) was introduced several years ago. It has the same name preceded by ‘oral’, thus: oral desmopressin or oral Minirin. As an antidiuretic hormone analogue it is being used in the treatment of diabetes insipidus, nocturnal polyuria and enuresis.

References

Can you explain the way in which the drug cyclizine hydrochloride works in the body please?

12th June 1999

Cyclizine is a piperazine derivative which belongs to the anti-histamine group of drugs. Its main therapeutic use is in the suppression of vomiting, in particular preventing motion sickness. Vomiting (emesis) is essentially a protective mechanism for removing irritant or otherwise harmful substances from the upper GI tract. However vomiting has several other causes including drug-induced (e.g. cytotoxic drugs), vestibular disease, sea-sickness, migraine and pregnancy. The act of emesis is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). This area is extremely sensitive to the actions of drugs and chemical toxins, mainly because it is not protected by the blood brain barrier. The vomiting centre does not initiate but rather co-ordinates the act of emesis on receiving stimuli from various sources.

The vomiting centre possesses neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness principally involves overstimulation of these pathways due to various sensory stimuli. Hence the action of cyclizine which acts to block the histamine receptors in the vomiting centre and thus reduce activity along these pathways. Furthermore since cyclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked. Side effects due to these anti-cholinergic effects such as dry mouth, drowsiness and blurred vision do occur, but to a lesser extent with cyclizine as compared to other anti-histamines and may make it preferable as a prophylactic drug against motion sickness.

Streptokinase: pharmacokinetics and pharmacodynamics. As a student nurse, I am doing a group seminar on drugs used in the treatment of myocardial infarction. I am looking at streptokinase, and was hoping someone could explain the above areas in a more user-friendly way than my books.

7th June 1999

Pharmacokinetics - "the study of the actions of drugs within the body, including the routes and mechanisms of absorption and excretion, the rate at which a drug's action begins and the duration of the effect, the biotransformation of the substance in the body, and the effects and routes of excretion of the metabolites of the drug." pharmacokinetics - "the study of the actions of drugs within the body, including the routes and mechanisms of absorption and excretion, the rate at which a drug's action begins and the duration of the effect, the biotransformation of the substance in the body, and the effects and routes of excretion of the metabolites of the drug." pharmacokinetics - "the study of the actions of drugs within the body, including the routes and mechanisms of absorption and excretion, the rate at which a drug's action begins and the duration of the effect, the biotransformation of the substance in the body, and the effects and routes of excretion of the metabolites of the drug."

Pharmacodynamics -" the study of how a drug acts on a living organism, including the pharmacologic response observed relative to the concentration of the drug at an active site in the organism." pharmacodynamics -" the study of how a drug acts on a living organism, including the pharmacologic response observed relative to the concentration of the drug at an active site in the organism." pharmacodynamics -" the study of how a drug acts on a living organism, including the pharmacologic response observed relative to the concentration of the drug at an active site in the organism."

Mosby's Medical, Nursing, and Allied Health Dictionary (4th edition) (1994) p1205.

It is important that blood is capable of clotting effectively to protect against blood loss when a vessel is damaged, but it is also important for normal cardiovascular function that blood clots can be physiologically disposed of when their job is done. Removal is the function of the fibrinolytic system which dissolves away the fibrin framework of the clot (thrombus). Therefore the clotting and fibrinolytic systems are normally in dynamic equilibrium, each balancing the other in a harmonious way. Essentially the action of streptokinase is to boost the fibrinolytic system and remove thrombi which are potentially life-threatening.

Streptokinase is used to dissolve the fibrin of blood clots, especially those in the arteries of the heart and lungs. It is also used against the clots formed in shunts during kidney dialysis. It has an important application in the treatment of coronary heart disease. Acute myocardial infarction is the result of a coronary artery or one of its branches becoming blocked, often by the formation of a blood clot, so that a region of heart muscle is deprived of its blood supply and can no longer function. This is a major cause of death in many countries. Treatment of coronary thrombosis with thrombolytic agents was first introduced in the 1950s. However, clinical trials with streptokinase during the 1960s and early 1970s tended to be inconclusive, and it was not until 1976 that intracoronary streptokinase was demonstrated to produce prompt recanalization of a totally occluded artery. This reawakened interest in thrombolytic drugs such as streptokinase, and these have since been shown to produce a significant decrease in mortality in patients with myocardial infarction (Rapaport, 1991; Bizjak and Mauro, 1998; Stringer, 1998). Since the 1980s several large-scale clinical trials into the effectiveness of thrombolytic therapy have been conducted, for example ISIS-2 (1988), ISIS-3 (1992), and GUSTO (1993). In the ISIS-2 trial, short-term mortality was reduced from 13% to 8% by thrombolytic therapy. However, great care is required in the use of thrombolytics since they can increase the risk of intracerebral hemorrhage (Price, 1990).

