Pharmacology Flashcards
What are someof the therapeutic uses of antacids?
- Treat ruminal acidosis
- Gastritis
- Oesophagitis
Describe how antacids work
- Bicarbbonate used to neutralise acids
- Mucus protects stomach wall
- Nutralisation by magnesium hydroxide and trisilicate, aluminium hydroxide gel, alginates and simeticone
Describe the mechanisms of action of alginates and simeticone in the stomach
- Antacids
- Adsorbents
- Coating action, bind bacteria adn toxins, mop up HCl
- Can be used to treat ruminal acidosis, gastritis and oesophagitis
Describe the mechanism of action of sucralfate
- Disaccharide
- Sticks to stomach lining
- protects against acids
- Can prevent uptake of other drugs
What is the effect of H2 antagonists in the stomach?
- Prevent binding of histamine receptor, reduces action of cAMP on ion pums and so reduces proton production
- Inhibits gastrin, histmaine and ACh stimulated secretion of HCl
- Pepsin secretion falls (less volume of fluid)
- Rebound increase on withdrawal
- E.g. ranitidine
Why should cimetidine not be used?
- H2 antagonist
- Inhibits cytochrome P450, slows metabolism
- can lead to toxic build up of other drugs
What is the effect of proton pump inhibitors in the stomach?
- Prevent action of proton pump, reduce acidity of lumen of stomach
- Highly effective
- last around 24 hours
Describe the mechanism of action of proton pump inhibitors in the stomach
- Bind irreversibly and competitively to enzyme that catalyses proton pump, shuts down process
- Immature cells mature within 24 hours, ATP ase available again
- Shut down pump for 24 hours
- Irreversible binding to ATPase
- Basal and stimulated release of HCl inhibited
What is the effect of prostaglandin analogues on the stomach?
- Increase mucus and bicarbonate secretion (prostaglandin E2)
- Inhibit acid secretion
- Increase mucosal blood flow
- (Increase uterine contraction so contra-indicated in late gestation)
Describe the mechanism of action of prostaglandin analogues in the stomach
- NSAIDs inhibit COX1 and COX1 and so reduce production of prostaglandin 2, so increase acid production = increased risk of ulcers
- Artificial prostaglandins (mesoprostol) bind to receptors, reduce acid production, increase bicarbonate and mucus production
- Mesoprostol is stable analogue of PGE1
What are the 2 centres controlling vomiting?
- CRTZ - chemoreceptor trigger zone
- Vomiting centre in brainstem
Briefly outline the chemoreceptor trigger zone in vomiting
- Not protected by BBB so drugs can interact here
- Responds to chemical stimuli
- Also for motion sickness
- Input from vestibular apparatus
- Impulses pass to vomiting centre in brainstem
What is the function of the vomiting centre inthe brainstem?
Coordinates and integrates vomiting
Describe the process of vomiting
- Controlled by emetic centre
- Nerve impulses reach emetic centre from 2 pathways
- Central and peripheral
- Motion sickes input from vestibular apparatus
- Substance P key NT in vomiting
- Binds to NK-1 receptors, found in highest concentration in emetic centre
- NK-1 receptors on cell membrane
- Binding of correct ligand on external side, conformational change, triggers series of reactions
- Stimulation of NK-1 by substance P in nucelsu tractus solitarus of emetic centre = vomiting reflex
- Output via dorsal vagal complex
- Fibres from DVC go first to gut
- Close pylorus, reduce gastric tone, open cardiac sphincter, increase tone in duodenum and jejunum
- Motor vagal fibres infor via resp muscles to contract diaphragm, contract abdo muscles to expel contents from upper GI tract
= vomiting
What are drugs and compounds called that induce vomiting and give examples
- Emetics
- Apomorphine
- Alpha-2-agonists (xylazine)
- Syrup of Ipecac
Describe the mechanism of action of apomorphine
- Dopamine agonsit
- Applied via IV or mucosa
- Rapid effect
- Contra-indicated in cats
- Central pathway
Describe the mechanism of action of Syrup of Ipecac
- Direct irritant
- Cardiotoxic in high doses
What are the key receptors used by anti-emetics?
