BASIC PRINCIPLES AND DEFINITIONS

Definitions

• Pharmacology: The total knowledge of drugs including history, chemistry, source, biochemical & physical effects, pharmacokinetics (what the body does to the drug), pharmacodynamics (what the drug does to the body), therapeutics, site of action, interactions, distinctive features, etc.

• Drug: A drug is any substance which, when introduced into the body, produces a physiological change, a biological change, a decrease in population of resident or invading microorganisms, or a decrease in abnormal tissue development.

• Clinical pharmacology: The study of the effect of drugs in man (as compared to animal or comparative pharmacology).

• Pharmacotherapeutics (or Therapeutics): deals with use of drugs in prevention & treatment of disease, usually to alleviate symptoms or, sometimes, to alter the course of the disease.

• Toxicology: deals with adverse effects of drugs

• Tolerance: Decreased response to a dose of a drug after chronic administration as seen with opioids or alcohol etc

• Idiosyncrasy: Describes an unusual effect of a drug. It usually occurs in a very small percentage of patients and may not be related to the dose of the drug.

• Side effect: usually describes any action of the drug other than the desired (therapeutic) effect.

• UNTOWARD EFFECT (or ADVERSE EFFECT) is any noxious, unintended, and undesired effect that occurs at normal drug doses.

• TOXIC effect is that effect (usually expected) produced by large doses of the drug.

Definition: Pharmacokinetics is the quantitative study of the absorption, distribution, metabolism and excretion of drugs and their metabolites. In simple terms, pharmacokinetics (often simply called “kinetics”) is what the body does to the drug.

Plasma membranes and factors affecting passage

1. Drug factors that influence the ability of a drug to cross plasma membranes include molecular size and shape, solubility at the site of absorption, the degree of differences in pH across the membrane, the electrochemical gradient for the lipid form of the drug, degree of ionization, vascularity of the tissue, and relative solubility of ionized and nonionized forms.

2. The plasma membrane

3. The three most important ways by which drugs cross cell membranes are through channels, active transport, or direct penetration. The primary method of passage of drugs across plasma membrane is by passive diffusion and is directly proportional to magnitude of concentration gradient of the drug across the membrane & lipid solubility of the drug. Polar molecules (e.g., soluble in water) and ions cannot penetrate membranes.

Example: propranolol and nadolol are both non-selective beta-blockers. Propranolol is lipid soluble and nadolol is water soluble. Propranolol is rapidly & completely absorbed from the gut, has a large first pass effect (70%), is primarily metabolized by hepatic metabolism, and can cross the blood brain barrier to produce CNS side effects. Nadolol is poorly absorbed (30%), has no first pass effect, is primarily eliminated as such by renal filtration, and does not cross the blood brain barrier.

c. For nonpolar or lipid soluble drugs, the concentration of free drug is same on both sides of a membrane at steady state.

d. Many drugs are weak acids or weak bases and are present in solution as both ionized and nonionized. The nonionized is usually lipid soluble and able to penetrate the lipid membrane while the ionized form cannot penetrate the membrane and hence is not absorbed.

Thus, a weak acid (such as salicylic acid, the active metabolite of aspirin), in an acid medium (such as the stomach or acid urine,) is predominantly in the nonionized state (hence lipid soluble and can be absorbed). A weak base (e.g., morphine) in an acid medium is predominantly in the ionized state.

Clinical examples:

1. Treating salicylate toxicity by using sodium bicarbonate which is basic, alkalinizes the urine and hence increase the ionized form of salicylate that cannot be reabsorbed though the kidney tubules and hence excreted.

2. Phenobarbital (sodium - weak acid) is the only barbiturate with an ionization constant (7.4) close enough to blood and urine to be markedly affected by physiologically feasible pH changes. Treat phenobarbital toxicity with forced alkaline diuresis.

Carrier mediated membrane transport

(1) Active transport of some drugs (e.g., levodopa) occurs across neuronal membranes, the choroid plexus, renal tubular cells, and hepatocytes. Active transport is characterized by selectivity, competitive inhibition by congeners (similar drugs or metabolites), a requirement for energy, saturability, and movement against an electrochemical gradient

(2) Facilitated diffusion is a carrier-mediated transport process but there is no input of energy. The substance moves according to electrochemical gradient (some amino acids).

Absorption is the transfer of a substance from the site of application to the blood stream (usually the systemic circulation).

"Bioavailability" is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route.

Absorption of Drugs from the GI Tract

• For drugs administered orally, bioavailability may be less than 100% because of either incomplete extent of absorption or first-pass elimination (in both the gut and the liver). First pass effect refers to hepatic inactivation of certain orally administered drugs. Drugs administered via the GI tract are termed enteral. All other forms of administration are parenteral, however this term is often reserved for injected drugs.

• Drugs given with fluid on an empty stomach will quickly pass from the stomach into the intestine. Most drugs given with food will have delayed absorption because of delayed stomach emptying.

• Solid oral dosage forms (e.g., tablets, capsules) must first disintegrate, then must dissolve in the intestinal fluids. Drugs, to be absorbed, must be a mix of water solubility (to dissolve in the GI fluids; drugs must be solubilized to be absorbed) and lipid soluble (to cross the lipid plasma membrane). Drugs may be too hydrophilic (e.g., nadolol) or lipophilic (e.g., acyclovir) to be absorbed easily. Some drugs, particularly water-soluble compounds (e.g., amino acids) are absorbed by an active transport mechanism.

• When absorbed from the intestine, drugs travel via the portal vein to the liver where some drugs are extensively metabolized before reaching the systemic circulation (e.g., nitroglycerin; propranolol). This effect is termedfirst pass effect . Sublingual & transdermal administration avoids hepatic first pass effect. Drugs with a large first pass effect have a low bioavailability.

Drugs may be nebulized & inhaled, some with rapid absorption of drug with avoidance of first pass effect and, in the case of pulmonary disease, local application of the drug at the desired site of action. Disadvantages: With inhalation administration, it may be difficult to regulate the dose and inhalation is a cumbersome method of administration. Some drugs irritate the pulmonary epithelium and aerosol particles larger than 1 micrometer fail to reach alveoli.

Distribution is the process of a substance leaving the blood stream and moving to cells or tissues.

Absorptive phase

After a drug is absorbed (or injected) into the blood stream, it may be distributed into interstitial and cellular fluids, then into various tissues. In the blood, the drug may be “free” or bound to plasma proteins. Only the free drug is further distributed. An initial phase of distribution may be distinguished that reflects cardiac output and regional blood flow.

a. Heart, liver, kidney, brain, & other highly perfused organs receive most of drug in initial phase of distribution.

b. A second phase involves delivery of the drug to muscle, viscera, skin, and fat (minutes to hours before equilibration). This is limited by blood flow but involves far larger fraction of body mass.