Pharmacokinetics of Streptokinase (absorption, distribution, metabolism, and excretion)

Streptokinase is a protein extracted from haemolytic streptococci. It has a short half-life of less than 20 minutes and so must be given by continuous intravenous infusion. Most patients will have antibodies to streptococcal proteins already in their blood, and these will lock on to the streptokinase molecules and neutralise their action. Therefore streptokinase therapy must start with a large loading dose in order to mop up the antibodies. The initial loading dose is followed by a maintenance dose by continuous intravenous infusion for 24 hours or sometimes longer. Subsequent dosage should be adjusted according to the thrombin time which should be prolonged by 2-4 times compared to normal. Streptokinase therapy is most useful when thrombosis is of recent origin, i.e. less then 7 days. Thereafter it may be less effective. In patients with acute myocardial infarction caused by a thrombus in a coronary artery, beneficial effects are greatest if the drugs are given within 3 hours with progressively less benefit over 24 hours. Streptokinase in these patients is given intravenously or through a cardiac catheter into the coronary artery.

The objectives of thrombolytic therapy with streptokinase are:

The main side effects of streptokinase therapy are nausea, vomiting and adverse bleeding. The latter may normally occur near the injection site and if excessive can be treated with transexamic acid. The main disadvantage of the treatment is that it will cause the dissolution of all thrombi, both the protective ones preventing haemorrhage and the life-threatening ones.

Pharmacodynamics of Streptokinase (biological actions)

The blood fibrinolytic system involves the activation of blood plasminogen by various factors to form the enzyme plasmin. This is the stage at which streptokinase works. Plasmin is a proteolytic enzyme which degrades fibrin and hence dissolves the thrombus. Streptokinase is not an enzyme but when it binds to plasminogen it forms an activator complex by which plasmin is formed. Normally there are naturally occurring inhibitors of plasmin (antiplasmins) in blood which prevent plasmin itself from being used as a fibrinolytic agent, whereas there are no such inhibitors for streptokinase. Plasmin formed inside a thrombus by streptokinase is protected from blood antiplasmins thus allowing it to dissolve the thrombus from within.

streptokinase (3K bytes)Alternative Thrombolytics

Alternative thrombolytic agents have proved successful. Tissue plasminogen activators (tPA) such as alteplase are derived from the activator produced by human tissue. The genes for these molecules have been identified and transferred to bacteria using recombinant DNA technology so that therapeutically useful quantities can be obtained. tPA binds avidly to fibrin and it digests thrombi in coronary arteries at least as well or better than streptokinase without affecting plasma fibrinogen to any degree and thus without causing systemic fibrinolysis. Reteplase is the most recent in a succession of thrombolytic agents used in the management of acute myocardial infarction in adults (Wooster and Luzier, 1999). Generally, however, little difference has been found in the effectiveness of different thrombolytic treatments (Gillis and Goa, 1996; Bizjak and Mauro, 1998).

Who should receive thombolytic therapy?

According to the British National Formulary (1996) "thrombolytic drugs are indicated for any patient with acute myocardial infarction for whom the benefit is believed to outweigh the risk of treatment. Trials have shown that the benefit is greatest in those with ECG changes that include ST segment elevation and in those with anterior infarction. Patients should not be excluded on account of age alone because mortality in this group is high and the percentage reduction in mortality is the same as in younger patients."

References

Please can you give me any information on the use of antipyretic drugs.

19th January 2000

Antipyretic drugs are by definition those drugs which lower the body temperature when it is raised, i.e when fever (pyrexia) is present. The biological function of fever is not clearly understood: one possible explanation is that fever is part of the body's defence mechanism against infection. Alternatively fever is produced by bacterial toxins as a toxic manifestation of the infection. Whichever is correct, the main reason for using antipyretic drugs is that an excessive rise in body temperature may cause irreversible tissue damage and in extreme cases can be lethal.

Before the development of synthetic antipyretic drugs, notably aspirin in the late nineteenth century, the main standby for the treatment of fever was quinine which possesses antipyretic activity in febrile conditions in addition to its antimalarial actions. Reduction in body temperature by the use of quinine or antipyretic compounds was essential in treating fevers. Nowadays the introduction of specific antibiotics for the chemotherapy of infections has rendered the use of antipyretic drugs as largely unnecessary. The two most important antipyretic drugs are aspirin and paracetamol which are common household remedies for the treatment of high temperature associated with the common cold and influenza. As well as antipyresis they also have anti-inflammatory and analgesic properties which are utilised in the treatment of illness.

Antipyretic drugs have no effect on normal body temperature in the doses that are effective in reducing the pyrexia of febrile conditions. Nor do they have any effect on the rise of body tempersture caused by heat stroke. (Reduction in body temperature in this condition should be achieved by physical means and not with aspirin). However they do prevent the rise in temperature in response to endogenous or microbial pyrogens. During fever, interleukin-1, an endogenous pyrogen, is released from leucocytes and acts directly on the thermoregulatory centre in the hypothalamus to increase body temperature. This effect is associated with an increase in the synthesis of prostaglandins in the hypothalamus, especially PGE1. Aspirin prevents the temperature raising effects of interleukin-1 by blocking prostaglandin synthetase and hence preventing the rise in brain prostaglandin levels. Other antipyretic drugs such as paracetamol similarly produce this effect on pyrogens.

Pyrazolone drugs such as phenylbutazone, dipyrone and amidopyrine were formerly used in the treatment of fever but their potentially serious side effects have restricted their use in favour of aspirin. As antipyretics they are largely confined to the reduction of severe and prolonged hyperpyrexia due to malignant conditions such as Hodgkin's disease.

References

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