- H1 (histamine receptor)
- 5-HT3 (serotonin receptor)
- Muscarinic receptors
- Dopamine antagonists
What action does an anti-emetic have on the H1 receptors?
- Antagonistic
- Reduces vomiting
- most drugs are H1 antagonists*
What action does an anti-emetic have on 5-HT3 receptors?
- Antagonistic
- Reduces vomiting
What action does an anti-emetic have on muscarinic receptors?
- Antagonistic
Describe the mechanism of action of phenothiazine derivatives and give an example
- Dopamine antagonists
- Chlorpromazine
Where can dopamine antagonists exert their action?
- CRTZ
Where can H1 receptor antagonists exert their action?
- Vestibular nuclei
- Nucleus of solitary tract (tractus solitarus)
Where can 5-HT3 antagonists exert their action?
- Visceral afferents
- CRTZ
Where can muscarinic antagonists exert their action?
- Vestibular nuclei
- Nucleus of solitary tract (tractus solitarus)
- Vomiting centre
Describe the mechanism of action of metaclopramide
- Local anaesthetic derivative
- Short action (need to infuse IV)
- Central and peripheral effects
- Central anti-dopamine effects at CRTZ
- Increases gastric emptying and increases motility
- Contra-indicated if vomiting due to obstruction
Describe the effects of metaclopramide and domperidone
- Increase gastric emptying
- Increase motility
- (Contra-indicated if vomiting due to obstruction)
Describe the mechanism of action of cerenia (maropitant)
- NK-1 antagonist
- Competes with substance P
- Specifically designed for dogs, also used in cats
- Shuts down last step of vomiting initiation
Described how the motility of the stomach can be altered
- Prokinetics
- Serotenergic H-HT4 receptor agonist (cisapride)
- Antidiarrhoeal agents - narcotic analgesics (codeine), anticholinergics, act peripherally to reduce GI spasm, nausea, vomiting, diarrhoea, reduce gastric emptuing and may increase vomiting
When would antifoaming agents be used?
- treat frothy bloat in ruminants
- Cause bubble to break down
Describe the pharamcological management of diarrhoea
- Maintenance of fluid balance
- Maintenance of electrolytes and acid base status
- Use of anti-infectives
- Altered (reduce) motility - reduce pain, increase transit time and reabsorption window
- Oral fluids (containing citrate)
- adsorbets (not proven)
Why is citrate added to oral fluids in the treatment of diarrhoea?
- Preservative
- Buffer
- Generates production of bicarbonate
What are the 2 types of intestine motility?
- Digestive and non-propulsive
Describe digestive motility
- Propulsive
- Peristalsis
- Short segments only
- Longitudinal muscle relaxes behind chyme, circular muscle contracts behind chyme
- Longitudinal muscle contracts infront of chyme, circular relaxes in front of chyme
Describe non-propulsive motilty
- Segmentation
- Circular muscle constricts lumen
- Used for mixing and distributing chyme for absorption
Describe the pharmacological management of constipation
- Liquid paraffin
- Laxatives
- Osmotics
Explain how liquid paraffin aids the treatment of constipation
- Lubriates and eases passing of faeces
Explain how laxatives aid the treatment of constipation
- Bulk e.g. methylcellulose or agar bran
- Polysaccharide polymers not easily didgested
- Form hydrated bulk in gut
- Holds water
- Promotes peristalsis (stretch)
- aids gut motility
Explain how osmotics aid the treatment of constipation
- Poorly absorbed solutes
- Lactulose (semi-synthetic dissacharide of fructose and galactose)
- Broken down in lower gut, alters oH to more acid, traps ammonia and therefore more water
- Aids movement
What are the classes of compounds used in the treatment of diarrhoea that do not act by direct effect on intestinal motility or secretion?
- Opiates
- Muscarinic antagonists
- Both are antimotility drugs
Describe the mechanisms of action of opiates in the treatment of diarrhoea
- Codeine or loperamide
- IMorphine increases contractions but decreases propulsion
- Increased large intestinal tone, overall leads to constipation
- More chomping, less secretion
- loperamide does not cross BBB but when combined with cerapamil can cross BBB and cause psychotropic effects
Describe the mechanism of action of muscarinic antagonists in the reatment of diarrhoea
- Neuronal control via parasympathetic from vagus (cholinergic and excitatory)
- Stimulates GIT motility
- Atropine not used - affects too many other systems
- Hyoscine (buscopan) used more frequently
- Can be used to treat colic
- Does not cross BBB, effects are outside CNS
What are the pathophysiogical mechanisms that can result in diarrhoea?