Distribution is also limited by drug binding to plasma proteins (p. 35) Drawing of blood for drug “blood levels” measures both bound and free drug in the blood but does not include drug bound in tissues or at receptor sites.

The concentration gradient across the plasma membrane for the diffusible fraction (lipid soluble, nonionized, unbound) determines both rate and direction of net transfer between plasma and tissues. The blood supply to the tissue may also affect the concentration gradient (poor tissue perfusion fails to carry the drug away from the absorption site).

A hypothetical quantitative estimation of drug distribution is called the volume of distribution (Vd). This provides some estimate of how much drug has entered the body and where it went (e.g., extracellular fluids; muscle; fat tissue).

The volume of distribution (Vd) is a mathematical expression of the sum of the apparent volumes of the compartments that constitute the body. Vd relates the amount of drug in the body to the concentration of drug in the plasma. It does not necessarily refer to an identifiable physiological volume but merely to the fluid volume that would be required to account for the entire drug in the body (based on the amount found in a blood sample). Vd may be stated in Liters or in L/kg. A drug with a large Vd is bound in peripheral tissues (e.g., fat) while a drug with a small volume of distribution is primarily in plasma or body fluids (intercellular and extracellular fluids).

Examples: Gentamicin 0.31 L/kg

Diazepam 1.1 L/kg

Amitriptyline 15 L/kg

Chloroquine 200 L/kg

• Neisseria

  • N. gonorrhoeae

  • N. meningitidis (contains a polysaccharide capsule)

  • Non-pathogenic species exist in upper respiratory and alimentary tracts

    • Non-motile gram –ve cocci existing as two cocci joined together forming a bean shaped structure (diplococci)

    • Aerobes – pathogenic species prefer ↑ [CO₂]

    • Oxidase +ve, catalase +ve, most ferment glucose

Differentiating Neiserria from other genera:

The main point here is:

• Neisseria can be differentiated from other members of Neisseriaceae family biochemically: i.e.: catalase +ve, oxidase +ve, and most ferment glucose

Identifying Neisseria species:

The main point here is:

• Different species of the Neisseria genus form different colonies and have different morphologies:

  • N. gonorrhoeae and N meningitidis have non-pigmented, non-haemolytic, glistening, mucoid, raised, convex, elevated colonies

  • Other have: yellow pigmentation, opaque, brittle, wrinkled colonies.

  • Environmentally fragile: so inoculate immediately in pre-warmed agar plates

Main points here are:

• Causes gonorrhoeae, infects columnar epithelial cells of cervix (females) & urethra (males). Colonies also form in mucosa of pharynx and rectum.

• Transmission between humans (only), only via intimal contact (genital, anal, oral sex)

• 50% of women contract disease post-sex with infected male, 20% of men contract disease post-sex with infected female.

• Symptomology:

  • Males:

    • Painful urination, copies purulent discharge from urethra (investigation of discharge reveals diplococci within polymorphonuclear leukocytes). 10% asymptomatic.

  • Females:

    • Symptoms more obvious, purulent discharge from vagina may be present with pain and itching. 50% asymptomatic.

  • Pharyngitis and purulent anal discharge evident if colonisation to throat or rectum.

• Untreated infections:

  • Female

    • Salpingitis, PID, infertility

  • Male

    • Prostatitis, epidydimo-orchitis, balantitis (inflammation of glans penis)

  • Septacaemia (1% of total cases):

    • Multiple pustular skin lesions in extremities leading to ≫septic arthritis, endocarditis, & meningitis. Can infect pregnant women ≫ infect babies as they pass vagina ≫ infant blindness ≫ ophthalmia neonatorum.

Pathogenesis

• Strategies employed to cause disease:

  • Pili  initial cell adhesion, Protein II (opa) ≫ more intimate attachment + initiates phagocytosis, Protein I (por) ≫creates pores in host membrane vacuole therefore phagolysosome not able to function, outer membrane oligosaccharide LOS mediates attachment btw bacterial cells ≫ initiates inflammatory process (cause most symptoms by this process ≫ eg: LOS mediates sterility in women with gonococcal salpingitis due to TNF-alpha release mediating scar tissue of uterine tubes).

  • Specific destruction of IgA by IgA1 protease

  • Continuous variation of surface of N.gonorrhoeae makes re-infection possible (immunity difficult).

Vaccines

• No vaccine available become surface proteins change. Protein I (not well displayed for antibody binding) only candidate for vaccination as it doesn’t change within strains but does change btw strains (but some areas in gene coding for this protein are conserved).

Prevention

• Safe sex practices, screening of society, antibiotics (cocktail of them).

Main points here are:

• Causes meningococcal meningitis, human transmission via aerosols (e.g.: coughing, sneezing).

• Colonies found in nasopharynx (attaching to microvilli of non-ciliated columnar epithelial cells)

• Infection by N.meningitidis ≫ bacteraemia (septicaemia) + acute inflammation of subarachnoid space (CSF is cloudy). Sometimes bacteraemia doesn’t lead to CNS involvement ≫disseminated IV coagulation + shock.

Most at risk

• Children <>

Symptomology

• Sore throat, headache, muscle aches, pains, chills, drowsiness. Signs include: fever, stiff neck, photophobia, irritations, petechial rash (peculiar to meningococcal meningitis)

Confirmation of Meningococcal Meningitis:

• CSF culture, blood culture. Requires special conditions: cultures show ↑ no. of gram –ve diplococci

Pathogenesis

• Survival on mucosal surface improved by IgA1 protease, contains polysaccharide capsule improving survival in serum (inhibits phagocytosis).

• Polysaccharide capsule variable: therefore divided into serogroups:

  • A, B, C, W₁₃₅, Y

  • Australia: B most common. Group B polysaccharide doesn’t cause immune response so vaccine not possible.

  • Vaccines available against A, C, W₁₃₅, Y. 2 yrs protection. Cannot be given to children <>

Treatment

• Mortality is 85-100% in untreated cases, 10% in treated cases.

• Penicillin, cephalosporins, erythromycin + chloramphenicol. Type give depends on drug allergies, local resistance patterns etc.

• Prophalyaxis important: chemotherapeutic (drugs) or vaccination.

“Abbreviations” and “Major Drugs”

The most common drugs include L-Dopa (Levo-dopa), dopamine receptor agonists. Anticholinergic agents, more central acting than atropine, are used to correct the disbalance of cholinergic pathways that are involved with Parkinson’s syndrome… anticipate that if a pt is on an anticholinergic drug, expect severe xerostomia and other effects of muscarinic receptor blockade. Selegiline is a MAO-B inhibitor, it works on the enzyme that breaks down catecholamines, to decrease dopamine breakdown. Secondarily, selegiline may be involved in the pathway to the production of oxidative substances which are thought to play a role in basal cell destruction.