- Secretory
- Osmotic
- Motlity-related
- Inflammatory
Explain how secretory diarrhoea can occur
- Increase in active secretion OR
- Inhibition of absorption
- Little to no structural damage
Explain how osmotic diarrhoea can occur
Too much water drawn into bowels
Explain how motility related diarrhoea can occur
- Rapid movement of food thorugh intestines
- Hypermotility
Explain how inflammatory related diarrhoea can occur
- Damage to mucosal lining or brush border
- Loss of protein-rich fluids and decreased ability to absorb lost fluids
How do hydrophilic and hydrophobic drugs interacct with the body?
- Hydrophilic do not interact, are excreted
immediately - Have to be hydrophobic to interact
Why do drugs need to be hydrophobic to interact with the body?
Need to be hydrophic to cross cell membrane to interact with cells
How are drugs excreted?
- Hydrophilic excreted without modification
- Excretion via kidneys, hepatobiloary system, lungs
- Secondary routes via milk and sweat
- Not a ficed process, in renal failure get faecal excretion
Compare excretion of hydrophilic drugs and lipophilic drugs
- Hydrophilic excreted without modification
- Lipophilic metabolised into hydrophilic compounds using CYP450 enzymes
Explain the fundamental role of CYP450 enzymes and how they function
- Break down lipophilic drugs into parts that will be excreted and parts that will go into systemic circulation
- Used in phase I of metabolism
- Adds oxygen on to drug
- Oxygen charged, for most molecules will be enough to make it hydrophilic and then excreted
Describe the metabolism of drugs in the liver
- 2 phase reaction
- Phase I (catabolism) may be sufficient to iinactivate then excrete
- Phase II is synthetic conjugation
Describe phase I of drug metabolism in the liver
- Drug oxidised/reduced/hydrolysed
- Add oxygen on to drug via CYP450
- Oxygen charged, makes molecule hydrophilic
- Can now be excreted
- If not water soluble enough then processed by phase II
Describe phase II of drug metabolism in the liver
- If phase I not enough, transferases add on chemical groups
- Increases water solubility
- Once water soluble then can excrete drug in urine
Where is CYP450 found within the cell and why?
- Endoplasmic reticulum
- Large membrane surface area, more likely for lipophilic drugs to end up on endoplasmic reticulum
- Adjacent to/forms continuum with nucleus
What is meant by “first pass/presystemic” with regard to drugs?
- First pass metabolism is when a drug reaches the liver, liver acts on drug and metabolises it, excrete it in part before going on to systemic circulation
- Reduces concentration of drug that will reach systemic circulation
- From Gi initial concentration) to portal sstem to liver then broken down adn some excreted
- Rest into blood
What is the importance of the enterohepatic circulation in drug metabolism?
- Blood from GI goes to liver via portal system
- Contains drugs
- Metabolised in liver, reducing concentration in systemic circulation
- Protects body from drugs/xenobiotics
- Drugs can return to GI in the bile
Explain how variable drug responses are possible
- Genetic variability, polymorphism
- Intra-species differences in CYP enzyme activity
- One patient may respond differently to another
- Variable drug responses lead to drug toxicity
- Extensive, poor and ultrarapid metabolisers
Describe the drug activity where genes encode for an extensive metaboliser
Some drug activity
Describe the drug activity where genes encode for a poor metaboliser
Increased drug activity
Describe the drug activity where genes encode for an ultrarapid metaboliser
Drug activity decreased
Describe how interaction between drugs is related to CYP enzyme function
- Allosteric control of CYP
- Products of metabolism of one drug affects the action CYP450 has on another drug
- May be inhibition of CYP, so increased drug activity of drug 1 (where drug 2 metabolites inhibit CYP450)
- May be stimulation of CYP so decreased drug activity of drug 1