Pts with Parkinson’s will present with a slow, shuffling motion (bradykinesia) and also may have muscle rigidity in their upper torso. Also, the primary symptom is tremor. Usually, Parkinson’s pts will be somewhat controlled, their tremor will be reduced to an acceptable level, so their quality of life isn’t too bad.


The cause of Parkinson’s dz lies in a defect in the brainstem nuclei, especially the substantia nigra (which has dopamine producing cells essential for muscle control). In Parkinson’s dz, there is a loss of these dopamine producing cells. The future management of Parkinson’s dz probably lies in stem cell research. Whatever assaults the basal cell ganglia causes Parkinson’s dz, we haven’t figured out the exact cause yet, but it is not a genetic disorder. Whenever the basal cell ganglia are assaulted, the acetylcholine producing neurons become prominent, making acetylcholine. It is a very rich pathway, and because there are a lot of cholinergic pathways in the motor cortex, you get stimulation of muscles from the acetylcholine. So anti-cholinergic drugs are used to treat Parkinson’s.


Therapeutic Overview

The cause of Parkinson’s is idiopathic (unknown). From the point of view of managing the pt, you’d like to enhance dopamine production but we can’t do it if the neurons aren’t making it. So we have to put back dopamine into the pt. Dopamine isn’t stable if we give it orally, so we give a precursor, Levodopa. Levodopa can be given orally, gets into systemic circulation, and eventually gets to the brain where it is converted to dopamine and acts on dopamine receptors. Dopamine receptors in the brain have a multitude of functions. If you can block muscarinic receptor you can neutralize the emergence of the acetylcholine pathway.



One of the things that results from the activation of monoamine oxidase B is the production of iron metabolites with peroxide in the formation of hydroxyl radicals. Current theories about the cause of aging say that it is due to oxidative stress; the body is producing more peroxides or hydroxyl radicals, which retards or destroys cell function. So the idea that MAO inhibitors may play a role here is a lot of speculation.



When you see drug names you should recognize the class that its in (not responsible for structures). Levodopa is very prominent… although tolerance is low, you’ve got to take a high dose and there is often a wearing off of efficacy, so sometimes a pt will have to switch drug classes for a while and then come back to L-dopa. L-dopa has a short half-life. Carbidopa (a decarboxylase inhibitor) is often co-prescribed to enhance L-dopa’s blood levels (because L-dopa is metabolized by decarboxylase); the two are combined in a single drug called Sinemet. Carbidopa by itself has no efficacy, it must be used as an adjunct. Anticholinergics (ie. trihexyphenidyl) are atropine-like in action. Amantadine is a surprising drug to see here. It was originally designed to fight the flu virus, but was not very effective and not accepted by the medical community, and died a slow death. However, Parkinson’s pts who took amantadine for the flue noticed decreased symptoms of Parkinson’s. Amantadine will never be encountered, even though its mentioned in textbooks, because its very very weak. Selegiline is a MAO-B inhibitor.



The drugs that are being used are all orally effective, but look at the difference in ½ life. So L-dopa, which is the mainstay, has a very short half-life; it must be repeatedly dosed. The anti-cholinergic drugs have a very long ½ life, but xerostomia is quite severe.



Depending on which subtype of dopamine receptor is in which location, activation or blockade will cause different neurological effects. If you have a deficiency of dopamine being released, if the receptor is still intact and you have a dopamine agonist you may get the same response. That’s why dopamine agonists are alternatives.



The neuroprotective effects of selegiline can prevent the progressive neuro-degeneration of what we thought was a drug-induced toxicity. A lot of people speculate that the underlying cause of damage leading to Parkinson’s is the formation of peroxide hydroxyl radicals. So if you can prevent that conversion using an MAO-B inhibitor, that would be good. So people took that theory a little further, and many physicians will tell their pts to supplement their diets with anti-oxidase supplements. The evidence there is a little weak, and many times in controlled studies, supplements have no effect.



“Clinical Problems”

L-dopa has limited effectiveness after 3-5 yrs of treatment. There is fluctuation in response to L-dopa. There is some disorder of movement, called dyskinesia. Some pts show significant psychotic problems. With the anti-cholinergic drugs there are bizarre changes that can occur when you’re dealing with the CNS, including confusion, and memory impairment.


“Oxidative stress and Parkinson’s Disease”

If a pt has the early symptoms of Parkinson’s dz and you put the pt on high doses of an anti-oxidant like vitamin E, think alpha tocopherol or ascorbic acid (vitamin C), selenium, or beta-carotine, would that prevent and retard the development of Parkinson’s dz? If these anti-oxidants are used its usually as an adjunct in the hopes that it will modify the progression.


“Trade Names”

Pts will often refer to brand names. Sinemet is the number 1 prescribed drug, which combines carbidopa and L-dopa. Benztropine has brand name Cogentin. Artane is trihexyphenidyl. Be alert, your pts may be on these drugs.

The underlying insult causing Parkinson’s dz is in the basal gangion, unique to Parkinson’s is loss of dopaminergic neurons in the substantia nigra.



The distribution of dopamine receptors is extensive throughout the CNS, but when the D1 and D2 receptors are the targets for drug therapy because they are the only ones found in the substantia nigra. If you can get agonist activity of D1 and D2 its good. D4 is in the frontal cortex in the medulla, this will have importance in the anti-psychotic drugs when the major dysfunction has to do with behavior. D5 involves the limbic system, which controls the emotional component of pain. So D4 and D5 become important in treating mental illness. D1/D2 are important in Parkinson’s dz.



They are slow, shuffling, and usually will not move their arms too much. They have motor instability. Help your pt get to the chair and avoid obstacles and anything that causes them to turn suddenly.



The most common motor instability is so-called retropulsion. The pt is unaware that he is leaning backward, and will often step backward involuntarily. This is not drug induced (sedatives and anti-HTN can cause dizziness and loss of balance, this is not the same thing as is seen with Parkinson’s pts). By the way, parkinson’s dz is more common in men than women. High amounts of caffeine produce tremors, but not the same kind as in Parkinson’s pts.

Dental aspects of Parkinson’s disease and its therapy include “Drooling.” This is due to diminished frequency of swallowing allowing saliva to pool in the throat. When severe, saliva will spill forward in the mouth and be manifested by a “drooling.” The condition is not due to excess production of saliva, but due to inability to swallow normal amounts of saliva. So don’t provide an anticholinergic drug to treat excess salivation, because the drooling isn’t caused by excess saliva production. Treatment with anti-Parkinson drugs improves the frequency of swallowing, thus reducing the extent of externalized saliva.


Bradykinesia can result in difficulty arising from your dental chair and difficulty in brushing and flossing.

L-Dopa: dizziness, orthostatic hypotension (30%), irregular heartbeat, nausea and vomiting (80%)

Bromcriptine (D1/D2 agonist): decreased salivary production and flow, with risk of caries, periodontal disease, candidiasis

Benztropoine, Trihexylphenidyl: anticholinergic agents cause significant xerostomia, risk of tachycardia.

Selegiline: decrease salivary flow, development of caries, periodontal disease, risk of candidiasis. Meperidine (Demerol) is CONTRAINDICATED. This is very important, because deaths have occurred with one dose of Demerol given parenterally (in conscious sedation), the metabolite that Meperidine goes to, in the presence of an MAO inhibitor like Selegiline, is neurotoxic and leads to convulsions, coma and death.

L-dopa: orthostatic hypotension, probably a vascular effect; tongue thrusting, dysphagia, dysguesia (altered taste), increased cardiac epi effect (although many texts will say to avoid epi for pts on L-dopa, this is not valid… we want good anesthesia to prevent a huge release of endogenous epi if pain occurs. Just don’t inject a couple of carps of 1:100,000 epi lidocaine into a blood vessel, and you’ll be ok.)

Selegiline: rarely, transient nausea

Anticholinergics: xerostomisa (severe), dysphagia, vagolytic effects

Artane (trihexylphenidyl) and Cogentin (benztropine) are the most common anticholinergic drugs. These are almost exclusively used for Parkinson’s disease.

The emergence of Entacapone (Contan) and Tolacone (Tasmar) is important because they prevent the peripheral catabolism of L-dopa to inactive metabolites, thus enhancing the actions of L-dopa and its product dopamine, incidentally reducing the dose requirement. These drugs are in use more and more, the consequences are not exactly known, but we are theoretically worried about enhancement of epinephrine effects for pts taking COMT inhibitors.



Entacapone (Contan) is only used for pts taking L-dopa/carbidopa; it is an adjunct. It is used in pts where levodopa therapy is wearing off. Contan decreases the metabolism of levodopa before reaching the brain and prolongs the actions of levodopa/carbidopa. Side effects of Contan include: dsykinesia, nausea, diarrhea, abdominal pain, urine discoloration. Contan is not used as monotherapy for Parkinson’s disease.



Requip (ropinirole) was the first D3 receptor agonist. It isn’t popular among neurologists. Mirapex (pramipexole) is also a D3 receptor agonist. With this drug, pt may fall asleep abruptly, have hallucinations, become demented, and have orthostatic hypotension, so there’s a lot to worry about. D3 receptors might be in the basal ganglion and control movement disorders, but they’re also stimulating the D3 receptor elsewhere where behavior and cognitive function is occurring.

Antioxidant supplements (ascorbic acid, alpha-tocopherol, beta-carotene). Currently, neurologists are exploring electrode implants in different parts of the brain to get dis-inhibition of block the tremors. Pts who don’t respond to anything can go in and get their thalamic tract cut. Finally, with stem cell research they’re trying to get fetal nigral cell implants to work, making dopamine.

1. The body handles most drugs by 1^st order reactions, e.g., rate is of absorption and elimination is proportional to concentration. The higher the blood concentration, the faster it is eliminated.
2. Few drugs (Eg- alcohol, phenytoin etc) follow zero order kinetics, where rate is independent of concentration (sometimes called "saturation kinetics", capacity-limited elimination, or Michaelis Menten kinetics). These drugs, at therapeutic concentrations, are the best known drugs with zero order elimination.

1. Plasma proteins

1. Many drugs bind to plasma proteins (generally, albumin for acid drugs or alpha₁-acid glycoprotein [AAG] for basic drugs although many basic drugs also bind to albumin). Binding is usually reversible and is very complex.
2. The binding of a drug to plasma proteins limits its concentrations in tissues and at the locus of action because only unbound drug is in equilibrium across membranes (bound drug acts as a depot.
3. Binding may be relatively nonselective for drugs with similar physicochemical characteristics. Such drugs may compete with each other as well as with endogenous substances for binding sites
4. Alcoholism, pregnancy, aging, congestive heart failure, malnutrition, burns, trauma, kidney and liver disease and many other conditions may lower plasma albumin. Renal disease may also change albumin configuration resulting in decreased binding. “Usual doses of a highly bound drug to persons with diminished plasma albumin may result in drug toxicity because of the increase in free drug.

2. Half Life:

1. Half-life is the time it takes the total amount of the drug in the body to be 50% eliminated from the body. However, when we measure "half-life" we determine the time it takes plasma concentration to be reduced by 50%. This is more correctly termed the plasma elimination half-life (symbolized as t½). A drug’s half-life can vary greatly from patient to patient (usually associated with impairment of the liver or kidneys).
2. The half-life can be determined from a plasma elimination curve or can be calculated. Half-life changes inversely with clearance and directly with volume of distribution, hence:t½ = 0.693 x V/Cl

The half-life is not always a good indicator of drug elimination or even of duration of action of a drug. However, it does provide a good indication of the time required to reach steady state after a dosage regimen is initiated or to decay by 50% from steady state after stopping a drug.

With repeated drug administration it takes about five (texts vary from 4 to 7) doses of drug administered on the half-life for the drug to reach a plateau in plasma concentration (steady state)

3. Clearance is the measure of the body's ability to eliminate a drug. It can be calculated.

The organs can only clear drugs from the blood with which they are in direct contact. As clearance is decreased (due to disease, for example), half-life would be expected to increase provided there is no change in Vd. Similarly, diseases that change protein binding of drugs may affect clearance as well as Vd. Generally, lipid soluble drugs are cleared through the liver; water soluble drugs through the kidneys. The balance of hepatic and renal clearance of both the parent drug and any active metabolites must be understood to prescribe wisely.

Drug metabolism has five possible consequences of therapeutic significance. With many exceptions, the primary purpose of metabolism is to change lipid soluble active compounds (which are not readily eliminated from the body) to water soluble inactive compounds that can easily be excreted. Metabolites are usually less lipid soluble and less active than the parent compound. However, many drug metabolites have pharmacological activity or, occasionally, are more toxic than the parent compound (e.g., acetaminophen). Some drugs may be "prodrugs", which must be metabolized to active compounds (many of the ACE inhibitors, e.g., lisinopril, are prodrugs).

The rate of drug metabolism differs markedly among races as well as individuals. Infants & elderly often having decreased drug metabolizing capabilities.

Pharmacogenetics is a consideration of increasing importance in determining drug effect in certain individuals.

Pattern of biotransformation

a. Reactions are classified as phase I and phase II

ACTIVE DRUG ≫ PHASE I(ASYNTHETIC)≫OXIDIZED PRODUCT≫ PHASE II (SYNTHETIC)≫CONJUGATED PRODUCT(INACTIVE)

b. Phase I (termed "asynthetic") usually converts the parent drug to more polar metabolites by oxidation, reduction, hydrolysis, dealkylation, etc. Phase I products may or may not be active.

c. Phase II ("synthetic") involves coupling the drug or its phase I metabolite to endogenous water-soluble substrates, such as glucuronic acid, sulfuric acid, mercapturic acid, acetic acid, or amino acid. Phase II products are usually inactive. All conjugation reactions except glucuronidation are catalyzed by nonmicrosomal enzymes.

d. Drug metabolism may take place in any portion or organ of the body although hepatic microsomal enzyme systems are responsible for the biotransformation of the majority of drugs. Plasma, kidney, lung, and GI tract also contain enzymes that contribute to drug metabolism.

. The microsomal enzymes (described as the P450 system) catalyze most of the oxidations of drugs. Lipid solubility is an important factor in drugs to be metabolized by microsomal enzymes, since this property favors penetration of the drug into the endoplasmic reticulum and binding with enzymes.

c. An important oxidizing enzyme system is the cytochrome P-450 system (CYP 450). It is composed of at least 30 isoenzymes.

The more important ones are;

• CYP1A2 (metabolizes theophylline, caffeine; acetaminophen),

• 2D6 {metabolizes tricyclic antidepressants, opioids, B-blockers, phenothiazines, 1-B & 1-C antiarrhythmics),

• 3A4 (metabolizes cyclosporine, erythromycin, calcium channel blockers, lovastatin, triazolam, tamoxifen, quinidine and many others),

• 2C group (phenytoin, S-warfarin, imipramine, tolbutamide).

These enzyme systems may be stimulated (enzyme induction) or inhibited (enzyme inhibition). Cytochrome requires an electron obtained from NADPH plus oxygen to be function. Cytochrome P-450 goes from the reduced to oxidized state by change in valence of an iron molecule.

Cimetidine binds to the iron molecule, preventing the change in valence and inhibiting the action of cytochrome P-450. Thus, cimetidine affects several of the P450 isozymes.

The oxidation enzymes are occasionally called the "mixed function oxidases" (MFO) because of the variety of metabolic processes affected (e.g., hydroxylation, demethylation, etc). Certain ethnic groups or individuals possess genes that cause alterations on aminoacid sequences of enzymes or receptor sites (sometimes termed polymorphisms).

Clinical observations of inherited differences in drug effects have given rise to the field of pharmacogenetics.

d. Many phase I enzymes, particularly oxidizing enzymes, are "inducible" (i.e., certain compounds will increase enzyme activity). A number of enzymes are can also be inhibited. Phase II enzymes generally are not (as always, in pharmacology, there are exceptions) capable of being induced by drugs or other chemicals. These terms are further discussed under drug interactions.

e. Glucuronidation

Glucuronic acid is a large endogenous water soluble compound that is attached (by glucuronyl transferase) to many phenols, alcohols, amines, hydroxyl compounds, & carboxylic acids during phase II metabolism. These reactive groups (phenols, alcohols, etc.) are often produced by phase I metabolism. Glucuronides are generally inactive (exception, morphine-6-glucuronide), are not affected by enzyme induction or inhibition, and are rapidly secreted into the urine or bile. Glucuronyl transferase is deficient in neonates & premature infants (hence drugs largely glucuronidated [e.g., chloramphenicol] quickly reach toxic levels in neonates).

a. The kidneys are the most important organs for elimination of drugs and their metabolites.

b. Substances excreted in feces are either unabsorbed orally ingested drugs or metabolites excreted in bile.

c. Excretion of drugs in milk is important because of potential unwanted pharmacological effects in nursing infants.

d Pulmonary excretion is important mainly for elimination of anesthetic gases & vapors.

Renal excretion

a. Excretion of drugs & metabolites in the urine involves three processes: glomerular filtration, active tubular secretion, and passive tubular reabsorption.

b. The amount of drug entering the tubular lumen by filtration is dependent on its fractional plasma protein binding and glomerular filtration rate (GFR).

c. In the proximal renal tubules, certain organic anions and cations are added to glomerular filtrate by active, carrier-mediated tubular secretion (e.g., penicillin)

d. In the proximal & distal tubules the nonionized forms of weak acids & bases undergo net passive reabsorption (following a concentration gradient between the renal tubular fluid and the blood

e. P-glycoprotein is an "efflux drug transporter" that may be important in the transport of certain drugs (e.g., renal elimination of digoxin; movement of quinidine across the blood brain barrier; increased first pass effect with felodipine).

Biliary & fecal excretion

Many metabolites formed in the liver are excreted into the intestinal tract via the bile. They may be excreted in feces or may be enzymatically converted to the active drug and be reabsorbed (termed enterohepatic circulation).

This is a non-motile, non-spore forming and aerobic bacilli genus. The cell wall is rich in lipids, making it resistant to many disinfectants and laboratory stains. Due to the complexity of the cell wall, some bacteria only divides every 12-24 hrs therefore requiring many weeks of incubation, whilst others of the same genus require only 3 days.

The stain most commonly used is the Ziehl-Neelsen – acid fast – decolourisation is not possible once stain is established. The different types of species is identified by growth temperature, rate of growth and whether they are:

• Photochromogens: pigment prod in light

• Scotochromogens: pigment in light + dark

• Nonchromogens: no pig prod

Mycobacteria

This can be divided into two main groups:

• M TB (Mycobact. Tuberculosis complex)

  • Mycobact. Tuberculosis; M bovis; M africanum

• PPEM (Potentially pathogenic environment mycobacteria)(Atypical mycobacteria; runyan groups)

  • 95% are Mycobact. Avium intracellulare

This is a gram +-ve acid fast bacilli. It grows slowly in Lowenstein-Jensen medium (2-8 weeks) and main disease caused is tuberculosis. In most patients, the disease is asymptomatic (as will be discussed later below). 90% of cause is due to inhaled air droplets involving the lungs. There are 3 main strains: 2 human and 1 bovine. Mycobact TB and Mycobact africanum (human): both form niacin under culture, and reduce nitrate whereas Mycobact bovis (bovine): does not form niacin, does not reduce nitrate. Both varieties are intracellular in host, therefore antibody mediated immunity is rather useless.

Pathogenicity and Immunity

Inhalation of aerosolised infectious particles ≫ travel to terminal airways ≫ penetrate into unactivated macrophages located in the alveoli and replicate freely ≫ infected cells destroyed eventually by build up of bacteria≫ cell lysis ≫ new cycle begins of unactivated infected phagocytic cells ≫ meanwhile, circulating macrophages and lymphocytes brought to infectious foci (i.e.: chemotactic factors etc) ≫ formation of a multinucleated giant cells made up of fused macrophages ≫ meanwhile, already infected macrophages can now spread into the blood stream and into other organs (i.e.: spleen, kidney, CNS etc).

Intracellular replication of bacteria leads to CD4+ and CD8+ cells to be activated  CD4+ cells lead to antibody production ≫ due to intracellular nature, this is proved useless ≫ CD4+ release cytokines which activate macrophages ≫ these engulf and kill mycobacteria ≫ cytotoxic T cells lyse macrophages, release mycobacteria therefore now out in the open to be phagocytosed by other activated macrophages≫ if mycobacteria numbers are large then will cause tissue damage due to immune response (i.e.: cytokine toxicity, activation of complement cascade, ischaemia, hydrolytic enzymes derived from macrophages and cell lysis etc).

Collections of activated macrophages trying to control the mycobacterium can be seen histologically as: granulomas. These cells form a wall, preventing spread of bacilli. Larger granulomas become encapsulated with fibrin therefore – protecting bacilli from phagocytosis. This way the bacilli can remain dormant for years only to be reactivated at a later stage, when the person’s immune response is suppressed due to the age related factors, or immunosuppressive condition/therapy.

Clinical Picture

Route of infection: mainly via respiratory tract, can be via gut or skin.

Primary TB: Mostly via respiratory tract, survives intracellularly, healing, fibrosis. From lung can go to lymph nodes, spread systemically. Cell mediated immune response (as documented above) forms granulomas – prevents spread of infection, but if suppressed then can lead to uninhibited spreading and/or eventual death. Some possible conditions:

• bronchopneumonia, septicaemia, infections of spleen, GIT, UGT, bones, skin, miliary tuberculosis

• remains dormant for some years in some cases, only to be reactivated later in life.

Secondary infection:

This can be described simply as reinfection or reactivation of the primary dormant infection.

Diagnosis (Murray 3^rd Ed pp 326)

The clinical signs and symptoms of tuberculosis is representative of the site of infection. Onset of disease is insidious, malaise, weight loss, cough (blood in sputum), and night sweats. Radiographic evidence, positive skin test, and positive culture tests are all used in determining the diagnosis of TB. In miliary TB, positive pulmonary disease may not be present.

For laboratory cultures, you must isolate the bacilli from sputum, pus, urine, CSF etc. Skin tests are used most commonly inoculated with M TB. This gives an idea whether the person is infected, has had previous exposure.

Treatment (Murray 3^rd Ed pp 328)

Slow growing mycobacteria are resistant to most antibiotics, therefore treatment is achieved only my giving multidrug therapy over an extended period of time – to avoid development of drug resistant TB. Frontline drugs include: INH (isoniazid), rifampin, pyrazinamide for 2 months. Additional four months of therapy with INH and rifampin alone. If patient is from a drug resistant area, then you can add ethambutol and streptomycin to the frontline drugs.

Control (Murray 3^rd Ed pp 329)

TB is a highly infectious disease, so developing contacts and tracing cases is essential to maintain a infection free area. Animal sources must be treated, or eradicated – and milk must be pasteurised to avoid Mycobact. Bovis. Vaccination using Mycobact Bovis is commonly used in countries where TB is endemic. Unfortunately BCG cannot be used in immunocompromised patients. Also, another problem is that positive skin reactivity test results in all patients immunised with BCG, therefore proving quite useless as one of the testing methods. The efficacy of immunisation is about 50-80% in children, decreasing with age.

Leprosy is caused my mycobacterium leprae. Clinically divided into lepramatous leprosy and tuberculoid leprosy. Patients with tuberculoid leprosy have strong cellular immunity and a weak antibody mediated response. Like M tuberculosis infections, macrophages are activated, phagocytosis occurs, and bacilli replicate and are cleared. In contrast, lepramatous leprosy – in this we have a strong antibody response and a weak cell mediated response. This is the most infectious form of leprosy.

Clinical features include:

• Muscle wasting, deformity, digital resorption, blindness, and digital loss due to trauma, burns. This type of leprosy is not easily transmissible. Transmission is though to be also by inhalation of infectious aerosols, and skin contact with respiratory secretions and wound exudates. M Leprae cannot be grown in cell free cultures, so diagnosis is confirmed by histopathogical findings, and clinical signs and symptoms.

Lepramatous (nodular)

This is when you have a strong antibody response and a weak CMI. The earliest sign of infection is presented by indeterminate leprosy – a inconspicuous macule. Macular lesions become raised (skin raised), nodular lesions appear in late stage lepramatous leprosy usually on face, ears.

Tuberculoid

Skin lesions are raised, macular or appear as rings and usually have a central healing part. The lesion is anaesthetic unless lesion is on the face. The peripheral nerve supplying the lesion may be enlarged (i.e.: ulnar, popliteal nerve etc). Tends to heal spontaneously but very slowly, often without later disability.

Borderline

This is not clear cut, but may have lesions in between lepramatous and tuberculoid.

Lepramatous and borderline leprosy are diagnosed by appearance of M leprae in slit skin smears. The dermis is scraped with a blade sent off for microscopy. The stain used is Ziehl-Neelsen method. Nasal smears may also be used to show evidence of lepramatous leprosy.

The lepromin test is like the tuberculin test, but read after 4 weeks. The degree of cell immunity is evident, and is useful in classification of disease and the type of treatment and prognosis that can be estimated.

Serological diagnosis can be achieved because M leprae has a characteristic surface lipid (PGL I) which can be detected in tissue by monoclonal antibody – i.e.: antibody binds to this therefore we know M leprae is present.

Treatment: Sulphones (eg: Dapsone), Rifampicin, lofazimine. The former two used together to prevent resistance.

• Introduction:

These drugs are classified as Anti-Muscarinic and Anti- Nicotinic drugs. Anti-nicotinic drugs are ganglion blockers and neuromuscular junction blockers. The ganglion blockers have a very little clinical use.

Muscarinic Receptor Antagonists/ Muscarinic Receptor Blockers

• Antimuscarinic agents were of plant origin.

• Belladonna (beautiful woman, a reference to the drug's mydriatic effects,) are found in many plants.

• Atropa belladonna (Solanaceae) or the deadly nightshade contains atropine (dl-hyoscyamine) as does Datura stramonium (Jamestown or jimsonweed, thorn-apple, etc.)

• Scopolamine, also an alkaloid, is found in the shrub Hyosyamus niger and Scopolia carniolica.

  • An alkaloid is one of a large group of organic, basic plant substances. They are usually pharmacologically active and bitter in taste

  • Alkaloids

    • atropine

    • caffeine

    • morphine

    • nicotine

    • quinine

    • strychnine

• Tertiary and Quaternary Antimuscarinic Agents

  • Tertiary amines: Eg Atropine, scopolamine, homatropine, Pirenzepine, Benztropine, are, generally well-absorbed and able to penetrate the CNS.

  • Quaternary muscarinic receptor antagonists: Eg-, Ipratropium, Glycopyrolate etc - tend to be more potent as muscarinic blockers and have increased ganglionic blocking action.

  • Quaternary (permanently charged) antagonists do not penetrate the CNS to a significant extent. Therefore, CNS activity is limited.

Central Nervous System: In normal doses, atropine produces little CNS effect. In toxic doses, CNS excitation results in restlessness, hallucinations, and disorientation. At very high doses, atropine can lead to CNS depression which causes circulatory and respiratory collapse. By contrast, scopolamine at normal therapeutic doses causes CNS depression, including drowsiness, fatigue and amnesia. Scopolamine may exhibit more CNS activity than atropine because scopolamine crosses the blood brain barrier more readily.

Eye:

Muscarinic receptor antagonists block parasympathetic responses of the ciliary muscle and iris sphincter muscle, resulting in paralysis of accommodation (cycloplegia) and mydriasis (pupillary dilation). Mydriasis results in photophobia, whereas cycloplegia fixes the lens for far vision only (near objects appear blurred). Systemic atropine at usual doses does not produce significant ophthalmic effect. By contrast, systemic scopolamine results in both mydriasis and cycloplegia. Note that sympathomimetic-induced mydriasis occurs without loss of accommodation. Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in patients with narrow-angle glaucoma. An increase in intraocular pressure is not typical in wide-angle glaucoma.

Cardiovascular System:

The dominant effect of atropine or other antimuscarinic drug administration is an increase in heart rate.This effect is mediated by M₂-receptor blockade thereby blunting cardiac vagal tone.

Muscarinic Type M2
Agonist	Antagonist	Tissue (Heart)	Responses	Molecular Aspects
methacholine	atropine	SA node	decreased phase 4 depolarization; hyperpolarization	K+ channel activation (hyperpolarizing) through ß-gamma Gi subunits*; Gi -mediated inhibition of adenylyl cyclase* (negative inotropism) (Gi can inhibit directly Ca2+ channel opening)
		Atrium	decreased contractility; decreased AP duration
		AV node	decreased conduction velocity
		Ventricle	decreased contractility

• * K+ channel activation has a hyperpolarizing effect. The increase in membrane-potential (more negative) moves the membrane-potential away from threshold. The consequence of this effect is to take longer for diastolic depolarization (phase 4) to reach threshold in SA nodal pacemaker cells. Accordingly, muscarinic receptor activation decreases rate and muscarinic receptor blockade increases rate.

• Atropine by blocking parasympathetic tone may facilitate AV nodal conduction. In some clinical conditions, atropine may reduce heart block. Excessive vagal tone in digitalis toxicity can be diminished with atropine.

• Severe bradycardia and AV blockade associated with myocardial infarction may be reduced by atropine.

• Respiratory Tract:

• Parasympathetic activity produces bronchoconstriction. Activation of nicotinic and M₁-muscarinic receptors in parasympathetic ganglia which lie in the airway wall then activate postganglionic fibers. These postganglionic fibers release acetylcholine which activate M₃ muscarinic receptors which produce bronchiolar smooth muscle contraction. M₂ receptors may also be present.

Muscarinic Type M3
Agonists	Antagonists	Tissue	Responses	Molecular Aspects
acetylcholine, methacholine	atropine	Smooth muscle	Contraction	Phospholipase C (PLC) stimulation through Gq/11 formation: (IP3 ) + diacylglycerol (DAG): increased cytosolic Ca2+
		Secretory glands	Increased Secretion

• Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often resulting in bronchodilation. The magnitude of the effect depends on the basal parasympathetic tone. Ipratropium has been prominent in treating respiratory disease.

• Atropine and other antimuscarinic inhibit mouth, bronchial, and pharyngeal secretion which reduce reflex laryngospasm during general anesthesia. Also, atropine or other antimuscarinics are given during general anesthesia to blunt increases in vagal tone due to mechanical effects on viscera during abdominal surgeries.

• Ipratropium, along with sympathomimetics, are useful in management of asthma, because of the following advantages over atropine:

• Ipratropium does not inhibit mucociliary clearance (atropine does)

• Ipratropium has no significant CNS effects.

• Inhaled ipratropium (a quaternary, charge molecule) has limited or no systemic effects.

• Gastrointestinal Tract

• Vagal effects on the gut are mediated not only by acetylcholine but also by actions on intramural serotonergic and dopaminergic neurons. Atropine can block Ach effects while having no effect on non-cholinergic modulation of GI motility. Vagal input affects gastrin release and may be blocked by atropine; however, gastric acid release is more effectively prevented by M₁ specific antimuscarinic drugs (pirenzapine) and H₂-selective histamine receptor blockers.

Anesthesia Applications

• Pre-anesthetic medication – inhibit mouth, bronchial, and pharyngeal secretion which reduce reflex laryngospasm during general anesthesia.

• Management of intra-operative bradycardia.

• Use in antagonism of nondepolarizing neuromuscular-blocking agents

2. Central Nervous System Uses

• Antimuscarinics are used clinically as preanesthetic medication to reduce vagal effects secondary to visceral manipulation during surgery.

• Centrally acting antimuscarinics like benztropine, benzhexol etc are used in Parkinson's disease & in treating extrapyramidal side effects induced by antipsychotic drugs.

• Scopolamine (transdermal) is effective in preventing motion sickness.

• Atropine is an effective specific antidote to excessive cholinergic stimulation following organophosphate intoxication.

• By blocking muscarinic receptors, the consequence of cholinesterase inhibition is attentuated.

• Atropine may be used in conjunction with Pralidoxime which may reactivate phosphorylated & inhibited acetylcholinesterase.
  

• Treatment of Reflex-Mediated Bradycardia
• Anticholinergic drugs: drugs of choice for management of intraoperative bradycardia --especially if due to increased vagal tone
  
• Correction of Heart Block – 1^st, 2^nd & 3^rd Degree AV Block
  

4. Respiratory Uses

Bronchial Asthma

• Bronchodilation following anticholinergic drug administration is due to blockade of acetylcholine effects on airway smooth muscle muscarinic receptors-M3

• Preferred Route of Administration for bronchodilation: aerosol

• most effective in preventing/treating bronchospasm due to ß-adrenergic antagonists

• Ipratropium - synthetic quaternary ammonium atropine congener is the drug most commonly used for aerosol administration --

  • more effective than ß-adrenergic agonists in producing bronchodilation in patients with chronic bronchitis or emphysema (high cholinergic tone)

• Ipratropium has an advantage in asthma compared to atropine because:

  • Ipratropium does not inhibit mucociliary clearance (atropine does)

  • Ipratropium has no significant CNS effects.

5. Gastrointestinal Tract

• Vagal input affects gastrin release and may be blocked by atropine; however, gastric acid release is more effectively prevented by M₁ specific antimuscarinic drugs (pirenzapine) and H₂-selective histamine receptor blockers.

• Combined with Opioid antidiarrhoeal in traveller’s diarrhea.

6. Eye Disorders

• Opthalmoscopic examination of the retina –

  • Short acting drugs (Tropicamide, Cyclopentolate) prefered over atropine

  • Cyclopentolate –prefered in children

• To prevent adhesion formation in uveitis & iritis

7. Urinary Disorders

   • Provide symptomatic relief in the treatment of urinary urgency –inflammatory bladder disorders

   • Helps in reducing involuntary voiding in patients with neurologic diseases

8. Cholinergic drug poisoning

• Irreversible Anticholinesterase compounds poisoning either accidental or suicidal

  • Atropine 2mg every 5-15min till signs of atropinization –

  • Enzyme reactivator – like Pralidoxime are used to reactivate the enzyme acetylcholinesterase.

• Cholinergic Blockers:Adverse effects

  • Dry mouth (xerostromia), Blurred vision (cycloplegia), Photophobia (mydriasis), Tachycardia,

Questions

1. Describe the general properties of this group of viruses

2. What are two main subtypes of this group, describe in detail?

3. How would you prevent polio.

4. Coxsackie virus has several groups, describe the pathological conditions associated with each?

5. How would you diagnose and treat coxsackie viruses?

Picornavirus are 20-30nm, icosahedral, enveloped, ss, +ve polarity. There are two main groups based on resistance to ph between 3-5 and habitat. 1^st group is rhino viruses, 2^nd group is enteroviruses. Note that enteroviruses do not cause gastroenteritis. The former has more than 100 serotypes, which cause common cold infections, upper and lower respiratory tract infections and bronchiolitis in infants. Development of vaccine is unlikely. The latter has different viruses. The polio virus causes poliomyelitis in adults. There are 3 serotypes of which, only A is highly virulent, has a faecal oral route of spread. It penetrates the intestinal mucosa and then spreads to regional lymph nodes. In some cases, further multiplication may cause viraemia, and sometimes may infect the meninges causing meningitis. It may also spread to the anterior horn of the spinal cord, causing motor neurone lesions, or to the brain cause poliomyelitis or polioencephalitis. Prevention is by an oral vaccine, live, attenuated, sabine vaccine. Covers the three polioviruses, give at 2, 4, 6 months, again at 4-6 yrs and then again at 12-15yrs old. Earlier a dead Salk vaccine was used.

The Coxsackie virus is another group belonging to the enterovirus group. It has four different types: A, B, Echo virus, Enteroviruses. These have 24, 6, 34,& 4 serotypes respectively. Type A causes (HH) – herpangina, hand/foot & mouth disease. Type B causes (BMPPP): Bornholm’s disease (epidemic myalgia  muscular pain), Myocarditis, pericarditis, pancreatitis, poliomyelitis like illness. Enterovirus type 68, 70, 71 cause: (PAE): Pneumonitis, bronchiolitis, acute haemorrhagic conjunctivitis, encephalitis. Diagnosis is isolation of virus in faeces, sometimes throat and CSF specimens required. Use serology to confirm for antibodies. Pleconaril is a new anti-viral inhibits several types of picornaviruses by binding irreversibly to viral capsid.

Questions

1. Describe the general properties of these types of viruses?

2. Norwalk agent causes what type of infection, describe its transmission, and diagnosis?

Caliciviruses/Astroviruses are icosahedral, non-enveloped, resemble picornaviruses or star shaped, ss, +ve polarity. Norwalk agent probably accounts for up to 1/3 of all non-bacterial causes of gastroenteritis. Usually severe in older children and some adults. Cause winter vomiting disease. Transmission is via: faecal oral route, contaminated or eating raw shell fish, contaminated food and water, airborne transmission is also important. Diagnosis is by EM of stools.

Questions

1. Describe the general properties, also name the subtypes?

2. Describe the subtypes in general, especially the condition caused by rotaviruses?

Reoviruses are: 50-80nm, icosahedral, non-enveloped, ds, segmented genome. There are three main groups. Rotavirus, Reovirus, Orbivirus. The first one is an important cause of infantile diarrhoea, has a double wheel capsid structure, five groups of which A is most common, and has faceal oral and respiratory route of spread. Reoviruses are usually found in the nasopharynx and intestinal tract of man, but not associated with any disease. Orbiviruses are important in veterinary illnesses such as: blue tongue sheep, and Colorado tick fever.

Rotaviruses cause rotaviral gastroenteritis, caused by group A. Have a faecal oral route of spread, incubation period of 1-3 days, duration of 4-6days, fever, vomiting, and diarrhoea. Diagnosis is done by ELISA, EM, and latex agglutination.

Questions

1. Describe the general properties, including its relation to arboviruses.

2. What are the main Genus types present, describe in detail each one, including diagnosis and symptomology?

General properties of togaviruses include: 40-50nm in size, enveloped, icosahedral, ss, +ve polarity. Contains some important arbo viruses ≫these viruses are transmitted from infected arthropods via bites and stings. Symptoms are discussed according to the target organ infected. There are two main genus types include: alpha and rubivirus. Alpha virus cause sub-clinical infections which may cause fever, encephalitis ≫ EEE, WEE, VEE. Ross River fever is called ≫ which is a case of epidermic polyarthritis, caused by Culex anulirostris, Aedes vigilax, and other Aedes spp. Barmah Forest Virus infection: causes epidermic polyathritis and is an important virus nowadays. Ross River Virus: this is the most common arboviral infection in Australia, as domestic and native animals become reservoirs. Symptoms include: pain in muscles and joints, polyarthritis, maculopapular rash, malaise, and headache. Diagnosis is confirmed serologically. The Rubivirus causes Rubella, to which there is now a vaccine ≫ MMR, given to all women before puberty. You get rash, enlarged glands behind neck, polyarthralgia. Confirmation of rubella is done via serological testing, looking for IGM or four fold increase in IgG. Congenitial rubella is a killer if acquired during early weeks of pregnancy (<>12 wks presents deafness only.

Site of action:

GABA_A receptor

Structure of GABA_A receptor:

• Comprised of 5 subunits

  • 2 α subunits (to which GABA binds)

  • 2 β subunits (to which barbiturates bind)

  • 1 γ subunit (to which benzodiazepines bind)

• Benzodiazepine receptor of GABA_A is heterogeneous

  • 13 known subunits of the GABA_Aγ receptor

    • Benzodiazepine-sensitive

      • α1, α2, α3, α5

    • Benzodiazepine-insensitive

      • α4 and α6

• Receptor channel contains either positively or neutrally charged amino acid residues that select exclusively for anions (i.e., Cl^-)